Pyrimidine hydrazide compounds as pgds inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

 

The technical FIELD

The present invention is devoted pyrimidinediamine compounds, their receipt, containing these compounds, pharmaceutical compositions and their pharmaceutical use in the treatment of pathological conditions that can be regulated by inhibition of prostaglandin D-synthase.

The LEVEL of TECHNOLOGY

Allergic rhinitis, the most common atopic disease, affects approximately 5 to 22 percent of the total population, and its characteristic symptoms are sneezing, nasal selection and stuffy nose. It is assumed that these symptoms are caused by multiple mediators secreted by mastocytoma and other inflammatory cells. Existing methods of treatment, such as antihistamines, effectively eliminate sneezing and nasal discharge but have little impact on congestion, which is a key symptom, affecting the quality of life of patients.

It is shown that local stimulation of allergen in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis leads to a rapid rise in the level of prostaglandin D2(PGD2)in nasal and bronchial wash fluid, tears, and fluid from the skin pores. PGD2 can have a variety of inflammatory action, for example to increase pranic the resistant vessels in the conjunctiva and skin, to increase the resistance of the Airways of the nose, narrowing the respiratory tract and the infiltration of eosinophils into the conjunctiva and trachea. PGD2 is the main ziklooksigenazny product of arachidonic acid produced by mastocytoma immunological stimulation [Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II, Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol 129, 1627-1631, 1982]. Activated mastocyte, one of the main sources of PGD2, play a key role in allergic reactions such diseases as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling CE, Bradding P, Pavord ID, Wardlaw AJ, New Insights into the role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556, 2003].

In the presence of sulfhydryl compounds PGD2 is formed by the isomerization of PGH2, the common precursor of prostanoids, when the catalytic effect of prostaglandin D synthase "(PGDS)". There are two isoforms of the enzyme PGDS: L-PGDS and H-PGDS. H-PGDS is a cytosolic enzyme, which is distributed in peripheral tissues and in which localized antigen-presenting cells, mastocyte, megakaryocytes and Th2 lymphocytes. The product PGD2 mediated by receptors associated with G-protein: prostaglandin D "(DP)" and crTH2. Cm. (1) Prostaglandin D Synthase: Structure and Function. T. Urade and O. Hayaishi, Vitamin and Hormones, 2000, 58, 89-120, (2) J.J. Murray, N. Engl. J. Med., 1986 Sept 25; 315(13):800, and (3) Urade et. al., J. Immunology 168: 443-449, 2002.

The inventors believe that the inhibition of the formation of PGD2 should have an effect on nasal congestion, and therefore to show a therapeutic effect in allergic rhinitis. In addition, the inventors believe that the PGDS inhibitor should have a therapeutic effect for some other indications, for example bronchial asthma.

There is evidence of PGDS inhibitors. You know that the connection HQL-79 is a weak inhibitor of PGDS and shows anti-asthma action research on Guinea pigs and rats (Matsusshita, et al., Jpn. J. Pharamcol. 78: 11, 1998). Connection Tranilast exhibiting the properties of PGDS inhibitor. (Inhibitory Effect of Tranilast on Prostaglandin D Synthesase. K. Ikai, M. Jihara, K. Fujii, and Y. Urade. Biochemical Pharmacology, 1989, 28, 2773-2676).

BRIEF description of the INVENTION

The present invention is devoted to the compound of formula (I)

where

R1is a (C1-C6)-alkyl, which is optionally independently substituted by one or more of the following substituents: halogen, hydroxy, (C1-C6)-alkoxy or (C1-C4)-halogenoalkane, or

(C3-C6-cycloalkyl, aryl or heteroaryl, each of which optionally has one or more of the following independent substituents: halogen, (C1-C6)-alkyl, hydroxy, C 1-C6)-alkoxy, (C1-C4-halogenated or (C1-C4)-halogenoalkane;

R2represents hydrogen or (C1-C4)-alkyl, which is optionally substituted by one or more Halogens;

R3represents hydrogen, alkyl, aryl or heteroaryl;

R4represents hydrogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylsulfonyl, heteroarylboronic, -C(=O)-NY1Y2, -C(=S)-NY1Y2, R5, -C(=O)-R5or-C(=S)-R5where aryl, heteroaryl or heterocyclyl group optionally has one or more independent substituents R6or

R3and R4together with the nitrogen atom to which they are bound, form heterocyclyl, heterocyclyl, heteroaryl, arylheteroacetic, arylheteroacetic, heteroalicyclic, heteroalicyclic, heterocyclisation or heterocyclisation, each of which optionally has one or more independent substituents R6;

R5is cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclyl or polycyclic alkaryl, each of which optionally has one or more independent substituents R6;

L1represents a bond, -O-, -C(=O)-, -NH-C(=O) -, or (C1-C2)-Alki the Yong, which is optionally substituted by one or more Halogens;

R6represents a cyano, nitro, halogen, hydroxy, carboxy, Y1Y2N, Y1Y2N-C(=O)-, Y1Y2N-SO2-,

acyl, acyloxy, alkyl, alkenyl, quinil, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfonyl or alkylsulfonyl, each of which may be independently one or more of the following independent deputies:

acyloxy, halogen, alkoxy, halogenoalkane, hydroxy, carboxy, alkoxycarbonyl,

Y1Y2N, Y1Y2N-C(=O)-, Y1Y2N-SO2-,

aryl, aryloxy, aroyl, heteroaryl, heteroaromatic, heteroaryl, heterocyclyl, heterocyclyl, cycloalkyl, cycloalkenyl or polycyclic alkaryl, each of which optionally has one or more of the following independent substituents: alkyl, halogen, halogenated, alkoxy, halogenoalkane, hydroxy, amino, alkylamino, dialkylamino, carboxy or alkoxycarbonyl, or

aryl, heteroaryl, aroyl, heteroaryl, aryloxy, heteroaromatic, heterocyclic, heterocyclyl, cycloalkyl, cycloalkenyl or polycyclic alkaryl, each of which optionally has one or more of the following independent substituents: alkyl, halogenated, halogen, alkoxy, halogenoalkane, hydroxy, carboxy, alkoxycarbonyl, Y1Y N or Y1Y2N-SO2-,

where heterocyclyl, heterocyclyl, cycloalkyl, cycloalkenyl or polycyclic alarilla group R6optionally independently substituted by one or more oxo;

Y1and Y2each independently is:

hydrogen, alkylsulfonyl, Arola, heteroaryl, or

the alkyl, which optionally has one or more of the following independent substituents: hydroxy, carboxy, halogen, amino, alkylamino, dialkylamino, alkoxy, heterocyclyl, aryl or heteroaryl, or

Y1and Y2together with the nitrogen atom to which they are bound, form heterocyclyl;

or its hydrate, MES or N-oxide, or its pharmaceutically acceptable salt.

Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of formula (I) or its hydrate, MES or N-oxide or pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable carrier.

Another aspect of the present invention is directed to a method of treating allergic and/or inflammatory disorders, in particular disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD) in a patient in need of such treatment, introduced by the I to a patient compounds of formula (I) or its hydrate, the MES or N-oxide or its pharmaceutically acceptable salt.

DETAILED description of the INVENTION

Definition of terms

Used above and throughout the description of the invention, the following terms, unless otherwise indicated, have adopted the following values:

"Acyl" means an H-CO - or (aliphatic or cyclic)-CO-. Specific atilov are lower alkanoyl that contains the lowest alkali. Examples atilov are formyl, acetyl, propanol, 2-methylpropanol, butanol, Palmitoyl, acryloyl, propanol and cyclohexylcarbonyl.

"Acyloxy" means acyl-O-.

"Alkenyl" means a linear or branched aliphatic hydrocarbon group with a double carbon-carbon bond, having from 2 to about 15 carbon atoms. Specific alkenyl includes from 2 to about 12 carbon atoms. More specific alkenyl includes from 2 to about 4 carbon atoms. Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. "Lower alkenyl" means about 2 to 4 carbon atoms in the chain, which may be linear or branched. Examples of alkenyl are ethynyl, propenyl, n-butenyl, Isobutanol, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylmethanol and decenyl.

"Alkoxy" oznacza the t alkyl-O-. Examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptox.

"Alkoxycarbonyl" means alkyl-O-CO-. Examples of alkoxycarbonyl are methoxycarbonyl, etoxycarbonyl and tert-butyloxycarbonyl.

"Alkyl" means a linear or branched aliphatic hydrocarbon group having from 1 to about 20 carbon atoms. Specific alkyl contains from 1 to about 12 carbon atoms. In a more specific example, the alkyl is lower alkyl. Branched means that linear alkyl chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. "Lower alkyl" means from 1 to about 4 carbon atoms in the linear alkylenes chain which may be straight or branched.

"Alkylamino" means alkyl-NH-. Specific alkylaminocarbonyl is (C1-C6)-alkylamino. Examples of alkylamino are methylaminopropyl and atramentaria.

"Alkylsulfonyl" means alkyl-SO-. In a specific example, alkylsulfonyl is (C1-C6-alkylsulfonyl. Examples of alkylsulfonyl are CH3SO - and CH3CH2-SO-.

"Alkylsulfonyl" means an alkyl-SO2-. In a specific example, alkylsulfonyl is (C1-C6)-alkylsulfonyl. Examples alkylsulfonyl are CH3-SO 2and CH3CH2-SO2-.

"Alkylthio" means alkyl-S-. An example of alkylthio is CH3S.

"Quinil" means a linear or branched aliphatic hydrocarbon with a triple carbon-carbon bond, having from 2 to about 15 carbon atoms. In the specific example quinil includes from 2 to about 12 carbon atoms. In a more specific example quinil includes from 2 to about 6 carbon atoms. Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. "Lower quinil" means from 2 to about 4 carbon atoms in a straight alkenylphenol chain that may be linear or branched. Examples of alkinyl are ethinyl, PROPYNYL, n-butynyl, 2-butynyl, 3-methylbutyl, n-pentenyl, heptenyl, octenyl and decenyl.

"Aroyl" means an aryl-CO-. Examples of Arola are benzoyl and 1 - and 2-naphtol.

"Aryl" means an aromatic monocyclic or polycyclic ring system having from 6 to about 14 carbon atoms. In a specific example, the aryl has from about 6 to about 10 carbon atoms. Examples of arilou are phenyl and naphthyl.

"Arylchloroalkanes" means a condensed aryl and cycloalkenyl. In a specific example, arylcycloalkylamine is one in which the aryl is Anil, and cycloalkenyl ring has from about 5 to 7 atoms. Arylchloroalkanes connected through any of the atoms cycloalkenyl group, allowing such communication. Examples of arylcyclohexylamines are 1,2-dihydronaphthalene and inden.

"Aristically" means a condensed aryl and cycloalkyl. In a specific example, arylcyclohexylamine is one in which the aryl is phenyl, and cycloalkyl ring has about 5 to 6 atoms. Aristically connected through any of the atoms cycloalkyl group, allowing such communication. Examples of arylcycloalkylamine are 1,2,3,4-tetrahydronaphthalen.

"Arylheteroacetic" means a condensed aryl and heterocyclyl. In a specific example, arylheteroacetic is one in which the aryl is phenyl, and heterocyclyl ring has from about 5 to about 6 atoms. Arylheteroacetic connected through any of the atoms heterocyclyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part arylheteroacetic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom arylheteroacetic may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part arylheteroacetic also which may be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of arylheteroacetic are 3H-indolinyl, 1H-2-oxoindole, 2H-l-occaisonaly, 1,2-dihydroquinoline, 3,4-dihydroquinoline, 1,2-dihydroisoquinolines and 3,4-dihydroisoquinolines.

"Arylheteroacetic" means a condensed aryl and heterocyclyl. In a specific example, heterocyclisation is one in which the aryl is phenyl, and heterocyclyl ring has about 5 to 6 atoms. Arylheteroacetic connected through any of the atoms heterocyclyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part allheterocou mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom allheterocou may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part allheterocou can also be oxidized optional to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples allheterocou are indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroindol-2-yl, 2,3-dihydrobenzo[f]isoindole-2-yl and 1,2,3,4-tetrahydrobenzo[g]-isoquinoline-2-yl.

"Aryloxy" means aryl-O-. Examples of aryloxy are phenoxy, naphthoxy.

"Connections according to the present invention and the Academy of Sciences of the logical expression is intended to include previously described herein the compounds of formula (I), their hydrate, solvate and N-oxides, and their pharmaceutically acceptable salts, where permitted by the context. Similarly, reference to an intermediate connection, regardless of whether they are in the claims is intended to cover their salts, N-oxides and the solvate in cases where it is allowed by the context.

"Cycloalkenyl" means a non-aromatic mono - or polycyclic ring system having from about 3 to 10 carbon atoms, in particular from about 5 to 10 carbon atoms, which has at least one double carbon-carbon bond. In the specific case of ring ring systems contain from about 5 to 6 atoms in the ring; in this particular case, the ring is also referred to as "lower". Examples of monocyclic cycloalkenyl are cyclopentenyl, cyclohexenyl and cycloheptenyl. An example of a polycyclic cycloalkenyl is norbornylene.

"Cycloalkenyl" means a condensed aryl and cycloalkenyl. In a specific example, cycloalkylation is one in which the aryl is phenyl, and cycloalkenyl ring consists of about 5 to 6 atoms. Cycloalkenyl connected through any of the atoms of the aryl group, allowing such communication. Examples of cycloalkylation are 1,2-dihydronaphthalene and inden.

"Cycloalkylcarbonyl" means a condensed g is tetraaryl and cycloalkenyl. In a specific example, cycloalkylcarbonyl is one in which heteroaryl ring is about 5 to 6 atoms, and cycloalkenyl ring has about 5 to 6 atoms. Cycloalkylcarbonyl connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of cycloalkylcarbonyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of cycloalkylcarbonyl may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of cycloalkylcarbonyl may also be optionally oxidized to the corresponding N-oxide. Examples of cycloalkylcarbonyl are 5,6-dihydrohelenalin, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxaline, 5,6-dihydroquinazolin, 4,5-dihydro-1H-benzimidazolyl and 4.5-dihydroisoxazole.

"Cycloalkyl" means a non-aromatic mono - or polycyclic saturated ring system having from about 3 to 10 carbon atoms, in particular from about 5 to 10 carbon atoms. In the specific example of the ring ring systems contain from about 5 to 7 atoms in the ring; in this particular example rings are also referred to as "lower". Examples of monocyclic cycloalkyl are cyclopentyl, cyclohe the forces and cycloheptyl. Examples of polycyclic cycloalkyl are 1-decalin, norbornyl and adamant-(1 - or

2-)Il.

"Cycloalkenyl" means a condensed aryl and cycloalkyl. In a specific example, cycloalkylation is one in which the aryl is phenyl, and cycloalkyl ring has about 5 to 6 atoms. Cycloalkenyl connected through any of the atoms cycloalkyl group, allowing such communication. An example of cycloalkenyl is 1,2,3,4-tetrahydronaphthalen.

"Cycloalkylcarbonyl" means a condensed heteroaryl and cycloalkyl. In a specific example, cycloalkylcarbonyl is one in which heteroaryl ring is about 5 to 6 atoms, and cycloalkyl ring has about 5 to 6 atoms. Cycloalkylcarbonyl connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of the condensed cycloalkylcarbonyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of cycloalkylcarbonyl may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of cycloalkylcarbonyl may also be optionally oxidized to the corresponding N-oxide. Examples of cycloalkylcarbonyl are 5,6,78-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 5,6,7,8-tetrahydroquinazolin, 4,5,6,7-tetrahydro-1H-benzimidazolyl and 4,5,6,7-tetrahydrooxazolo.

"Cilil" means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclyl.

"Dialkylamino" means (alkyl)2-N. In a specific example, dialkylamino is (C1-C6alkyl)2-N. Examples of dialkylamino are dimethylamino, diethylamino and methylaminopropyl.

"Halo" or "halogen" means fluorine, chlorine, bromine or iodine. In the specific example halo or halogen is fluorine or chlorine.

"Halogenoalkane" means the CNS group having from one to three halogen as substituents. Preferred are lower CNS group having from one to three halogen as substituents. Most preferred are lower CNS group, substituted with one halogen.

"Halogenated" means an alkyl group having from one to three halogen as substituents. Preferred are lower alkyl groups having from one to three halogen as substituents. Most preferred are lower alkyl groups substituted with one halogen.

"Heteroaryl" means heteroaryl-CO-. Examples of heteroaryl are thiophenol, nick is tinfoil, pyrrol-2-ylcarbonyl and pyridinoyl.

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system having from about 5 to 14 carbon atoms, in which one or more carbon atoms of the ring system are heteroatoms other than carbon, for example nitrogen, oxygen or sulfur. Specific aromatic ring system have approximately 5 to 10 carbon atoms and from 1 to 3 heteroatoms. More specific ring systems include about 5 to 6 atoms. Indicate "Aza", "oxa" or "thio" as a prefix in the name of heteroaryl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heteroaryl can be basic nitrogen atom and may be optionally oxidized to the corresponding N-oxide. If heteroaryl substituted hydroxyl group, it also includes the appropriate tautomer. Examples of heteroaryl are pyrazinyl, thienyl, isothiazolin, oxazolyl, pyrazolyl, furanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, honokalani, phthalazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofuranyl, isoindolyl, benzimidazolyl, benzothiazyl, cyanopyridyl, thienopyrimidine, pyrrolopyridine, imidazopyridine, benzoxazinones, 1,2,4-triazinyl, benzothiazolyl, the imidazole is l, indolyl, indolizinyl, isoxazolyl, ethenolysis, isothiazolin, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, hintline, chinoline, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl.

"Heteroaromatic" means heteroallyl-. In a more specific case, heteroallyl contains (C1-C4)-alkyl group. An example of heteroallyl includes tetrazol-5-ylmethyl.

"Heteroalicyclic" means a condensed heteroaryl and cycloalkenyl. In a specific example, heteroalicyclic is one in which heteroaryl ring is about 5 to 6 atoms, and cycloalkenyl ring has about 5 to 6 atoms. Heteroarylboronic connected through any of the atoms cycloalkenyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part heteroarylboronic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heteroarylboronic may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion heteroarylboronic can also be oxidized optional to the corresponding N-oxide. Examples of heteroarylboronic are 5,6-dihydrohelenalin, 5,6-dihydroisoquinolyl, 5,6-d is hydrogenation, 5,6-dihydroquinazolin, 4,5-dihydro-1H-benzimidazolyl and 4.5-dihydroisoxazole.

"Heteroalicyclic" means a condensed heteroaryl and cycloalkyl. In a specific example, heteroalicyclic is one in which heteroaryl ring is about 5 to 6 atoms, and cycloalkyl ring has about 5 to 6 atoms. Heteroalicyclic connected through any of the atoms cycloalkyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of heteroalicyclic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heteroalicyclic may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of heteroalicyclic may also be optionally oxidized to the corresponding N-oxide. Examples of heteroalicyclic are 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 5,6,7,8-tetrahydroquinazolin, 4,5,6,7-tetrahydro-1H-benzimidazolyl and 4,5,6,7-tetrahydrooxazolo.

"Heteroalicyclic" means a condensed heteroaryl and heterocyclyl. In a specific example, heterooligomerization is one in which heteroaryl ring is about 5 to 6 atoms, heterocyclyl ring has about 5 to 6 atoms. Heterooligomerization connected through any of the atoms heterocyclyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part heterooligomerization mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterokedasticity may be the basic nitrogen atom. The nitrogen atom or sulfur or heteroaryl heterocyclyl part heterooligomerization may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterooligomerization are 7,8-dihydro[1,7]naphthyridine, 1,2-dihydro[2,7]-naphthyridines, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridine, 1,2-dihydro-1,6-naphthyridine, 1,2-dihydro-1,7-naphthyridine, 1,2-dihydro-1,8-naphthyridine and 1,2-dihydro-2,6-naphthyridine.

"Heteroalicyclic" means a condensed heteroaryl and heterocyclyl. In a specific example, heterooligomerization is one in which heteroaryl ring is about 5 to 6 atoms, and heterocyclyl ring has about 5 to 6 atoms. Heteroalicyclic connected through any of the atoms heterocyclyl group, allowing such communication. Indicate "Aza", "oxa" and and "thio" as a prefix in the name heteroaryl or heterocyclyl part of the condensed heteroalicyclic mean, that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom condensed heteroalicyclic may be the basic nitrogen atom. The nitrogen atom or sulfur or heteroaryl heterocyclyl part heteroalicyclic may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples heterooligomerization are 2,3-dihydro-1H-pyrrole[3,4-b]quinoline-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,7]naphthiridine-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthiridine-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indole-2-yl, 1H-2,3,4,5-tetrahydrothieno[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepine[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepine[4,5-b]indol-2-yl, 5,6,7,8-tetrahydro[1,7]naphthyridin, 1,2,3,4-tetrahydro[2,7]naphthyridin, 2,3-dihydro[1,4]like[2,3-b]pyridyl, 2,3-dihydro-[1,4]like[2,3-b]pyridyl, 3,4-dihydro-2H-l-oxa[4,6]diazonaphthalene, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazonaphthalene, 1,2,3,4-tetrahydro[1,5]-naphthyridine, 1,2,3,4-tetrahydro[1,6]naphthyridine, 1,2,3,4-tetrahydro[1,7]naphthyridine, 1,2,3,4-tetrahydro[1,8]naphthyridine and 1,2,3,4-tetrahydro[2,6]naphthyridine.

"Heteroaromatic" means heteroaryl-O-. An example of heteroaromatic includes pyridyloxy.

"Heterocyclyl" means nonaromatic m is neziklicescoy or polycyclic hydrocarbon ring system, having from about 3 to 10 carbon atoms, in which one or more carbon atoms of the ring system are heteroatoms other than carbon, for example nitrogen, oxygen or sulfur, and which contains at least one double carbon-carbon bond or a double carbon-nitrogen bond. Specific non-aromatic ring system have approximately 5 to 10 carbon atoms and from 1 to 3 heteroatoms. More specific ring systems include about 5 to 6 atoms, and the ring system in this specific case is also referred to as "lower". Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterocyclyl may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic azaheterocycles are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridin, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl and 2-pyrazolines. Examples exegetically are 3,4-dihydro-2H-Piran, dihydrofuran and fordevelopment. Exampl the polycyclic exegetically is 7-oxabicyclo[2.2.1]heptenyl. Examples of monocyclic togetheronline are dihydrothiophene and dihydrothiophene.

"Heterocultural" means a condensed aryl and heterocyclyl. In a specific example, heterocyclization is one in which aryl is phenyl, and heterocyclyl ring has about 5 to 6 atoms. Heterocultural connected through any of the atoms of aryl, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part of the condensed heterocultural mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heterocultural may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part of heterocultural may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterocyclization are 3H-indolinyl, 1H-2-oxoindole, 2H-l-occaisonaly, 1,2-dihydroquinoline, 3,4-dihydroquinoline, 1,2-dihydroisoquinolines and 3,4-dihydroisoquinolines.

"Heterocyclisation" means a condensed heteroaryl and heterocyclyl. In a specific example, heterocyclisation is one in which heteroaryl ring is about 5 to 6 atoms, and heterocyclyl the second ring has about 5 to 6 atoms. Heterocyclisation connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part of geterotsiklicheskikh mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of azaheterocyclic may be the basic nitrogen atom. The nitrogen atom or sulfur or heteroaryl heterocyclyl part of geterotsiklicheskikh may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of geterotsiklicheskikh are 7,8-dihydro[1,7]naphthyridine, 1,2-dihydro[2,7]naphthyridines, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridine, 1,2-dihydro-1,6-naphthyridine, 1,2-dihydro-1,7-naphthyridine, 1,2-dihydro-1,8-naphthyridine and 1,2-dihydro-2,6-naphthyridine.

"Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system having from about 3 to 10 carbon atoms, in which one or more carbon atoms of the ring system are heteroatoms other than carbon, for example nitrogen, oxygen or sulfur. Specific ring system have approximately 5 to 10 carbon atoms and from 1 to 3 heteroatoms. The particular ring is the ring system include about 5 to 6 atoms, moreover, the ring system in this specific case is also referred to as "lower". Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterocyclyl may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic heterocyclyl are piperidyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,3-DIOXOLANYL, 1,4-dioxane, Tgfr, tetrahydrothiophene and tetrahydrothiopyran.

"Heterocyclisation" means a condensed aryl and heterocyclyl. In a specific example, heterocyclisation is one in which the aryl is phenyl, and heterocyclyl ring has about 5 to 6 atoms. Heterocyclisation connected through any of the atoms of the aryl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part of heterocyclisation mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heterocyclisation may be the basic nitrogen atom. ATO is nitrogen or sulfur heterocyclyl part of heterocyclisation can also be oxidized optional to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterocyclisation are indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroindol-2-yl, 2,3-dihydrobenzo[f]isoindole-2-yl and 1,2,3,4-tetrahydrobenzo[g]isoquinoline-2-yl.

"Heterocyclisation" means a condensed heteroaryl and heterocyclyl. In a specific example, heterocyclisation is one in which heteroaryl ring is about 5 to 6 atoms, and heterocyclyl ring has about 5 to 6 atoms. Heterocyclisation connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part of geterotsiklicheskikh mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of geterotsiklicheskikh may be the basic nitrogen atom. The nitrogen atom or sulfur or heteroaryl heterocyclyl part of geterotsiklicheskikh may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of geterotsiklicheskikh are 2,3-dihydro-1H-pyrrole[3,4-b]quinoline-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,7]naphthiridine-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthiridine-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro the-9H-pyrido[4,3-b]indol-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydrothieno[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepine[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepine[4,5-b]indol-2-yl, 5,6,7,8-tetrahydro[1,7]naphthyridin, 1,2,3,4-tetrahydro[2,7]naphthyridin, 2,3-dihydro[1,4]like[2,3-b]pyridyl, 2,3-dihydro-[1,4]like[2,3-b]pyridyl, 3,4-dihydro-2H-l-oxa[4,6]diazonaphthalene, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazonaphthalene, 1,2,3,4-tetrahydro[1,5]-naphthyridine, 1,2,3,4-tetrahydro[1,6]naphthyridine, 1,2,3,4-tetrahydro[1,7]naphthyridine, 1,2,3,4-tetrahydro[1,8]naphthyridine and 1,2,3,4-tetrahydro[2,6]naphthyridine.

"Polycyclic alkaryl" means polycyclic ring system having at least one aromatic ring condensed with at least one non-aromatic ring which may be saturated or unsaturated, and may contain in the ring one or more heteroatoms, such as nitrogen, oxygen or sulfur. Examples of polycyclic alkaryl are arylchloroalkanes, aristically, arylheteroacetic, arylheteroacetic, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heteroalicyclic, heteroalicyclic, heteroalicyclic, heteroalicyclic, heterocultural, heterocyclization, heterocyclisation and heterocyclisation. In exactly the example polycyclic alkalline groups are bicyclic system, consisting of one aromatic ring condensed with one non-aromatic ring, which may contain in the ring one or more heteroatoms, such as nitrogen, oxygen or sulphur.

"Patient" means humans and other mammals.

"Pharmaceutically acceptable salts" means non-toxic, inorganic and organic salts of the compounds according to the present invention formed by adding acid or base. These salts can be obtained in situ during the final phase of isolation and purification of compounds or in a separate reaction purified compound in free base form with a suitable organic or inorganic acid and allocation thus obtained salt. In some cases, connections can be sampradayas basic sites on the molecule and to form internal amphoteric salt.

Examples of salts formed by adding acid are hydrobromide, hydrochloride, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valerate, oleates, Almaty, stearates, laurate, borate, benzoate, lactates, phosphates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, naphthalate, mesylates, glucoheptonate, lactobionate, sulfamate, malonate, salicylates, propionate, methylene-bis-β-hydroxynaphthoate, gentisate, zeinati, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and laurylsulphate. See, for example, the work of S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977), which due to the references included in this document. Salts formed by adding the base, you can also get independent manner by the reaction of purified compound in its acid form with a suitable organic or inorganic base and the allocation thus obtained salt. The salts formed by the addition of bases include pharmaceutically acceptable metal salts and amines. Suitable metal salts include salts of sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Specific examples of salts formed by adding bases are sodium or potassium salt. Suitable inorganic salts formed during the addition of base, obtained from the grounds of the metals, which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide and zinc hydroxide. Suitable amine salts formed by addition of a base, derived from amines, basicity of which is sufficient for the formation of a stable salt, and, in particular, amines, commonly used in medicinal chemistry n is because of their low toxicity and suitability for use in medical purposes. Examples of amines are ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, diethylamine, piperazine, Tris(hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium, triethylamine, dibenzylamine, fenamin, dehydroabietylamine, N-ethylpiperidine, benzylamine, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and dicyclohexylamine.

"MES" means a compound according to the present invention, physically associated with one or more solvent molecules. To the physical linking applies, in particular, the formation of hydrogen bond. In certain cases, the MES can be identified, for example, when one or more solvent molecules included in the crystal lattice of a solid crystalline substance. The term "MES" applies to both the solution phase and insoluble solvate. Typical solvate is a hydrate, ethanolate and methanolate.

"To have one or more independent substituents" means substitution of one or more of the same or different substitute groups, in particular when replacing one, two or three times, equal or different substitute groups.

oncrete embodiment of the present invention

One private embodiment of the present invention is a compound of formula (I), where R1represents aryl or heteroaryl, each of which optionally has one or more of the following independent substituents: halogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkoxy, (C1-C4-halogenated or (C1-C4)-halogenoalkane, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R1represents phenyl or a five - or six-membered heteroaryl, each of which optionally has one or more of the following independent substituents: halogen, (C1-C6)-alkyl or hydroxy, (C1-C6)-alkoxy, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R1represents phenyl, pyridyl, pyrimidinyl, thiazolyl or oxadiazolyl, each of which optionally has one or more of the following independent substituents: halogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkoxy, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private in what proscenium of the present invention is a compound of formula (I), where R1represents phenyl, pyridyl or pyrimidinyl, each of which optionally has one or more of the following independent substituents in ortho - or meta-position: halogen, (C1-C6)-alkyl, hydroxy or (C1-C6)-alkoxy, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R1represents phenyl, which optionally has an independent substituent in the ortho - or meta-position halogen, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R1represents pyridyl, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R2represents hydrogen, methyl or trifluoromethyl, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where R2represents hydrogen, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another frequent the first embodiment of the present invention is a compound of formula (I), where R2represents methyl, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where L1represents a bond, -O-, -C(=O)-, -NH-C(=O)-, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where L1represents a bond, or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where

R3and R4together with the nitrogen atom to which they are bound, form heterocyclyl, heterocyclyl, arylheteroacetic or heteroaryl, each of which optionally has one or more independent substituents R6;

R6represents alkoxy, hydroxyl, cycloalkyl, carboxy, cycloalkyl, halogen, cyano, alkylsulfonyl, Y1Y2N, Y1Y2N-SO2-,

alkyl, which optionally has one or more of the following independent deputies: acyloxy, hydroxy, alkoxycarbonyl, alkoxy, carboxy, aryl, halogen, alkylsulfonyl, cyano, Y1Y2N or Y1Y2N-C(=O)-,

acyl or aryl, each of which is optional is entrusted independently substituted by one or more Halogens,

alkoxycarbonyl, optionally independently substituted by one or more Allami,

heteroaryl, optionally independently substituted by one or more alkilani,

heterocyclyl, optionally independently substituted by one or more oxo, or

aryloxy, optionally independently substituted by one or more halogenation; and

Y1and Y2, each independently, is hydrogen, alkylsulfonyl, Arola or alkyl, optionally substituted by morpholinyl, or

Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where

R3and R4together with the nitrogen atom to which they are bound, form [1,2,4]triazolyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl or pyrrolo[2,3-c]pyridyl, each of which optionally has one or more independent substituents R6;

R6represents alkoxy, carboxy, cycloalkyl, halo, cyano, alkylsulfonyl, Y1Y2N-SO2-,

alkyl, which optionally has one or more of the following independent deputies: Y1Y2N-C(=O)-, hydroxy, alkoxycarbonyl, alkoxy, is arbucci, aryl, halogen, heterocyclyl, cycloalkyl, alkylsulfonyl, cyano, heterocalixarenes,

acyl or aryl, each of which is optionally independently substituted by one or more Halogens,

alkoxycarbonyl, optionally independently substituted by one or more Allami,

heteroaryl, optionally independently substituted by one or more alkilani,

heterocyclyl, optionally independently substituted by one or more oxo, or

aryloxy, optionally independently substituted by one or more halogenation; and

Y1and Y2, each independently, is hydrogen or alkyl, optionally substituted by morpholinyl, or

Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where

R3and R4together with the nitrogen atom to which they are bound, form imidazolidinyl, [1,2,4]triazinyl, piperazinil, morpholinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyrimidines, piperidinyl, oxazolidinyl, 2,3-dihydroindole, octahydrocyclopenta[c]pyrrolyl or 3,4-dihydrobenzo[1,4]oxazin, each of which optionally has one more independent substituents R6;

R6represents oxo, alkoxy, carboxy, cycloalkyl, halogen, cyano, alkylsulfonyl, Y1Y2N-SO2-,

alkyl, which optionally has one or more of the following independent substituents: hydroxy, alkoxycarbonyl, alkoxy, carboxy, aryl, halogen, heterocyclyl, cycloalkyl, alkylsulfonyl, cyano, heterocalixarenes,

acyl or aryl, each of which is optionally independently substituted by one or more Halogens,

alkoxycarbonyl, optionally independently substituted by one or more Allami,

heteroaryl, optionally independently substituted by one or more alkilani,

heterocyclyl, optionally independently substituted by one or more oxo, or

aryloxy, optionally independently substituted by one or more halogenation; and

Y1and Y2, each independently, is hydrogen or alkyl, optionally substituted by morpholinyl, or

Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where

R3and R4together with the nitrogen atom to which they are bound, form an indolyl, who long is Ino has one or more independent substituents R 6;

R6represents the Y1Y2N-SO2-alkoxycarbonyl, carboxylic, cyano, alkylsulfonyl, alkoxy or acyl, each of which is optionally independently substituted by one or more halogen; and

Y1and Y2, each independently, is hydrogen or alkyl, optionally substituted by morpholinyl, or

Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), where

R5represents phenyl, pyridyl or benzo[1,3]dioxole, each of which optionally has one or more independent substituents R6;

R6represents the Y1Y2N-SO2, hydroxy, alkoxy, halogen, alkyl or halogenated; and

Y1and Y2, each independently, is hydrogen or alkyl,

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I), a

(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,

(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic to the slots,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,

(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-TRIFLUOROACETYL)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,

(2,3-dimethylindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-chloro-2-methylindol-1-yl)amide 2-(3-forfinal)--methylpyrimidin-5-carboxylic acid,

(5-bromoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

benzyl ester of 3-oxo-4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acid,

(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-sulfamoyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(4-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(4-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(4-Florinda-1-yl)who MFA 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid,

(4-Florinda-1-yl)amide 2-(pyridin-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-cyano-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[1,2,4]triazole-4-alamid 2-phenylpyrimidine-5-carboxylic acid,

piperidine-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

N'-(2-forfinal)hydrazide 2-phenylpyrimidine-5-carboxylic acid,

N'-ethyl-N'-tolylhydrazine 2-phenylpyrimidine-5-carboxylic acid,

(3-exmortis-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-benzoylpyridine-5-carboxylic acid,

[4-(2-hydro is setil)piperazine-1-yl]amide of 2-benzoylpyridine-5-carboxylic acid,

N'-methyl-N'-[5-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid,

N'-methyl-N'-[4-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid,

N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid,

N'-(2-chlorophenyl)hydrazide 2-phenylpyrimidine-5-carboxylic acid,

N'-(2-oxopiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

N'-cyclohexyl-N'-methylhydrazino 2-phenylpyrimidine-5-carboxylic acid,

N'-morpholine-4-alamid 2-phenoxypyridine-5-carboxylic acid,

(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

methyl ester of 3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid,

3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid,

(4-methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-phenylpyrimidine-5-carboxylic acid,

[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-karbonvansty,

[((s)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[((R)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazole-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

pyrrol-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(5-morpholine-4-ylmethyl-2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(4-cyclopentylpropionyl-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

(2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid,

ethyl ester [N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]acetic acid,

2-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]ndimethylacetamide,

4-[3-(4-morpholino)propyl]-1-(2-phenylpyrimidine-5-carbonyl)-3-thiosemicarbazide,

(2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

methyl ester {4-[2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}acetic acid,

(4-cinematelevision-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

2-{4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}-ethyl ester acetic acid,

(4-acetylpiperidine-1-yl)amide 2-phenylpyrimidine-5-Carbo the OIC acid,

[4-(2-oxitetraciclina-3-yl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(2-methoxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(2-morpholine-4-yl-2-oxoethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

piperazin-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

piperazin-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(hexahydrotriazine[c]pyrrol-2-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(2,3-dihydroindol-1-yl)amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid,

pyrrolidin-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(2,6-dimethylpiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(4-cyclopentylpropionyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(2-methyl-2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

N'-methyl-N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid,

(5-Florinda-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(2,3-dihydroindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

indol-1-alamid 2-pyridin-2-yl is eremein-5-carboxylic acid,

indol-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

indol-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

indol-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(6-methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(5-methanesulfonamido-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

(5-methanesulfonamido-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,

(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(5-Florinda-1-yl)amide 2-(3-forfinal-4-methyl)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic what islote,

pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-Florinda-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,

(5-Florinda-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,

(5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-methoxyindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(4-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[4-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid,

1-{[2-(3-CFT is henyl)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid,

(3-cyanomethyl-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-methoxyindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

[3-(1H-tetrazol-5-ylmethyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazinecarboxamide,

2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide,

(2,4-dioxoimidazolidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid,

N'-(2-phenylpyrimidine-5-carbonyl)hydrazide pyridine-2-carboxylic acid,

4-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]benzosulfimide,

N'-(2-phenylpyrimidine-5-carbonyl)hydrazide 3-hydroxybenzoic acid,

N'-(phenylpyrimidine-5-carbonyl)hydrazide benzo[1,3]dioxo-5-carboxylic acid,

N'-(phenylpyrimidine-5-carbonyl)hydrazide of 3,4-dimethoxybenzoic acid,

N'-methyl-N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid,

(5-methoxy-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid,

(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-hydroxyphenyl)pyrimidine-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-thiazol-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide [2,2']bipyridinyl-5-carboxylic acid,

(3-chloro-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

amide 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-3-carboxylic acid,

2-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionic acid,

2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionic acid,

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

[5-fluoro-3-(2-pyridin-3-retil)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3-formylindole--yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid,

(5-fluoro-3-hydroxymethylene-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(6-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(6-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(6-cryptomaterial-1-yl)amide of 4-m is Teal-2-thiazol-2-Yeremey-5-carboxylic acid,

(6-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-methoxy-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

N',N'-diphenylhydrazine 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(7-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-methanesulfonyl-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-acylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-acylpyrrole[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-acylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-acylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-methyl-5-triform tylendel-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-nitroindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-aminoindan-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-(dimethanesulfonate)aminoindan-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-benzoylamino-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-yl-4-cryptomaterial-5-carboxylic acid,

(2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-ileri the one-5-carboxylic acid,

(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-fererro[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-methoxyindol-1-yl)amide 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(3-deformational)pyrimidine-5-carboxylic acid, or

(5-fluoro-3-methylindol-1-yl)amide 2-(3-triptoreline)pyrimidine-5-carboxylic acid,

or its hydrate, Solvay is or N-oxide, or its pharmaceutically acceptable salt.

Another private embodiment of the present invention is a compound of formula (I)represents:

(4-benzylpiperazine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

piperazine-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(4-methanesulfonylaminoethyl-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-(2-methylthiazole-4-yl)pyrimidine-5-carboxylic acid,

[4-(1-methyl-1H-imidazole-2-carbonyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(1-methyl-1H-imidazole-4-carbonyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

tert-butyl ester 4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acid,

[4-(4-triptoreline)piperidine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(4-triptoreline)piperidine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

indol-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(4-methoxypiperidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)amide 2-penile is kidin-5-carboxylic acid,

methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-3-(2-morpholine-4-retil)-1H-indole-6-carboxylic acid,

[5-fluoro-3-(tetrahydropyran-4-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

N-methyl-N-(5-fluoro)indole-3-ylsulphonyl N'-[2-(3-fluoro)phenylpyrimidine-5-carbonyl]hydrazide,

[5-fluoro-3-(tetrahydropyran-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-(1-oxy)pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-(4-Mei is a thiazol-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,/p>

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(4-methylthiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(2-methyl-3-oxo-2,3-dihydroindol-1-yl)who MFA 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-Florinda-1-yl)amide)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

6-(4-chlorothiazole-2-yl)-2-methyl-N-pyrrolo[2,3-c]pyridine-1-iniatiated,

(5-methyl-4-oxo-4,5-dihydropyrrolo[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-Carbo the OIC acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)the MFA 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carbon is th acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-deformational-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-deformational-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid, or

(3-deformational-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

It should be clear that the invention applies to all relevant specific combinations mentioned in this application.

In the scope of the present invention also includes a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds according to the invention in a mixture with a pharmaceutically acceptable carrier.

Compounds of the present invention are PGDS inhibitors and thus useful for treatment of allergic and/or inflammatory disorders, in particular disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD). Therefore, another invention, described herein, is directed to a method of treating a patient suffering from allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD), through the introduction of patient pharmaceutically effective amount of the compounds of formula (I) or its hydrate, MES or N-oxide or its pharmaceutically acceptable salt.

Included here links to treatment applicable to profilakticheski therapy for inhibition of PGDS, and for treatment of established acute or chronic, or physiological diseases associated with PGDS, in order to cure the patient suffering from these diseases, or to improve the physiological state associated with them. Discussed here the physiological state include some, but not all, possible clinical situations in which appropriate treatment of allergic rhinitis and/or asthma. The practitioners in this field are well aware of the circumstances requiring treatment.

In practice, the compounds according to the present invention can be administered in the form of pharmaceutically acceptable dosage forms for humans and other mammals by local or systemic application, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, intestinal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. You should take into account that the specific route of administration may vary, for example, depending on the physiological state of the patient.

"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compounds according to the present invention, which include, e.g. the measures tablets, pills, powders, elixirs, syrups, liquid formulations, including suspensions, sprays, inhalation pills, pellets, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposomal drugs. A General description of the methods and compositions can be found in the latest edition Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

A special aspect of the present invention is a compound according to the present invention, which must be entered in the form of pharmaceutical compositions.

Pharmaceutically acceptable carriers are composed of at least one of the components, which can be pharmaceutically acceptable carriers, diluents, shell, adjuvants, formative or environment, such as preservatives, fillers, disintegrating agents, moistening agents, emulsifiers, stabilizing the emulsion of the substance, suspendresume substances, isotonic agents, sweeteners, flavorings, fragrances, dyes, microbicides, antifungal agents, other therapeutic agents, lubricants, chemicals, slowing down or accelerating the suction and dispensing substances, depending on the characteristics of the route of administration and dosage forms.

Examples suspendida substances are ethoxylated isostearyl alcohols, poly setrenderer and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant or mixtures of these substances.

Examples of bactericidal and antifungal substances that prevent the action of microorganisms, are parabens, chlorobutanol, phenol, sorbic acid and similar substances.

Examples of isotonic substances are sugars, sodium chloride and similar substances.

Examples of substances that slow down and prolong the absorption are aluminum monostearate and gelatin.

Examples of substances accelerate and stimulate absorption, are dimethyl sulfoxide and its analogs.

Examples of diluents, solvents, carriers, solubilizing additives, emulsifiers and emulsion stabilizers are water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl ester of carbonic acid, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butyleneglycol, glycerin, glycols, dimethylformamide, Tween® 60, Span® 60, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate, ethers of sorbitol and fatty acids, vegetable oils (such as cottonseed oil, peanut oil, olive oil, castor oil and sesame oil) and injectable organic esters, such as etiloleat and the like, or the right mixture of these compounds.

Examples of formative fillers are lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.

Examples of disintegrating agents include starch, alginic acid and certain complex silicates.

Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene glycols of high molecular weight.

The choice of pharmaceutically acceptable carrier, in General, determined in accordance with the chemical properties of the active compound, such as solubility, application method and precautions to be observed in pharmaceutical practice.

The pharmaceutical compositions according to the present invention suitable for oral administration may be a single dose, such as solid dosage forms such as capsules, pills or tablets, each of which contains a certain amount of the active ingredient, or such as powders or granules, or liquid dosage forms such as solutions or suspensions in aqueous or non-aqueous liquid medium, or a liquid emulsion of oil-in-water or water-in-oil. The active ingredient can also be in the form of bolus, electuary or paste.

"Solid dosage form" means a dosage form of the compounds according to the present izobreteniya the form of solids, for example capsules, tablets, pills, powders, pills, or granules. In such dosage forms, the compound according to the present invention is added in at least one traditionally used excipient (or carrier)such as sodium citrate or dicalcium phosphate or (a) fillers or environment, such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum, (c) moisturizing agents, such as, for example, glycerol, (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain complex silicates and sodium carbonate, (e) solutions-retardants, such as, for example, paraffin, (f) absorption accelerators, such as Quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerylmonostearate, (h) adsorbents, such as kaolin or bentonite, and (i) moving substances such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) fogging components (k) of the buffer substances and substances, slowly releasing the connection according to the present invention in a certain part of the intestinal tra is the same.

A tablet may be prepared by compressing or molding and may have one or more auxiliary components. Molded tablets can be obtained by compressing in a suitable machine the active ingredient in granular form, such as powder or granules, which may be mixed with a binder, a sliding agent, inert diluent, preservative, surface active or dispersing agent. Can be used with inert fillers such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and leavening agents, such as starch, alginic acid and certain complex silicates, mixed with sliding agents such as magnesium stearate, sodium lauryl sulfate and talc. A mixture of powdered compounds moistened with an inert liquid diluent, can be molded in a suitable machine to obtain a molded tablets. Tablets may be uncoated or notches, or may have a composition that provide slow or controlled allocation of the contained active ingredient.

Solid compositions may also be used as fillers in gelatin capsules with soft or hard content with the use of such inert excipients as lactose or milk sugar, as well as glycols with large molecules is rim weight and similar substances.

If desired, and for more effective distribution, the connection can be microencapsulating systems slow or directional release, such as biocompatible biodegradable polymer matrix (e.g., copolymer of d,l-lactide with glycolide), liposomes and microspheres for subcutaneous and intramuscular injection method, called subcutaneous or intramuscular injection, slow absorption, providing a slow release of the compound or compounds in a period of 2 weeks or longer. Connections can be sterilized, for example, by filtration through inhibiting bacteria filter or adding sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately before use.

Liquid dosage form" means a form of active compound that is administered to the patient in liquid form, for example in the form of a pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compounds, the liquid dosage forms may contain commonly used in this field inert diluents, such as solvents, solubilizing agents and emulsifiers.

When using aqueous suspensions they can contain the emulsifier is or substances, which favour the formation of suspensions.

Pharmaceutical compositions suitable for topical application, are drugs in the form, allowing for local administration to the patient. Drugs can be in the form of ointments, topical application, balms, powders, sprays and inhalants, gels (water or alcohol based), creams, usually used in this field, or to be included in the matrix base for use as a patch that provides a controlled release of compound through the skin barrier. In the form of an ointment, the active ingredients can be used with paraffin or water-soluble bases. Alternatively, the active ingredients can be in the form of a cream with an oil-water basis. Drugs intended for local use through eyes that are eye drops, in which the active ingredient is dissolved or suspended in a suitable medium, typically an aqueous solvent. Drugs intended for local use through the oral mucosa include tablets, having in its composition the active ingredient in the flavor additive, normally sucrose and gum or tragakant; lozenges, having in its composition the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and gum; and compositions for rinsing of the mouth, having in its composition and the active ingredient in a suitable liquid carrier.

The oil phase of the emulsion pharmaceutical compositions can be obtained in the usual way from the well-known ingredients. This phase can be composed of only the emulsifier (also known emulsifying substance), however, it is desirable that it also included at least one emulsifier containing fat or oil, or emulsifier-containing fat and oil. In a particular embodiment of the invention, the formulation includes a hydrophilic emulsifier, together with a lipophilic emulsifier, which acts as a stabilizer. The emulsifier(s) with stabilizer(s) or without form emulgirujushchie wax together with the oil or fat to form emulgirujushchie materials, which is the oily dispersed phase of the cream formulations.

If necessary, the aqueous phase of the cream base may include, for example, not less than 30% wt. a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Compositions for topical application may, if necessary, to have a connection, stimulating the absorption or penetration of the active ingredient through the skin or other treated areas.

The choice of suitable oils or fats for use in the preparation depends on the properties, is the quiet you need to get. It is desirable that the cream was particularly non-greasy, does not leave stains and washable product with suitable consistency, preventing leakage from tubes or other containers. Can be used with linear and branched one - and dibasic alkalemia esters, such as diisopropylamide, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixture of esters with branched chain, known as Crodamol CAP. They can be used separately or in mixtures, depending on the desired properties. Alternatively can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin or other mineral oils.

Pharmaceutical compositions for rectal or vaginal use are compounds whose shape allows for rectal or vaginal administration to the patient and which contain at least one compound according to the present invention. Suppositories are one of the forms of such compositions, which can be obtained by mixing the compounds according to the present invention with suitable non-irritating inert environments or carriers such as cocoa butter, polyethylene glycol or wax base of the suppository, which are in a solid state at ordinary temperatures, but become liquid at the rate which the body temperature and therefore melt at rectal or vaginal insertion and release the active ingredient.

The pharmaceutical composition introduced by injection, may be injected intramuscularly, intravenously, intraperitoneally and/or subcutaneously. The preparations according to the present invention is prepared in liquid solutions, in particular in physiologically compatible buffers such as Hanks solution or ringer's solution. In addition, the composition can be prepared in solid form and dissolved or suspended immediately prior to use. It is also possible lyophilized form. The compositions are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions which may contain suspendresume substances, thickeners and anti-oxidants, buffers, bacteriostats and additives that make the composition isotonic, and to have the correct pH level corresponding to the indicator of the patient's blood, which will be administered the drug.

The pharmaceutical compositions according to the present invention, suitable for nasal or inhalation use, are compounds which form is suitable for administration to a patient or nasal inhalation. The composition may contain a carrier in powder form with a particle size of, for example, in the range from 1 to 500 microns (including particle sizes in the range from 20 to 500 microns in increments of 5 microns, i.e. with dimensions of 30 microns, 35 microns, etc). Suitable compositions sidcom carrier for use, for example, as a spray or nasal drops include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration, can be obtained in accordance with conventional methods and implemented with other therapeutic agents. To provide inhalation therapy can be used dosing inhalers or any dry powder inhalers, such as Eclipse, Spinhaler® or Ultrahaler®, as described in patent application WO 2004/026380 and in U.S. patent No. 5176132.

The actual dosage of the active ingredient (ingredients) in the compositions according to the present invention may vary with the purpose of obtaining the amount of the active ingredient (ingredient), effective to produce a desired therapeutic effect for a particular composition and method of its introduction to the patient. Therefore, the dosage selected for each patient depends on many factors such as the desired therapeutic effect, the route of administration, the desired duration of treatment, etiology and severity of the disease, the patient's condition, weight, sex, diet, and age, the type and effectiveness of each active ingredient, speed of absorption, metabolism and/or selection, and other factors.

Full daily dose of the compounds according to the present invention, administered to the patient one or more doses, can the be, for example, from about 0.001 to about 100 mg/kg of body weight per day, in particular from 0.01 to 10 mg/kg/day. For example, the adult dose usually ranges from about 0.01 to about 100, in particular from about 0.01 to about 10 mg/kg of body weight per day by inhalation, from about 0.01 to about 100, in particular from 0.1 to 70, preferably from 0.5 to 10 mg/kg of body weight per day by oral administration and from about 0.01 to about 50, in particular from 0.01 to 10 mg/kg of body weight per day intravenously. The percentage of active ingredient may be different, but it should provide optimum dosage. Dosage forms may contain such amounts or such fraction of a unit dose, which allow to obtain the desired daily dose. It is obvious that the form that contains multiple units of dose can be administered at about the same time. The dose may be as frequent as needed to achieve the desired therapeutic effect. Some patients are able to respond quickly to large or smaller doses, and it may be adequate to lower maintenance dose. For other patients may require prolonged treatment with intensity from 1 to 4 doses per day in accordance with the physiological needs of each patient. Needless to say, for other patients may trebovalsya not more than one or two doses per day.

Standard dose formulations may be obtained by any of the conventionally used in pharmacy practices. Such methods include phase binding pharmaceutically active ingredient with a carrier consisting of one or more accessory ingredients. Typically, the compositions will receive a uniform and irreversible binding of the active ingredient with liquid carriers, or fine solid carriers, or both, with the subsequent formation of the product if necessary.

Drugs can be packaged in a single dose or in several doses, for example sealed ampoules and vials with elastic tubes, and can be stored in a lyophilized condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Individual injection solutions and suspensions may be prepared from sterile powders, granules or pellets of the above described types.

Compounds according to the present invention can be obtained by application or adaptation of known methods, by which is meant a method previously used or described in the literature, for example, described in R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

The following reactions may be necessary to protect reactive fu is clonally group, for example, hydroxyl group, amino group, aminogroup, tigroup or carboxy groups, where these groups are required in the final product, to avoid their unwanted participation in the reactions. Conventional protective groups can be used in accordance with standard procedures, for example, see T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.

The compound of formula (I), where R2represents hydrogen, L1represents a bond, -NH-C(=O) -, or (C1-C2-alkylene, optionally substituted by one or more halogen, and where R1, R3and R4submitted in accordance with the definition in this document, can be obtained as shown in scheme I below, (i) in the reaction of the corresponding amidnogo the compounds of formula (1) with a reagent of formula (2) to obtain the compounds of formula (3), (ii) by hydrolysis of the compounds of formula (3) to obtain the compounds of formula (4), and (iii) combinations of the compounds of formula (4) with the appropriate compound of formula (5).

Scheme I

R2represents hydrogen, and

L1represents a bond, -NH-C(=O) -, or (C1-C2-alkylene, optionally substituted by one or more halogen

The reaction in the first stage is convenient to carry out, for example, when the temperature is ur about 100°C in an inert solvent, for example, in DMF). The reaction in the second stage is convenient to carry out, for example, at room temperature, in the presence of inorganic bases such as LiOH, KOH or NaOH, in a solvent such as THF, MeOH, water, or mixtures thereof. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about room temperature up to 100°C, in the presence of a condensing agent such as HCTU, HOTT, PyBrOP, DMTMM or HATU with HOAt, and base, such as DIPEA or Et3N, in an inert solvent, such as DMF. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about 0°C to room temperature, initially in the reaction of compounds of formula (4) with oxalylamino and then by adding the compounds of formula (5) and a base such as DIPEA, Et3N, K2CO3or Na2CO3in an inert solvent, for example in DGM or DMF.

The compound of formula (I), where R2is a (C1-C4)-alkyl, which is optionally substituted by one or more halogen, L1represents a bond, -NH-C(=O) -, or (C1-C2-alkylene, optionally substituted by one or more halogen, and where R1, R3and R4submitted in accordance with the definition in this document can also be obtained as shown in scheme II below, (i) in the reaction corresponding to Edinboro the compounds of formula (1) with a reagent of formula (6) to obtain the compounds of formula (7), (ii) by hydrolysis of the compounds of formula (7) to obtain the compounds of formula (8), and (iii) combinations of the compounds of formula (8) with the appropriate compound of formula (5).

Scheme II

R2=(C1-C4)-alkyl, optionally substituted by one or more halogen

and

L1represents a bond, -NH-C(=O) -, or (C1-C2-alkylene, optionally substituted by one or more Halogens.

The reaction in the first stage is convenient to carry out, for example, at a temperature of about 100°C in the presence of metallic sodium in an inert solvent, such as EtOH. The reaction in the second stage is convenient to carry out, for example, at room temperature, in the presence of inorganic bases such as LiOH, KOH or NaOH, in a solvent such as THF, MeOH, water, or mixtures thereof. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about room temperature up to 100°C, in the presence of a condensing agent such as HCTU, HOTT, PyBrOP, DMTMM or HATU with HOAt, and base, such as DIPEA or Et3N, in an inert solvent, such as DMF. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about 0°C to room temperature, initially by the reaction of compounds of formula (8) with oxalylamino and then by adding the compounds of formula (5) and the base is, such as DIPEA, Et3N, K2CO3or Na2CO3in an inert solvent, for example in DGM or DMF.

The compound of formula (I), where L1represents-C(=O) -, and where R1, R2, R3and R4submitted in accordance with the definition in this document can also be obtained as shown in scheme III below, (i) in the reaction of the corresponding compounds of formula (9) with the reagent of the Grignard reagent of formula R1MgBr to obtain the compounds of formula (10), (ii) converting the compounds of formula (10) compound of formula (11), (iii) by hydrolysis of the compounds of formula (11) to obtain the compounds of formula (12), (iv) hydrolysis of compounds of formula (12) to obtain the compounds of formula (13) and (v) combinations of the compounds of formula (13) with the appropriate compound of formula (5).

Scheme III

The reaction in the first stage is convenient to carry out, for example, at a temperature from about room temperature up to 50°C in an inert solvent, for example in Et2O. the Reaction in the second stage is convenient to carry out, for example, at a temperature of about 150°C, in the presence of three-hydrate of hexacyanoferrate(II) potassium, palladium(II) acetate and a base such as Na2CO3or K2CO3in an inert solvent, such as dimethylacetamide or DMF. The reaction in the third stage, is convenient to carry out, in the example, at a temperature of from about 0°C to room temperature in the presence of inorganic bases such as KOH, NaOH or LiOH in a solvent such as MeOH or a mixture of MeOH and water. The reaction in the fourth stage is convenient to carry out, for example, at room temperature, in the presence of inorganic bases such as LiOH, KOH or NaOH, in a solvent such as THF, MeOH, water, or mixtures thereof. Response to the fifth stage is convenient to carry out, for example, at a temperature from about room temperature up to 100°C, in the presence of a condensing agent such as HCTU, HOTT, PyBrOP, DMTMM or HATU with HOAt, and base, such as DIPEA or Et3N, in an inert solvent, such as DMF. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about 0°C to room temperature, initially in the reaction of compounds of formula (4) with oxalylamino and then by adding the compounds of formula (5) and a base such as DIPEA, Et3N, K2CO3or Na2CO3in an inert solvent, for example in DGM or DMF.

The compound of formula (I), where L1represents-O-, and R1, R2, R3and R4submitted in accordance with the definition in this document can also be obtained as shown in scheme IV below, (i) by oxidation of compounds of formula (14) to obtain the compounds of formula (15), (ii) in the reaction Conn is of formula (15) with the appropriate compound of formula R 1ONa to obtain the compounds of formula (16), (iii) by hydrolysis of the compounds of formula (16) to obtain the compounds of formula (17) and (iv) combinations of the compounds of formula (17) with the appropriate compound of formula (5).

Scheme IV

The oxidation reaction in the first stage is convenient to carry out, for example, at room temperature in the presence of MCPBA and Na2S2O3in an inert solvent, for example in DHM. The reaction in the second stage is convenient to carry out, for example, in a microwave oven, heated to a temperature of about 100°C, in an inert solvent, such as NMP. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about 0°C to room temperature in the presence of inorganic bases such as KOH, NaOH or LiOH in a solvent such as THF, MeOH or mixtures thereof. The reaction in the fourth stage is convenient to carry out, for example, at a temperature from about room temperature up to 100°C, in the presence of a condensing agent such as HCTU, HOTT, PyBrOP, DMTMM or HATU with HOAt, and base, such as DIPEA or Et3N, in an inert solvent, such as DMF. The reaction in the third stage, is convenient to carry out, for example, at a temperature from about 0°C to room temperature, initially in the reaction of compounds of formula (17) with oxalylamino and then by adding the compounds of formula (5) and reasons, that the CSOs as DIPEA, Et3N, K2CO3or Na2CO3in an inert solvent, for example in DGM or DMF.

Compounds according to the present invention can also be obtained by conversion of one of the compounds according to the present invention in the other.

It should be noted that the compounds according to the present invention may contain asymmetric centers. These asymmetric centers can independently be either in R or S configuration. For the person skilled in the art it is obvious that certain compounds according to the present invention can also exhibit geometric isomerism. It should be understood that the present invention applies to the individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures of compounds of the above formula (I). Such isomers can be distinguished from their mixtures by known methods or their modifications, e.g. chromatographic methods or methods of recrystallization, or get a separate from the appropriate isomers of their intermediates.

Compounds of the invention, methods for their preparation and their biological activity will be more apparent from the analysis in the following examples, which are given purely as illustrations and should not be construed as limiting the scope of the invention. Connection this is part II of the invention are identified, for example, using the following analytical methods.

Mass spectra (MS) are recorded on a mass spectrometer Micromass LCT. The method is based on ionization of positive elektrorazpredelenie and scanning mass m/z 100 to 1000.

The spectra of nuclear magnetic resonance (1H NMR) 300 MHz1H recorded at room temperature on the spectrometer Varian Mercury (300 MHz) with 5 mm ASW sensor. In1H NMR chemical shifts (δ) are quoted in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard.

In the following examples and descriptions of the synthesis, as well as in the rest of the application, the terms used have the following meanings: "kg - kilograms, "g" for grams, "mg" - milligrams, "μg " - micrograms, "mol" - moles, "mmol" mmol, M - moles per liter, mm - mmol per liter, "μm" - micromol per liter, "nm" - nanomole per litre, l - liters, "ml" is milliliter, "μl" - Microlitre, "°C" degrees Celsius, "TPL" melting point, "BP." - boiling point, "mm of RT. Art." is the pressure in millimeters of mercury, "cm" - centimeters, "nm - nanometers, "abs." absolute, "conc." - concentrated, "c" is the concentration in g/ml, "K.T." room temperature, "TLC" - thin layer chromatography, "HPLC" is a high - performance liquid chromatography, "V/b" intraperitoneally, "/" intravenous, "s" is singlet, "d", which duplicates the t; t - triplet; "kV" Quartet; m - multiplet, "DD" is doublet of doublets; "ush." broadened, "LC" - liquid chromatograph, "MS - mass spectrometry, "ESI/MS" - ionization in electrospray/mass spectrometry, "RT" - retention time, M is the molecular ion, "psi" is pounds per square inch, "DMSO - dimethylsulfoxide, "DMF" - N,N-dimethylformamide, "DHM" - dichloromethane, "HCl" - hydrochloric acid, "SPA" SPA assay (scintillation analysis using molecular imprinted polymers), "EtOAc - ethyl acetate, "PBS" phosphate buffered saline "IUPAC international Union of pure and applied chemistry, "MHz" - megahertz, "MeOH - methanol, N - normality, "THF" is tetrahydrofuran, min - minute(s), "N2" is gaseous nitrogen, "MeCN" or "CH3CN - acetonitrile, "Et2O - ethyl ester, "TFU" - triperoxonane acid, "~" - roughly, "MgSO4" magnesium sulfate "Na2SO4" sodium sulfate, "NaHCO3" sodium bicarbonate, Na2CO3" sodium carbonate "MCPBA" - 3-chloroperoxybenzoic acid, "NMP" - N organic, "PS-DCC - dicyclohexylcarbodiimide on the polymer carrier, "LiOH - lithium hydroxide, "PS-trisamin" - trisamin on the polymer carrier, "PGH2" -prostaglandin H2, "PGD2" - prostaglandin D2; "PGE2 - prostaglandin E2, "hPGDS" -hematopoietic PGD2 synthase, "GSH" - CH who tation (restored), "ELISA" - enzyme-linked immunosorbent assay, "KH2PO4'- phosphate of potassium monoosnoc, K2HPO4'- phosphate of potassium dwuhosnovny, "FeCl2" the iron chloride (II), "MOX" - methoxylamine; "EtOH" is ethanol, DMSO - dimethylsulfoxide, "Ag2O" = silver oxide (I), "HATU" = hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea, "HOAt" = 1-hydroxy-7-asobancaria, "DIPEA" = N,N-diisopropylethylamine, "HOTT" = hexaphosphate S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylurea, "HCTU" = hexaphosphate N,N,N',N'-tetramethyl-O-(6-chloro-1H-benzotriazol-1-yl)Urania, "PyBrOP" = hexaphosphate bromo-Tris-pyrrolidinone, "LiAlH4" = alumoweld lithium, "PyAOP" = hexaflurophosphate (7-asobancaria-1 yloxy)-triprolidine, "TBTU" = tetrafluoroborate O-benzotriazol-1-yl-N,N,N,N,-tetramethylurea, "NaHMDS" = bis(trimethylsilyl)amide and sodium, "NMP = N-methyl-2-pyrrolidinone, "GOSC" = hydroxylamine-O-sulfonic acid, "DMTMM" = chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine, "TMSN3" = trimethylsilylmethyl, "TBAF" = tetrabutylammonium, "TFAA" = triperoxonane anhydride.

EXAMPLES

Example 1

(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid

Stage 1. A solution of tert-butoxide potassium (1.84 g, 16,43 mmol) and 5-fluoro-2-methylindole (1,21 g of 8.09 mmol) in DMF (20 ml) is stirred in a stream of N2the ri room temperature for 60 minutes The monochloramine solution in ether (65 ml, of 9.75 mmol) is added through the funnel within 10 minutes the resulting mixture was stirred at 23°C for 2 hours and then concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% EtOAc in heptane, to obtain5-fluoro-2-methylindol-1-ylamine(290 mg, 22%) as a solid. MC 165 (M+H);1H NMR (300 MHz, CDCl3): δ 7.24 to 7,19 (m, 1H), 7,12 (DD, 1H), 6,92 (dt, 1H), 6,12 (s, 1H), 4,23 (USS, 2H), 2,39 (s, 3H).

Stage 2. Three-neck round bottom flask with magnetic stirrer and reflux condenser with a capacity of 250 ml product N2. In the flask was successively added methyl-3,3-dimethoxypropionate (5,22 g, 35,3 mmol), anhydrous 1,2-dimethoxyethane (25 ml), anhydrous methylformate (5 ml), 60% sodium hydride (1.7 g, 42,5 mmol) and the mixture is heated to 40-50°C until the termination of allocation of gaseous hydrogen. The reaction mixture is cooled in a water bath with ice and slowly allowed to warm to room temperature overnight with stirring. Add anhydrous ether (25 ml) and the resulting suspension is filtered under N2, washed with anhydrous ether (10 ml) and dried in vacuum for 2 hours to getn is trieval salt of methyl ester of 2-dimethoxymethyl-3-hydroxyacrylates acid (3.51 g, 50%) in powder form.1H NMR (CD3OD): δ of 3.33 (s, 6H), of 3.60 (s, 3H), 5,31 (s, 1H), 8,89 (s, 1H). (see: P. Zhichkin, D.J. Fairfax, S.A. Eisenbeis, Synthesis, 2002, 720-722.)

Stage 3. To a solution of nicotineinduced (1 g, 6,35 mmol) in anhydrous DMF (12 ml) add sodium salt of methyl ester of 2-dimethoxymethyl-3-hydroxyacrylates acid (1,46 g, 7.36 mmol) and the reaction mixture is heated at 100°C in nitrogen atmosphere for 3 hours. After that the reaction mixture is cooled to room temperature and add water (48 ml). The precipitate is collected by filtration, washed with water and dried in vacuum to obtainmethyl ester of 2-pyridine-3-Yeremey-5-carboxylic acid(0.7 g, 51%). MC: 216 (M+H).

Stage 4. A solution of methyl ester of 2-pyridine-3-Yeremey-5-carboxylic acid (0.73 g, of 3.32 mmol) and 1M aqueous LiOH (3,32 ml) in MeOH (5 ml) was stirred at room temperature overnight. Meon removed in vacuum and the aqueous solution is treated with aqueous 3n. HCl solution to adjust the pH in the range between 2 and 3. The solid is filtered, washed with water and dried in vacuum to obtain2-pyridine-3-Yeremey-5-carboxylic acid(0.2 g, 30%) as a solid. MS: 202 (M+H).

Stage 5. A solution of 2-pyridine-3-Yeremey-5-carboxylic acid (506 mg, 2,13 mmol), HCTU (970 mg, 2.34 mmol) and DIPEA (1 ml, 5,72 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 1 minutes To the mixture is added 5-fluoro-2-methylindol-1-ylamine (311 mg, 1,89 mmol). The reaction mixture is stirred at a temperature of 75°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 45% EtOAc in heptane, to obtain(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid(300 mg, 46%) as a solid. MS: 348 (M+H).1H NMR (300 MHz, DMSO-d6): δ 12,02 (s, 3H), 9,60 (d, 1H), 9,49 (s, 2H), 8,82-8,76 (m, 2H), to 7.64 (DD, 1H), 7,39 (DD, 1H), 7,29 (DD, 1H), 6,94 (dt, 1H), 6.35mm (s, 1H), 2,33 (s, 3H).

Example 2

(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. Na0(0.66 g, 28.6 mmol) is added to anhydrous EtOH (100 ml) and stirred at room temperature for 15 minutes Add 3-fermentatiegebied (4,87 g, 27.8 mmol) and the solution stirred for 15 minutes Add ethyl ester 2-dimethylaminomethylene-3-oxomalonate acid (5.3 g, 28.6 mmol) and the reaction mixture is refluxed under N2within 1 hour. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc (300 ml), washed with the left solution (2×100 ml), dried (Na2SO4), filtered and concentrated to obtainethyl ester of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(6.8 g, 99%). MS: 261 (M+H);1H NMR (300 MHz, CDCl3): δ was 1.43 (t, J=7.0 Hz, 3H), of 2.92 (s, 3H), 4,42 (kV, J=7,0 Hz, 2H), 7,24 (m, 1H), 7,45 (m, 1H), 8,27 (m, 1H), of 8.37 (m, 1H), of 9.21 (s, 1H).

Stage 2. A solution of ethyl ester of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (6.7 g, to 27.2 mmol) and NaOH (2.1 g, of 54.4 mmol) in a solution of 1:1:1 THF, MeOH and water (300 ml) is refluxed for 45 minutes THF/MeOH is evaporated and the aqueous solution is treated with 3h. HCl to adjust pH in the range of 2 to 3. The solid is filtered, washed with water and dried in vacuum to obtain2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(5,4 g, 91%) as a solid. MS: 233 (M+H);1H NMR (300 MHz, CD3OD): δ 2,85 (s, 3H), 7,24 (m, 1H), 7,50 (m, 1H), 8,17 (m, 1H), 8,32 (m, 1H), 9,20 (s, 1H).

Stage 3. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (340 mg, of 1.46 mmol, received according to the General procedure described in example 1, stage 3 and 4), HOAt (248 mg, 1.82 mmol) and HATU (645 mg, 1.70 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 20 minutes To a mixture of 5-fluoro-2-methylindol-1-ylamine (237 mg, 1.44 mmol) and DIPEA (380 μl, of 2.18 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20% EtOAc in heptane, to obtain(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(300 mg, 55%) as a solid. MS: 379 (M+H).1H NMR (300 MHz, CD3OD): δ 9,14 (s, 1H), scored 8.38-to 8.20 (m, 3H), 7,56-7,52 (m, 1H), 7,30-7,27 (m, 2H), 7,19-7,16 (m, 1H), of 6.96-6.90 to (m, 1H), 6,32 (s, 1H), and 2.83 (s, 3H), 2,42 (s, 3H).

Example 3

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. A suspension of NaH (2,01 g, 50.3 mmol, 60% in mineral oil) in DMF (45 ml) at 0°C is treated with 5-fluoro-3-methyl-1H-indole (500 mg, 3,55 mmol) and the mixture is stirred at 0°C for 1 hour. NH2OSO3H (1,9 g, x 16.75 mmol) is added in portions and the mixture is then warmed to room temperature and stirred for 2 hours. The mixture is quenched with MeOH, diluted with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to obtain5-fluoro-3-methylindol-1-ylamine. MS: 165 (M+H);1H NMR (300 MHz, CD3OD): δ 2,22 (s, 3H), 6,86 (m, 1H), 6,99 (s, 1H), was 7.08 (m, 1H), was 7.36 (m, 1H).

Stage 2. Na0(and 31.7 mmol) is added to anhydrous EtOH (100 ml) and stirred at room temperature for 15 minutes Add Ki is rochloride pyridine-2-carboxamidine (and 31.7 mmol) and the solution stirred for 15 minutes Add ethyl ester 2-dimethylaminomethylene-3-oxomalonate acid and 31.7 mmol) and the reaction mixture is refluxed under N2within 1 hour. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc (200 ml), washed with brine (2×100 ml), dried (Na2SO4), filtered and concentrated to obtainethyl ester of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(6,77 g, 88%). MS: 261 (M+H);1H NMR (300 MHz, CDCl3): δ of 1.44 (t, 3H), of 2.97 (s, 3H), of 4.44 (q, 2H), 7,44 (m, 1H), to $ 7.91 (m, 1H), at 8.60 (m, 1H), 8,90 (m, 1H), 9,31 (s, 1H).

Stage 3. A solution of ethyl ester of 4-methyl-pyridin-2-Yeremey-5-carboxylic acid (to 26.7 mmol) and LiOH (53,4 mmol) in a solution of 1:1:1 THF, MeOH and water (200 ml) was stirred at room temperature overnight. THF/MeOH is evaporated and the aqueous solution is treated with aqueous 10% HCl solution to adjust the pH in the range between 1.5 and 2.5. The solid is filtered off, washed with water and dried in vacuum to obtain4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(5.50 g, 96%) as a solid. MS: 233 (M+H);1H NMR (300 MHz, CD3OD): δ = 2,93 (s, 3H), to 7.59 (m, 1H), with 8.05 (t, 1H), to 8.62 (d, 1H), 8,76 (d, 1H), 9.28 are (s, 1H).

Stage 4. Method:

A solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (335 mg, 1.56 mmol), HOTT (638 mg, 1,72 mmol) and DIPEA (700 μl, 4,01 mmol) in DMF (6 ml) displaced the more at room temperature in a stream of N 2within 20 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (241 mg, about 1.47 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 60% EtOAc in heptane, to obtain (5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (193 mg, 36%) as a solid. MS: 362 (M+H).1H NMR (300 MHz, CDCl3): δ 10,41 (s, 1H), 8,84 (s, 1H), 8,55 (s, 2H), 8,48-to 8.45 (m, 1H), 7,86 (t, 1H), 7,40 and 7.36 (m, 1H), 7.24 to 7,20 (m, 1H), 7,05-7,01 (m, 2H), 2,82 (s, 3H), 2,32 (s, 3H).

Stage 4. The way B:

5-fluoro-3-methylindol-1-ylamine (10.6 mmol) is treated with 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (2,75 g, 12.8 mmol) in DMF (75 ml) and the mixture is stirred at room temperature for 10 minutes the mixture is Then treated with chloride 2,4-dimethoxy-6-(4-methylmorpholin-4-yl)-[1,3,5]triazine (3,82 g, 13,85 mmol) and stirred at 60°C for 1 hour. The mixture was concentrated in vacuo. The residue was diluted with Et2O (50 ml) and 10% NaHCO3(50 ml) and the mixture is stirred at room temperature for 20 minutes the Obtained solid is filtered, washed and dried to obtain (5-fluoro-3-methylindol-1-yl)amide of 4-met is l-2-pyridine-2-Yeremey-5-carboxylic acid (3.2 g, 83%). The solid is crystallized with a mixture of MeOH:water (4:1) to obtain a(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acidin the form of crystals. MS: 362 (M+H);1H NMR (300 MHz, DMSO-d6): δ, and 2.27 (s, 3H), 2,78 (m, 3H), 7,06 (m, 1H), 7,34 (m, 1H), 7,37 (s, 1H), 7,44 (m, 1H), to 7.59 (m, 1H), with 8.05 (m, 1H), 8,45 (m, 1H), 8,80 (m, 1H), 9,25 (s, 1H). IC50=7 nm.

Example 4

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 1, step 3, but replacing the hydrochloride of nicotinamide on hydrochloride pyridine-2-carboxamidine getmethyl ester of 2-pyridine-2-Yeremey-5-carboxylic acid.

Stage 2. In accordance with the methods similar to those described in example 2, step 1, but substituting the methyl ester of 2-pyridine-3-Yeremey-5-carboxylic acid methyl ester 2-pyridine-2-Yeremey-5-carboxylic acid, get2-pyridine-2-Yeremey-5-carboxylic acid.

Stage 3. A solution of 2-pyridine-2-Yeremey-5-carboxylic acid (209 mg, 0.88 mmol), HOTT (435 mg, 1,17 mmol) and DIPEA (400 μl, to 2.29 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 20 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (125 mg, from 0.76 mmol). The resulting mixture was stirred at room temperature overnight. The mixture distribution is elaut between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 70% EtOAc in heptane, to obtain(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(180 mg, 68%) as a solid. MS: 348 (M+H).1H NMR (300 MHz, DMSO-d6): δ 12,12 (s, 3H), for 9.47 (s, 2H), 8,82 (d, 1H), 8,51 (d, 1H), with 8.05 (dt, 1H), 7.62mm (DD, 1H), 7,42 (DD, 1H), 7,35 (DD, 1H), 7,33 (s, 1H), 7.03 is (TD, 1H), and 2.27 (s, 3H).

Example 5

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 2, step 1, but replacing the hydrochloride of nicotinamide 3-fermentatiegebied getethyl ester of 2-pyridin-3-yl-4-methylpyrimidin-5-carboxylic acid.

Stage 2. In accordance with the methods similar to those described in example 2, step 1, but substituting the ethyl ester of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid ethyl ester 2-pyridin-3-yl-4-methylpyrimidin-5-carboxylic acid, get4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid.

Stage 3. A solution of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (502 mg, of 2.33 mmol), HCTU (1,054 g, 2.55 mmol) and DIPEA (1,10 μl, 6,30 mmol) in DMF (10 ml) displaced the more at room temperature in a stream of N 2within 10 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (341 mg, of 2.08 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether (4 times) to obtain (5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (160 mg, 21%) as a solid. MS: 362 (M+H).1H NMR (300 MHz, DMSO-d6): δ up 11,86 (s, 1H), 9,58 (s, 1H), 9,24 (s, 2H), 8,79-8,78 (m, 1H), total of 8.74 (TD, 1H), 7.62mm (DD, 1H), 7,44 (DD, 1H), 7,37 and 7.36 (m, 2H), 7,06 (TD, 1H), 2,78 (s, 3H), and 2.27 (s, 3H).

Example 6

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid

A solution of 2-pyridine-3-Yeremey-5-carboxylic acid (664 mg, and 2.79 mmol), HCTU (1.27 g, of 3.07 mmol) and DIPEA (1.4 ml, 8,02 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (491 mg, 2.55 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in Vacu the IU. The residue is triturated in ether (3 times) and methanol to obtain(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid(375 mg, 42%) as a solid. MS: 348 (M+H).1H NMR (300 MHz, DMSO-d6): δ 12,10 (s, 1H), being 9.61-9,60 (m, 1H), 9,45 (s, 2H), 8,81-8,80 (m, 1H), 8,77 (dt, 1H), to 7.64 (DD, 1H), 7,41 (DD, 1H), 7,35 (DD, 1H), 7,32 (s, 1H), 7.03 is (TD, 1H), and 2.27 (s, 3H). IC50=10 nm.

Example 7

(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

A solution of 2-pyridine-2-Yeremey-5-carboxylic acid (485 mg, 2.04 mmol), HCTU (909 mg, 2.2 mmol) and DIPEA (1 ml, 5,72 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-2-methylindol-1-ylamine (299 mg, 1.82 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 70% EtOAc in heptane, to obtain(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(112 mg, 18%) as a solid. MS: 348 (M+H).1H NMR (300 MHz, DMSO-d6): δ a 12.03 (s, 1H), 9,51 (s, 2H), 8,83 (d, 1H), and 8.50 (d, 1H), with 8.05 (dt, 1H), 7.62mm (DD, 1H), 7,39 (DD, 1H), 7,28 (DD, 1H), 6,94 (dt, 1H), 6.35mm (who, 1H), 2,33 (s, 3H).

Example 8

(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. To a solution of 3-fermentatiegebied (4 g, and 22.6 mmol) in anhydrous DMF (35 ml) add sodium salt of 3,3-dimethoxy-2-carbomethoxy-1-EN-1-oxide (4,99 g of 25.2 mmol). The reaction mixture is heated at 100°C under N2for 3 hours and then cooled to room temperature. To the mixture is added water (150 ml) and the mixture extracted with EtOAc. The organic phase is washed with brine, dried (MgSO4), filtered and concentrated in vacuo to obtainmethyl ester 2-(3-forfinal)pyrimidine-5-carboxylic acid(1,76 g, 34%). MS: 233 (M+H).

Stage 2. To a solution of methyl ester of 2-(3-forfinal)pyrimidine-5-carboxylic acid (1,76 g, 7,58 mmol) in anhydrous MeOH (35 ml) is added LiOH (0,38 g, 15.9 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and aqueous 3n HCl solution (7,6 ml). A mixture of extravert EtOAc and the organic phase is washed with brine, dried (MgSO4), filtered and concentrated in vacuo to obtain2-(3-forfinal)pyrimidine-5-carboxylic acid(1,62 g, 98%) as a solid. MS: 219 (M+H).

Stage 3. A solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (372 g, 1.7 mmol), HTU (757 g to 1.83 mmol) and DIPEA (780 μl, 4,47 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (250 mg, of 1.52 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to obtain(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(332 mg, 60%) as a solid. MS: 365 (M+H).1H NMR (300 MHz, DMSO-d6): δ 12,08 (s, 1H), 9,43 (s, 2H), at 8.36 (d, 1H), to 8.20 (dt, 1H), 7,70 to 7.62 (m, 1H), of 7.48 (dt, 1H), 7,40 (DD, 1H), 7,35 (DD, 1H), 7,32 (s, 1H), 7,03 (dt, 1H), and 2.27 (s, 3H).

Example 9

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (504 mg, 2.34 mmol), HCTU (1.06 g, 2.55 mmol) and DIPEA (1.1 ml, 6,30 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-2-methylindol-1-ylamine (346 mg, 2,11 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous Rast is a PR NaHCO 3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 70% EtOAc in heptane, to obtain (5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (82 mg, 11%) as a solid. MS: 362 (M+H).1H NMR (300 MHz, DMSO-d6): δ RS 11.80 (s, 1H), 9,59 (d, 1H), 9,29 (s, 1H), 8,80-8,73 (m, 2H), 7,63 (DD, 1H), 7,22 (DD, 1H), 7,28 (DD, 1H), 6,97 (dt, 1H), 6.35mm (s, 1H), and 2.79 (s, 3H), is 2.37 (s, 3H).

Example 10

(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (645 g, 2,78 mmol), HCTU (1,25 g, to 3.02 mmol) and DIPEA (1.35 ml, 7,73 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3-methylindol-1-ylamine (380 mg, 2,31 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to obtain(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(533 mg, 61%) as a solid. MS: 379 (M+H).1H NMR (300 MHz, DMSO-d6): δ 11,84 (s, 1H) of 9.21 (s, 1H), 8,32 (d, 1H), 8.17-a of 8.15 (m, 1H), 7,66-to 7.61 (m, 1H), 7,47-7,41 (m, 1H), was 7.36-7,34 (m, 2H), 7,05 (dt, 1H), was 2.76 (s, 3H), and 2.26 (s, 3H). IC50=6 nm.

Example 11

(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

A solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (389 g, 1.78 mmol), HOAt (290 mg, 2,13 mmol) and HATU (811 mg, 2,13 mmol) in DMF (20 ml) was stirred at room temperature in a stream of N2within 20 minutes To a mixture of 5-fluoro-2-methylindol-1-ylamine (290 mg, 1.77 mmol) and DIPEA (450 μl, 2.58 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 25% DHM in heptane, to obtain(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(300 mg, 47%) as a solid. MS: 365 (M+H).1H NMR (300 MHz, CDCl3): δ 9,23 (s, 1H), 8,76 (s, 1H), 8,35 is 8.22 (m, 2H), 7,54 was 7.45 (m, 1H), 7,19-6,86 (m, 5H), and 6.25 (s, 1H), to 2.29 (s, 3H).

Example 12

(5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (810 mg, 3,76 mmol), PyBrOP (1,76 g, 3,78 the mol) and DIPEA (1.9 ml, 10,89 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-2-methylindol-1-ylamine (560 mg, to 3.41 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 3% MeOH in DHM, to obtain (5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (174 mg, 14%) as a solid. MS: 362 (M+H).1H NMR (300 MHz, DMSO-d6): δ 11,82 (s, 1H), of 9.30 (d, 1H), 8,81 (d, 1H), 8,46 (d, 1H), 8,03 (dt, 1H), to 7.59 (DD, 1H), 7,43 (DD, 1H), 7,29 (DD, 1H), 6,98 (dt, 1H), 6.35mm (s, 1H), and 2.79 (s, 3H), of 2.38 (s, 3H). IC50=8 nm.

Example 13

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. To a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (3.75 g, 22,69 mmol) in DHM add soliditet (3.4 ml, 25,42 mmol). The mixture is refluxed over night. The mixture is cooled and partitioned between DHM and water. The organic fraction is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and conc the Ute in vacuum to obtain 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole(to 4.23 g, 96%) as a solid. MS: 195 (M+H).1H NMR (300 MHz, CD3Cl): δ to 7.77 (DD, 1H), 7,08-6,98 (m, 2H), 3,94 (s, 2H), 1.39 in (s, 6H).

Stage 2. To a solution of 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (a 4.03 g, 20,75 mmol) in THF (70 ml) at 0°C is added dropwise a solution of LiAlH4(40 ml, 40 mmol) in THF. The reaction mixture is brought to room temperature and stirred over night. The mixture is quenched with saturated aqueous Rochelle salt. The resulting mixture is stirred until the formation of the suspension. The organic fraction is separated, washed with 10%aqueous HCl solution, saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 25% EtOAc in heptane, to obtain5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-ylamine(3.51 g, 94%) as oil. MS: 181 (M+H).1H NMR (300 MHz, CD3Cl): δ 6,85-of 6.78 (m, 1H), 6.75 in-6,98 (m, 2H), 3,44 (USS, 2H), 3,14 (s, 2H), 1.28 (in, 6H).

Stage 3. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (348 g, 1.5 mmol), HOTT (618 mg, of 1.66 mmol) and DIPEA (700 μl, 4,01 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-ylamine (239 mg, of 1.33 mmol). The resulting mixture is stirred at a temperature of 80°C for N. the Chi. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 15% EtOAc in heptane, to obtain(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(416 mg, 80%) as a solid. MS: 395 (M+H).1H NMR (300 MHz, DMSO-d6): δ 10,43 (s, 1H), 8,99 (s, 1H), 8,28 (d, 1H), 8,15-8,11 (m, 1H), 7,66-7,58 (m, 1H), 7,46-7,39 (m, 1H), 7,06 (DD, 1H), 6,95-to 6.88 (m, 1H), 6.75 in-of 6.71 (m, 1H), 3,51 (s, 2H), 2,68 (s, 3H), of 1.33 (s, 6H).

Example 14

[3-(2,2,2-TRIFLUOROACETYL)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 1, step 1, but substituting 5-fluoro-3-methylindol 3-(2,2,2-TRIFLUOROACETYL)indole, get1-(1-amino-1H-indol-3-yl)-2,2,2-triptoreline.

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (360 g, 1.55 mmol), HOTT (628 mg, was 1.69 mmol) and DIPEA (740 μl, 4,24 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 10 minutes To the mixture was added 1-(1-amino-1H-indol-3-yl)-2,2,2-triptoreline (322 mg, 1.4 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and distributed between the at EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified HPLC on a reversed-phase column, elwira mobile phase of 0.1% TFU/water to 100% MeCN with an inclination of about 30 min, to obtain[3-(2,2,2-TRIFLUOROACETYL)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(71 mg, 11%) as a solid. MS: 443 (M+H).1H NMR (300 MHz, DMSO-d6): δ 12,56 (s, 1H), to 9.32 (s, 1H), 8,90 (d, 1H), 8,35 (d, 1H), 8,30-of 8.27 (m, 1H), they were 8.22-8.17 and (m, 1H), 7,75-72 (m, 1H), 7,69 to 7.62 (m, 2H), 7,52-7,44 (m, 3H), of 2.81 (s, 3H).

Example 15

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (685 mg, 3,18 mmol), HOTT (1.29 g, of 3.48 mmol) and DIPEA (1.6 ml, 9,16 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-ylamine (542 mg, a 3.01 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 2 MeOH in DHM, to get(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(585 mg, 52%) as a solid. MS: 378 (M+H).1H NMR (300 MHz, DMSO-d6): δ 10,46 (s, 1H), of 9.02 (s, 1H), 8,78 (d, 1H), 8,42 (d, 1H), 8,00 (dt, 1H), 7,56 (DD, 1H), 7,06 (DD, 1H), 6,92 (dt, 1H), 6,76-6,72 (m, 1H), 3,32 (s, 2H), 2,70 (s, 3H), of 1.33 (s, 6H).

Example 16

(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (706 mg, or 3.28 mmol), HOTT (1,34 g, 3.6 mmol) and DIPEA (1.65 ml of 9.45 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-ylamine (560 mg, 3.11 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 35% EtOAc in heptane, to obtain (5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid (617 mg, 53%) as a solid. MS: 378 (M+H).1H NMR (300 MHz, DMSO-d6): δ 10,44 (s, 1H), of 9.55-9,54 (m, 1H), 9,01 (s, 1H), 8,77 is 8.75 (m, 1H), 8,72-8,68 (m, 1H), 7,60 (the d, 1H), 7,06 (DD, 1H), of 6.96-to 6.88 (m, 1H), 6,76-6,72 (m, 1H), 3,51 (s, 2H), 2,70 (s, 3H), of 1.33 (s, 6H).

Example 17

(2,3-Dimethylindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 1, step 1, but substituting 5-fluoro-2-methylindol 2.3-dimethylindole receive 2,3-dimethylindole-1-ylamine in the form of solids. MS: 161 (M+H).1H NMR (300 MHz, CDCl3): δ of 7.48 was 7.45 (m, 1H), 7,33-7,30 (m, 1H), 7,19-7,13 (m, 1H), 7,10-7,05 (m, 1H), 4,40 (USS, 2H), is 2.37 (s, 3H), of 2.23 (s, 3H).

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (764 g, 3,29 mmol), HOTT (1,33 g, 3.58 mmol) and DIPEA (1.65 ml of 9.45 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 2,3-dimethylindole-1-ylamine (497 mg, 3.1 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20% EtOAc in heptane, to obtain(2,3-dimethylindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(568 mg, 49%) as a solid. MS: 375 (M+H).1H NMR (300 MHz, DMSO-d6): δ 11,68 (s, 1H), 9,24 (s, 1H), with 8.33 (d, 1H, 8,20-of 8.15 (m, 1H), 7,69-to 7.61 (m, 1H), 7,50-the 7.43 (m, 2H), 7,37 (d, 1H), 7,17-7,05 (m, 2H), 2,78 (s, 3H), of 2.30 (s, 3H), 2,24 (s, 3H).

Example 18

(5-Chloro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 1, step 1, but substituting 5-fluoro-2-methylindol 5-chloro-2-methylindol, get 5-chloro-2-methylindol-1-ylamine in the form of solids. MS: 181 (M+H).1H NMR (300 MHz, CDCl3): δ 7,46-the 7.43 (m, 1H), 7,27-7,24 (m, 1H), 7,12-to 7.09 (m, 1H), 6,10 (s, 1H), of 4.44 (USS, 2H), 2,44 is 2.43 (m, 3H).

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (379 g of 1.63 mmol), HOTT (662 mg, 1.78 mmol) and DIPEA (800 μl, 4,58 mmol) in DMF (10 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-chloro-2-methylindol-1-ylamine (274 mg, of 1.52 mmol). The resulting mixture is stirred at a temperature of 80°C during the night. The mixture is cooled and partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to obtain(5-chloro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(93 mg, 16%) as a solid. MS: 395 (M+H).1H NMR (300 MHz, DMSO-d6): δ 11,83 (s, 1H), 9,27 (s, 1H), with 8.33 (d, 1H), 8,20-of 8.15 (m, 1H), 7,69-to 7.61 (m,1H), 7,56 (d, 1H), 7,50-the 7.43 (m, 2H), 6,36 (s, 1H), 2,78 (s, 3H), is 2.37 (s, 3H).

Example 19

(5-Bromoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 1, step 1, but substituting 5-fluoro-2-methylindol 5-bromoindole get5-bromoindole-1-ylaminein the form of solids. MS: 211 (M+H).1H NMR (300 MHz, CDCl3): δ 7,71-of 7.70 (m, 1H), 7,29-7,28 (m, 2H), 7,13 (d, 1H), 6,32 of 6.31 (m, 1H), 4,73 (USS, 2H).

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (596 g, 2.57 mmol), PyAOP (2,63 mmol) and DIPEA (830 μl, of 4.75 mmol) in DHM (20 ml) was stirred at room temperature in a stream of N2within 10 minutes To a mixture of 5-bromoindole-1-ylamine (500 mg, is 2.37 mmol). The resulting mixture was stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 2% EtOAc in heptane, to obtain(5-bromoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(246 mg, 24%) as a solid. MS: 425 (M) and 427 (M+2).1H NMR (300 MHz, DMSO-d6): δ 12,02 (s, 1H), 9,24 (s, 1H), 8.34 per (d, 1H), 8,20-of 8.15 (m, 1H), to 7.84 (d, 1H), 7.68 per-to 7.61 (m, 1H), to 7.59 (d, 1H), 7,50-the 7.43 (m, 2H), 7,35 (the d, 1H), to 6.57 (DD, 1H), 2,78 (s, 3H).

Example 20

Benzyl ester of 3-oxo-4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acid

Stage 1. In accordance with the methods described in M. A. Brook, T. H. Chan, Synthesis 1983, (3), 201-204, getethyl ester benzyloxycarbonylamino acid(95%). MS: 238 (M+H);1H NMR (300 MHz, CDCl3), δ 7.24 to 7,41 (m, 5H), 5,20 lower than the 5.37 (USS, 1H), 5,13 (s, 2H), 4,21 (kV, J=7,0 Hz, 2H), 3.96 points (USD, J=5.3 Hz, 2H), 1.27mm (t, J=7,1 Hz, 3H).

Stage 2. In accordance with the methods described in P. Shenbagamurthi, H.A. Smith, J.M. Becker, F. Naider, J. Med Chem. 1986, 29 (5), 802-809; R.K. Olsen J. Org. Chem. 1970, 35 (6), 1912-1915, getethyl ether (aliventiasylum)acetic acidliquid (92%). MS: 278 (M+H);1H NMR (300 MHz, CDCl3), δ 7,17-7,41 (m, 5H), 5,70-5,88 (m, 1H), 5,06-a 5.25 (m, 4H), was 4.02-to 4.23 (m, 2H), 3,81-was 4.02 (m, 4H), 1,10-1,30 (m, 3H).

Stage 3. To a solution of AD-mix-β (2,54 g) at 0°C in a mixture of tert-butanol (10 ml) and water (12 ml) add a solution of ethyl ether (aliventiasylum)acetic acid (0.52 g, at 1.91 mmol) in tert-butanol (2.00 ml). The reaction mixture was gradually warmed to room temperature over 2 hours and stirred at room temperature for 20 hours. Excess oxidant quenched by the addition of Na2SO3(2.58 g, 20,44 mmol) and the mixture is intensively stirred for 4 hours. The mixture is extracted with EtOAc (50 ml) and the organic fra is tion was washed with saturated aqueous NaCl (2×30 ml). The organic solution is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (1:1:1 EtOAc:DHM:heptane by gradient elution with 50:50 DHM:EtOAc) to obtainethyl ester [benzyloxycarbonyl-(2,3-dihydroxypropyl)amino]acetic acidin the form of oil (0,276 g, 46%). MS: 312 (M+H);1H NMR (300 MHz, CDCl3), δ 7,20-7,40 (m, 5H), of 5.05-by 5.18 (m, 2H), 3.95 to of 4.25 (m, 4H), 3,80-3,95 (m, 1H), 3,20-of 3.80 (m, 11H), 1,11-of 1.35 (m, 3H). (See H.Takahata, H.Ouchi, M.Ichinose, H.Nemoto Org. Lett. 2002, 4 (20), 3459-3462 and additional materials; J.Gonzalez, C.Aurigemma, L.Truesdale Org. Synth. 2002, 79, 93-102).

Stage 4. To a solution of ethyl ester [benzyloxycarbonyl-(2,3-dihydroxypropyl)amino]acetic acid (1.98 g, 6,37 mmol) in DHM (30 ml) was added silica gel impregnated NaIO4(13,04 g). The suspension is intensively stirred for 4.5 hours and then filtered through a porous sintezirovannoi glass funnel. The filtrate is concentrated to obtainethyl ester [benzyloxycarbonyl-(2-oxoethyl)amino]acetic acid(1.65 g, 92%). MS: 280 (M+H);1H NMR (300 MHz, CDCl3), δ 9,60-9,68 (m, 1H), 7,26-7,40 (m, 5H), 5,10-5,19 (m, 2H), 4,00-4,22 (m, 6H), 1.18 to 1.30 on (m, 3H). (see Y.-L. Zhong, T.K.M. Shing J. Org. Chem. 1997, 62 (8), 2622-2624).

Stage 5. N-aminophthalimide (0.55 g, 3.4 mmol) are added to a solution of ethyl ester [benzyloxycarbonyl-(2-oxoethyl)amino]acetic acid (0,72, 2.6 mmol) in 1,4-dioxane (10 ml) and the mixture is boiled with a reverse holodilniki is in the current of the N 2within 15 hours. The reaction mixture is cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated. The residue re-dissolved in CHCl3(30 ml) and again filtered through diatomaceous earth. The resulting filtrate is concentrated to obtainethyl ether (benzyloxycarbonyl-{2-[(E)-1,3-dioxo-1,3-dihydroindol-2-elimina]ethyl}amino)acetic acid((~100%). MS: 424 (M+H);1H NMR (300 MHz, CDCl3), δ 8,77-8,88 (m, 1H), 7,80-to 7.93 (m, 2H), to 7.67-7,80 (m, 2H), 7.23 percent-7,40 (m, 5H), 5,09-to 5.21 (m, 2H), 4,25 is 4.45 (m, 2H), 3,97-of 4.25 (m, 4H), 1,12-of 1.32 (m, 3H).

Stage 6. A solution of ethyl ester (benzyloxycarbonyl-{2-[(E)-1,3-dioxo-1,3-dihydroindol-2-elimina]ethyl}amino)acetic acid (7.7 mmol) in CH3CN (65 ml) is treated with cyanoborohydride sodium (1.92 g, 30,5 mmol) and add acetic acid (6.8 ml, of 118.8 mmol) while stirring in a stream of N2. After 5.5 hours, the reaction mixture was diluted with EtOAc (150 ml) and washed with saturated aqueous KHCO3(3×50 ml) and saturated aqueous NaCl (50 ml). The organic fraction is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (using a gradient elution of 75:25 to 50:50 heptane:ethyl acetate) to obtainethyl ester {benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydroindol-2-ylamino)ethyl]amino}acetic acidin the form of oil (2.66 g, 81%). MS: 426 (M+H); 1H NMR (300 MHz, CDCl3), δ 7,79-to $ 7.91 (m, 2H), 7,69-7,79 (m, 2H), 7,17-7,39 (m, 5H), 5,04-to 5.21 (m, 2H), 4,87-5,04 (m, 1H), 4.04 the-to 4.23 (m, 4H), 3,48-3,59 (m, 2H), 3,18-to 3.38 (m, 2H), 1,10-1,30 (m, 3H).

Stage 7. The solution {benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydroindol-2-ylamino)ethyl]amino}acetic acid (0,22 g, 0.52 mmol) in diphenyl ether (3 ml) is refluxed for 2 hours. Diphenyl ether is removed by vacuum distillation and the residue purified flash chromatography on silica gel (using a gradient elution of 2:1:1 : 1:1:1 heptane:DHM:EtOAc) to obtainbenzyl ester of 4-(1,3-dioxo-1,3-dihydroindol-2-yl)-3-oxopiperidin-1-carboxylic acidin the form of a solid (0.126 g, 64%). MS: 380 (M+H);1H NMR (300 MHz, CDCl3), δ 7,86-to 7.95 (m, 2H), 7,75-7,86 (m, 2H), 7.24 to 7,42 (m, 5H), 5,20 (s, 2H), 4,42 (s, 2H), 3,90-of 4.05 (m, 2H), 3,65-a 3.87 (m, 2H).

Stage 8. To a solution of benzamidomethyl hydrate (2 mmol) in anhydrous DMF (4 ml) addsodium salt of methyl ester of 2-dimethoxymethyl-3-hydroxyacrylates acid(0,46 g, 2.32 mmol) and the reaction mixture is heated at a temperature of 100°C under N2within 1 hour. The reaction mixture is cooled to room temperature and add water (15 ml). After adding water immediately see the precipitation of the product. The solid is collected by filtration, washed with water (2.5 ml) and dried in vacuum to obtainmethyl ester 2-phenylpyrimidine-5-carboxylic acid(0.32 g, 74%). (see: P. Zhichkin, D.J. Fairfax, S.A. Eisenbeis, Synthesis, 2002, 720-722.)

Stage 9. Solutionmethyl ester 2-phenylpyrimidine-5-carboxylic acid(3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF and water (1:1:1 by volume), 120 ml) was stirred at room temperature overnight. MeOH and THF is evaporated to obtain an aqueous solution. The aqueous solution acidified with 5% hydrochloric acid to adjust pH in the range between 2.5 and 3. The precipitate is filtered and washed with water, dried in vacuum, to obtain 2,94 g (~100%)2-phenylpyrimidine-5-carboxylic acidin the form of solids. MS: 201 (M+H).

Stage 10. A solution of benzyl ester of 4-(1,3-dioxo-1,3-dihydroindol-2-yl)-3-oxopiperidin-1-carboxylic acid (53 mg, 0.14 mmol) in MeOH (10 ml) is treated with anhydrous hydrazine (0.3 ml, of 9.56 mmol). The reaction mixture was stirred under reflux in a stream of N2within 3.5 hours, the Reaction mixture was concentrated. The residue is dissolved in a mixture of DMF (2 ml) and DHM (2 ml) and treated with 2-phenylpyrimidine-5-carbonylchloride (32 ml, 0.15 mmol). The mixture is stirred in a stream of N2for 16 h and then dissolved in EtOAc (35 ml). The mixture was sequentially washed with saturated aqueous KHCO3(15 ml), water (2×15 ml) and saturated aqueous NaCl (15 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel (gradient through suirou is of 80:20 to 0:100 heptane:EtOAc) to obtain benzyl ester 3-oxo-4-[2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acidin the form of oil (111 mg, 18%). MS: 432 (M+H);1H NMR (300 MHz, CDCl3), δ 9,70-10,10 (ush., 1H), 9,06 (s, 2H), 8,46 (DD, J=7,8, 1.7 Hz, 2H), 7,44-of 7.60 (m, 3H), 7,25-7,40 (m, 5H), is 5.18 (s, 2H), 4,36 (s, 2H), 3,93 (t, J=5,1 Hz, 2H), 3,69-3,81 (USS, 2H). IC50=103,5 nm.

Example 21

(3-Dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of 5-farindola (5,4 g) and toluene-4-sulphonylchloride (9,12 g (in toluene) (300 ml) is treated with a cooled solution of pellets of sodium hydroxide (23,2 g) in water (200 ml), followed by treatment of the catalyst tetrabutylammonium hydrosulfate (400 ml). The mixture is stirred at room temperature for 24 hours of the Organic fraction was separated, washed with water and brine, dried (MgSO4) and concentrated in vacuo to obtain5-fluoro-1-(toluene-4-sulfonyl)-1H-indole(10.7 g, 78%). MS: 290 (M+H).

Stage 2. A solution of 5-fluoro-1-(toluene-4-sulfonyl)indole (5,2 g) in dry CH3CN (80 ml) cooled in an ice bath and added dropwise chlorosulfonic acid (12 ml). The reaction mixture is heated to room temperature and stirred for 24 h, the Reaction mixture was carefully poured onto ice/water (300 ml). The precipitate is collected by filtration and washed with water to obtain5-fluoro-3-chlorosulfonyl-1-(tol the ol-4-sulfonyl)-1H-indole (6.8 g, 98%) as a solid. MS: 386 (M-H).

Stage 3. A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (2,52 g) in DHM (75 ml) is added to aqueous solution of dimethylamine (40%, 20 ml) in water (50 ml) and stirred at room temperature for 20 hours the Organic fraction was separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to obtaindimethylamide 5-fluoro-1-(toluene-4-sulfonyl)-1H-indole-3-sulfonic acid(2.55 g, 99%) as a solid. MS: 397 (M+H).

Stage 4. A mixture of dimethylamide 5-fluoro-1-(toluene-4-sulfonyl)indole-3-sulfonic acid (2.55 g) in MeOH (100 ml) and 5N. KOH (15 ml) is refluxed for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue is dissolved with water (50 ml) and acidified with aqueous 10h HCl solution to pH ~3. The mixture is extracted with EtOAc. The organic fraction was separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to obtaindimethylamide 5-fluoro-1H-indol-3-sulfonic acid(1.35 g, 87%) as a solid. MS: 241 (M-H).

Stage 5. The solution dimethylamide 5-fluoro-1H-indol-3-sulfonic acid (1.24 g) in dry DMF (50 ml) cooled to 0°C and treated in portions of 60%oil dispersion MaH (of 3.07 g). The mixture is stirred at 0°C for 30 minutes To the mixture in portions hydroxyl is in-O-sulfonic acid (2.9 g) and the mixture is heated to room temperature and stirred for 5 hours. The reaction mixture is poured on ice/water and extracted with EtOAc. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether. The solid is collected by filtration to obtaindimethylamide 1-amino-5-fluoro-1H-indol-3-sulfonic acid(0,53 g, 41%). MS: 258 (M+H).

Stage 6. A solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (76 g) in dry DHM (25 ml)/dry DMF (2 drops) is treated with oxalylamino (0.15 ml) and stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo. The residue is dissolved in toluene (15 ml) and then concentrated in vacuo. The residue is dried under high vacuum and then dissolved in EtOAc (7 ml). The solution is added to a mixture of dimethylamine 1-amino-5-fluoro-1H-indol-3-sulphonic acid (100 mg) and Na2CO3(106 mg) in EtOAc (5 ml)/water (5 ml). The mixture is stirred at room temperature for 24 hours the Organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 50% EtOAc in heptane, to obtain(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(100 mg, 62%) as a solid. MS: 458 (M+H);1H NMR (300 MHz, DMSO-d6): δ to 2.67 (s, 6H), 7,20 of 7.3 (m, 1H), 7,45-of 7.55 (m, 1H, EUR 7.57 and 7.6 (DD, 1H), the 7.65 to 7.75 (m, 2H), and 8.2 (d, 1H), scored 8.38 an 8.4 (d, 2H), 9,45 (s, 2H), and 12.6 (s, 1H).

Example 22

(3-Dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (116 mg) and HATU (190 mg) in dry DMF is treated with DIPEA (0,09 ml) and stirred at room temperature for 40 minutes To the mixture add dimethylamide 1-amino-5-fluoro-1H-indol-3-sulfonic acid (192 mg) and the mixture is stirred at room temperature for 24 h the Mixture was concentrated in vacuo. The residue is dissolved in EtOAc, washed with saturated aqueous 2n. NaOH solution, water and brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30% EtOAc in heptane, to obtain(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)-methylpyrimidin-5-carboxylic acid(85 mg, 40%) as a solid. MS: 472 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 2.68 (s, 6H), and 2.79 (s, 3H), 7,25-7,35 (m, 1H), 7,45-of 7.55 (m, 1H), EUR 7.57-7,80 (m, 3H), to 8.20 (d, 1H), 8,35 (s, 1H), of 8.47 (s, 2H), 9.28 are (s, 1H), 12,40 (s, 1H).

Example 23

[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (1 g) in DHM added to a solution of the research (2.26 and the l) in water (50 ml) and stirred at room temperature for 5 hours The organic fraction was separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to obtain5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole(1.3 g, ~100%). MS: 439 (M+H).

Stage 2. A solution of 5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole (1.3 g) in MeOH (50 ml)/5N KOH (3 ml) is refluxed for 1 hour. The reaction mixture was concentrated in vacuo. The residue is dissolved with water (30 ml) and acidified with aqueous 10h. HCl solution to pH ~4. The mixture is extracted with EtOAc. The organic fraction was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to obtain5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole(0.8 g, 95%) as a solid. MS: 285 (M+H).

Stage 3. In accordance with the methods similar to those described in example 21, step 5, but substituting dimethylamide 5-fluoro-1H-indol-3-sulfonic acid 5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole after purification of the product by chromatography on silica gel by elution with 20% EtOAc get1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole(16%) as a solid. MS: 300 (M+H).

Stage 4. In accordance with the methods similar to those described in example 21, step 6, but substituting dimethylamide 1-amino-5-fluoro-1H-indol-3-sulfonic acid 1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole, get[5-fluoro-3-(Moholy the-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid (27%) as a solid. MS: 500 (M+H).1H NMR (300 MHz, DMSO-d6): δ 2,95 (m, 4H), to 3.67 (m, 4H), 7,25-7,35 (m, 1H), 7,45-of 7.55 (m, 1H), EUR 7.57-of 7.60 (DD, 1H), 7,62-7,72 (kV, 1H), 7,75-7,80 (kV, 1H), to 8.20 (d, 1H), 8,35-to 8.40 (d, 1H), to 8.41 (s, 1H), 9,45 (s, 2H), and 12.6 (s, 1H).

Example 24

[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 22, but replacing dimethylamide 1-amino-5-fluoro-1H-indol-3-sulfonic acid 1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole, get[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(48%) as a solid. MS: 512 (M-H).1H NMR (300 MHz, DMSO-d6): δ 2,80 (s, 3H), 2.95 and (m, 4H), to 3.67 (m, 4H), 7,25-7,35 (m, 1H), 7,45-of 7.55 (m, 1H), EUR 7.57-of 7.60 (m, 1H), 7,62-7,72 (m, 1H), 7,75-7,80 (m, 1H), 8,15-to 8.20 (d, 1H), 8.30 to-8,35 (d, 1H), 8,45 (s, 1H), of 9.30 (s, 1H), and 12.4 (s, 1H).

Example 25

[5-fluoro-3-sulfamoyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of (5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid (0.35 g) in dry CH3CN (20 ml) is treated with chlorosulfonic acid (0.5 ml) and stirred at room temperature for 24 hours the Reaction mixture is poured on ice/water (150 ml) and extracted with EtOAc. The organic fraction was washed with water and salt concrete is, dried (MgSO4), filtered and concentrated in vacuo to obtain5-fluoro-1-{[2-(3-forfinal)pyrimidine-5-carbonyl]amino}-1H-indol-3-sulphonylchloride(of 0.43 g, 95%). MS: 449 (M+H).

Stage 2. A solution of 5-fluoro-1-{[2-(3-forfinal)pyrimidine-5-carbonyl]amino}-1H-indol-3-sulphonylchloride (0.14 g) in DHM treated with an aqueous ammonia solution (28%-5 ml) in water (15 ml) and stirred at room temperature for 24 hours the Reaction mixture is acidified with aqueous 10h. HCl solution to pH ~3 and extracted with DHM. The organic fraction was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 50% EtOAc in heptane, to obtain[5-fluoro-3-sulfamoyl-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid(10 mg, 8%) as a solid. MS: 430 (M+H).1H NMR (300 MHz, DMSO-d6): δ 7,20-7,30 (m, 1H), 7,40-to 7.50 (m, 2H), 7,60-7,72 (m, 2H), 8,10 (s, 1H), 8,19 is 8.22 (d, 1H), 8,33-of 8.37 (d, 1H), 9,44 (s, 1H), 12,45 (s, 1H).

Example 26

[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 25, but substituting aqueous solution of ammonia at 40%aqueous solution of methylamine, get[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(60%) in the form of solid substances is A. MS: 444 (M+H).1H NMR (300 MHz, DMSO-d6): δ of 2.45 (d, 3H), 7,20-7,30 (m, 1H), 7,40-to 7.50 (m, 2H), 7,60-of 7.70 (m, 3H), 8,19 is 8.22 (d, 1H), 8,24 (s, 1H), 8.34 per-of 8.37 (d, 1H), 9,44 (s, 1H), 12,50 (s, 1H).

Example 27

[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 25, but substituting aqueous solution of ammonia to 2-(morpholine-4-yl)ethylamine, get[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(35%). MS: 543 (M+H).1H NMR (300 MHz, DMSO-d6): δ 2,20-of 2.38 (m, 6H), 2,89-2,95 (kV, 2H), 3,40-3,50 (s, 4H), 7,20-7,30 (m, 1H), 7,42-of 7.55 (m, 2H), 7,63-of 7.70 (m, 3H), 8,19 is 8.22 (d, 1H), compared to 8.26 (s, 1H), 8.34 per-of 8.37 (d, 1H), 9,44 (s, 2H), 12,40-12,60 (s, 1H).

Example 28

[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of (5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1 g, a 2.75 mmol) in dry CH3CN cooled to 0°C and treated dropwise chlorosulfonic acid (0,55 ml), then stirred for 2 hours the Precipitate is filtered and washed with ether to obtain5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-3-sulfonic acid(1.06 g, 87%) as a solid substance not quite white. MS: 443 (MH-).

Stage 2. To suspend and 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-3-sulfonic acid (1.06 g) in DHM (60 ml) at 0°C add dry DMF (10 drops). To the mixture is added dropwise oxalicacid (1,05 ml) and the mixture is stirred at 0°C for 3 hours the Mixture is filtered and the resulting solids washed with ether to obtain5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-sulphonylchloride(0,94 g). MS: 461 (M-H).

Stage 3. In accordance with the methods similar to those described in example 25, step 2, but substituting aqueous solution of ammonia at 40%aqueous solution of methylamine and substituting 5-fluoro-1-{[2-(3-forfinal)pyrimidine-5-carbonyl]amino}-1H-indol-3-sulphonylchloride 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-sulphonylchloride get[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(40 mg, 35%) as a solid. MS: 456 (M-H);1H NMR (300 MHz, DMSO-d6): δ of 2.45 (d, 3H), 2,80 (s, 3H), 7,20-7,30 (m, 1H), 7,40-to 7.50 (m, 2H), 7,60-of 7.70 (m, 3H), 8.17-a to 8.20 (d, 1H), 8.30 to-8,35 (d, 2H), 9.28 are (s, 1H), 12,30 (s, 1H).

Example 29

{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 25, step 2, but substituting aqueous ammonia to an aqueous solution of 4-aminomethylpyridine and substituting 5-fluoro-1-{[2-(3-forfinal)pyrimidine-5-carbonyl]amino}-1H-indol-3-sulphonylchloride 5-fluoro-1-{[2-(3-Fortini is)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-sulphonylchloride, get{5-fluoro-[3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acidin the form of solids. MS: 542 (M+H);1H NMR (300 MHz, DMSO-d6): δ 1.00 each-of 1.15 (m, 2H), 1,50-1,70 (m, 3H), 2,60-2,70 (t, 2H), 2,80 (s, 1H), 3,1-3,2 (t, 2H), 3,70-of 3.80 (DD, 2H), 7,20-7,30 (m, 1H), 7,40-to 7.50 (m, 1H), 7,60-of 7.70 (m, 4H), 8,16-to 8.20 (d, 1H), 8,28-to 8.34 (d, 2H), 9.28 are (s, 1H), 12,25 (s, 1H).

Example 30

[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 25, step 2, but substituting aqueous ammonia to an aqueous solution of 2-(morpholine-4-yl)ethylamine and substituting 5-fluoro-1-{[2-(3-forfinal)pyrimidine-5-carbonyl]amino}-1H-indol-3-sulphonylchloride 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-sulphonylchloride get[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(-3-forfinal)-4-methylpyrimidin-5-carboxylic acid(58%). MS: 557 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,20-of 2.30 (s, 4H), 2,30-to 2.40 (t, 2H), 2,80 (s, 3H), 2,89-2,95 (kV, 2H), 3,40-3,50 (s, 4H), 7,20-7,30 (m, 1H), 7,42-of 7.55 (m, 2H), 7,63-of 7.70 (m, 3H), 8.17-a to 8.20 (d, 1H), 8,32-8,35 (d, 2H), 9.28 are (s, 2H), 12,25-12,30 (s, 1H).

Example 31

(4-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. The crude product 1-amino-4-farindola receive in accordance with meth is DAMI, described in J.Hymes et al., J.O.C., (2004), 69, 1368-1371. The crude product is then purified by chromatography on silica gel, elwira 30% DHM in heptane, to obtain1-amino-4-farindola(43%). MS: 151 (M+H).

Stage 2. A solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (0.33 g), HATU (0,67 g) and hydroxyisobutyrate (0.26 g) in dry DMF (15 ml) was stirred at room temperature in a stream of N2within 30 minutes, Add a solution of 1-amino-4-farindola (0.24 g) in dry DMF (5 ml) and then added DIPEA (0,39 ml). The mixture is stirred at a temperature of 80°C for 24 hours, cooled to room temperature and then concentrated in vacuo. The residue is dissolved EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 60% DHM in heptane, to obtain(4-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(0.24 g, 53%) as a solid. MS: 351 (M+H);1H NMR (300 MHz, DMSO-d6): δ only 6.64 (d, 1H), 6.89 in-6,92 (kV, 1H), 7,15-7,22 (m, 1H), 7,31-7,33 (d, 1H), 7,46-7,52 (m, 1H), 7,56 (d, 1H), 7,63-7,70 (kV, 1H), 8,18-8,23 (d, 1H), 8.34 per-of 8.37 (d, 1H), 9,45 (s, 2H), 12,30 (s, 1H). IC50=11 nm.

Example 32

(4-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 31, step 2, but substituting 2-(3-forfinal)pyrimidine-5-Urbanova acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, get(4-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(63%) as a solid. MS: 365 (M-H);1H NMR (300 MHz, DMSO-d6): δ 2,75 (σ, 1H), is 6.61 (d, 1H), 6,86-6,92 (kV, 1H), 7,15-7,22 (m, 1H), 7,30-to 7.32 (d, 1H), 7,40-7,46 (m, 1H), 7,56-the 7.65 (m, 2H), 8,13-is 8.16 (d, 1H), 8,28-8,31 (d, 1H), of 9.21 (s, 1H), 12,05 (s, 1H).

Example 33

(4-Florinda-1-yl)amide 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid

A suspension of 2-(pyridin-2-yl)pyrimidine-5-carbonylchloride (0,44 g) in EtOAc (20 ml) is added in portions to a mixture of 1-amino-4-farindola (0,30 g) and K2CO3(0,276 g) in EtOAc (10 ml)/water (20 ml) and the resulting mixture was stirred at room temperature for 24 hours the Aqueous fraction was separated and extracted with EtOAc twice. The combined organic phase washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira EtOAc to obtain(4-Florinda-1-yl)amide 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid(0,115 g, 17%) as a solid. MS: 334 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 6.65 (d, 1H), 6.89 in-6,95 (kV, 1H), 7,16-of 7.23 (m, 1H), 7,32-to 7.35 (d, 1H), EUR 7.57 (d, 1H), EUR 7.57-to 7.64 (m, 1H), 8,02-8,08 (t, 1H), 8,50-charged 8.52 (d, 1H), 8,82-8,83 (d, 1H), 9,49 (s, 2H), 12,30 (s, 1H).

Example 34

(4-Florinda-1-yl)amide 2-(pyridin-2-yl)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(pyridin-2-yl)-4-ethylpyrimidine-5-carboxylic acid (0.11 g) and HATU (0,19 g) in dry DMF (7 ml) is treated with DIPEA (0,09 ml) and stirred at room temperature in a stream of N 2within 30 minutes To the mixture was added 1-amino-4-Florinda (0,112 g) and the mixture is stirred at room temperature for 24 h the Mixture was concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 75% EtOAc to obtain(4-Florinda-1-yl)amide 2-(pyridin-2-yl)-4-methylpyrimidin-5-carboxylic acid(of 0.085 g, 50%). MS: 348 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,82 (s, 3H), of 6.65 (d, 1H), 6,93-6,97 (kV, 1H), 7,19-7,26 (m, 1H), 7,35-7,38 (d, 1H), 7.62mm (d, 1H), 7,74 for 7.78 (m, 1H), 8,20 is 8.25 (t, 1H), 8,58-8,61 (d, 1H), cent to 8.85-8,86 (d, 1H), was 9.33 (s, 1H), 12,15 (s, 1H).

Example 35

[6-(4-Forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

Stage 1. In accordance with the methods described in F.Chau, J.-C.Malanda, and R.Milcent J.Heterocyclic Chem. 1997, 34, 1603-1606, get5-methyl-3H-1,3,4-oxadiazol-2-he(24%). MS: 101 (M+H);1H NMR (300 MHz, CDCl3) δ 9,76 (USS, 1H), 2,28 (s, 3H).

Stage 2. To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-it (2,77 g, 27.7 mmol) in MeOH (25 ml) was added 25% by weight solution of NaOMe in methanol (6.4 ml of 27.9 mmol) and the mixture is stirred at room temperature for 10 minutes the Mixture was concentrated in vacuo and the residue added to a solution of 2-chloro-4'-fortetienne (4.71 g, 27,3 mmol) and bromide of Tetramethylammonium (0,174 g, 0.54 mmol) in CHCl3 (16 ml). The mixture is refluxed for 2.5 h in a current of N2. The reaction mixture is then cooled and stirred overnight at room temperature. The resulting suspension is filtered through ordinary filter paper and the filtrate concentrated to obtain the liquid. This liquid is filtered through a layer of silica gel, elwira 1:1 EtOAc/DHM. The filtrate was concentrated in vacuo to obtain3-[2-(4-forfinal)-2-oxoethyl]-5-methyl-3H-1,3,4-oxadiazol-2-it(~100%). MS: 237 (M+H);1H NMR (300 MHz, CDCl3) δ of 7.90-8,10 (m, 2H), 7,10-7,22 (m, 2H), to 5.08 (s, 2H), to 2.29 (s, 3H).

Stage 3. To a solution of 3-[2-(4-forfinal)-2-oxoethyl]-5-methyl-3H-1,3,4-oxadiazol-2-she (2.3 g, 9.7 mmol) in a mixture of 2-propanol (12 ml) and water (0.3 ml) is added hydrazine monohydrate (of 0.71 ml, 14.6 mmol). The reaction mixture was refluxed in a stream of N2in the course of 14.5 h and then add a solution of oxalic acid (0.3 g, 3.3 mmol) in 2-propanol (6 ml). The obtained precipitate was separated by filtration. The filtrate is concentrated to about 35 ml and then cooled to obtainN-[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]ndimethylacetamidein the form of crystals collected by filtration (0,83 g, 34%). MS: 251 (M+H);1H NMR (300 MHz, DMSO-d6) δ 10,37 (s, 1H), 10,16 (s, 1H), 7,65-7,79 (m, 2H), 7,16-7,27 (m, 2H), 4,57 (s, 2H), 1,90 (s, 3H).

Stage 4. To a suspension of N-[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]ndimethylacetamide (of 0.48 g, 1.9 mmol who) in MeOH (5 ml) was added 37%aqueous HCl solution. The mixture is refluxed for 3 h and then cooled to room temperature. The mixture is alkalinized 1M aqueous NaOH solution to pH ~12. The precipitate is collected by filtration and dried to obtain4-amino-6-(4-forfinal)-4,5-dihydro-2H-1,2,4-triazine-3-one(0.35 g, 88%). MS: 209 (M+H);1H NMR (300 MHz, DMSO-d6) δ 10,17 (s, 1H), to 7.67 to 7.75 (m, 2H), 7.18 in-7,29 (m, 2H), and 4.75 (s, 2H), of 4.45 (s, 2H).

Stage 5. To a suspension of 4-amino-6-(4-forfinal)-4,5-dihydro-2H-1,2,4-triazine-3-one (0.26 g, of 1.23 mmol), 2-phenylpyrimidine-5-carboxylic acid (0.25 g, of 1.23 mmol) and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,37 g, 1.94 mmol) in DMF (12 ml) was added Et3N (0.2 ml, to 1.435 mmol) in current of the N2and the reaction mixture was stirred at room temperature for 49 hours the Mixture is diluted with EtOAc (120 ml) and sequentially washed with saturated aqueous NH4Cl (2×50 ml), water (2×50 ml) and saturated aqueous NaCl (50 ml). The organic fraction is dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated with EtOH (30 ml) to obtain a[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(0.12 g, 25%). MS: 391 (M+H);1H NMR (300 MHz, DMSO-d6) δ of 11.25 (s, 1H), of 10.58 (s, 1H), 9,31 (s, 2H), of 8.47 (DD, J=7,7, 1.8 Hz, 2H), 7,70-7,86 (m, 2H), 7,49-to 7.67 (m, 3H), 7.18 in-7,34 (m, 2H), 4,77.

Example 36

[4-(2-Hydroxyethyl)piperazine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carbon is Oh acid

To a solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (0.28 g, 1.4 mmol) in anhydrous DHM (10 ml) at 0°C add oxalicacid (of 0.18 ml, 1.4 mmol), followed by addition of DMF (0,11 ml). The mixture is stirred at 0°C for 30 min and then warmed to room temperature and stirred for 30 minutes the Mixture was concentrated in vacuo. The residue is dissolved in anhydrous DHM (10 ml). 2-(4-Aminopiperidin-1-yl)ethanol (0,145 g, 1 mmol) is added at room temperature, followed by addition of NMP (to 0.19 ml, 2 mmol). The mixture is stirred at room temperature for 2 h and then the mixture was concentrated in vacuo. The residue is triturated with Et2O and the resulting solid collected by filtration to obtain[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid(0.16 g). MS: 346 (M+H).

Example 37

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

To a solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (MX 0.317 g, 1,45 mmol) in anhydrous DMF (5 ml) is added 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazine-3-one (0,206 g, 1,45 mmol), followed by the addition DMTMM (0,421 g of 1.52 mmol). The mixture is stirred at room temperature overnight. The mixture is partitioned between saturated in the s ' solution of NaHCO 3and EtOAc. The organic fraction was separated, dried (MgSO4), filtered and concentrated in vacuo to obtain(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(0,306 g) as a solid. MS: 329 (M+H).

Example 38

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of (5-fluoro-1H-indol-3-yl)acetic acid (1 g, 5.2 mmol) in MeOH (20 ml) is treated with sulfuric acid (20 ml) and stirred at room temperature for 1 h the mixture was treated with 10%aqueous solution of NaHCO3(200 ml) and then concentrated in vacuo to obtainmethyl ester (5-fluoro-1H-indol-3-yl)acetic acidthat is used in the next stage without additional purification. MS: 208 (M+H);1H NMR (300 MHz, CD3OD): δ 3,68 (s, 3H), and 3.72 (s, 2H), 6,86 (m, 1H), 7,16 (m, 1H), 7,21 (s, 1H), 7,28 (m, 1H).

Stage 2. The above methyl ester (5-fluoro-1H-indol-3-yl)acetic acid dissolved in THF (40 ml), cooled to 0°C and treated with MeMgBr (18.5 ml, 26 mmol, 1,4M in PhMe/THF (3:1)). The mixture is stirred at room temperature for 12 hours Add an additional amount of MeMgBr (5 ml, 7 mmol) and the mixture is stirred at room temperature for 6 hours the Mixture was poured on ice/water and extracted with EtOAc (100 ml), dried (Na SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20%-70% EtOAc in heptane, to obtain1-(5-fluoro-1H-indol-3-yl)-2-methylpropan-2-ol(0.65 g, 60%). MS: 208 (M+H);1H NMR (300 MHz, CDCl3): δ 1.28 (in, 6H), 2,87 (s, 2H), 6,94 (m, 1H), 7,14 (m, 1H), 7,26-7,30 (m, 2H).

Stage 3. Solution1-(5-fluoro-1H-indol-3-yl)-2-methylpropan-2-ol(207 mg, 1 mmol) in DMF (10 ml) cooled to 0°C, treated with NaH (600 mg, 15 mmol, 60% in mineral oil) and stirred for 30 minutes To the mixture portions H2NOSO3H (565 mg, 5 mmol) and the mixture is heated to room temperature within 2 hours the Mixture is diluted with EtOAc (100 ml), quenched with water and extracted with EtOAc, dried (Na2SO4), filtered and concentrated in vacuo to obtain1-(1-amino-5-Florinda-3-yl)-2-methylpropan-2-olthat is used in the next stage without additional purification.

Stage 4. A solution of 2-(3-forfinal)pyrimidine-5-carboxylic acid (175 mg, 0.8 mmol) in DHM (5 ml) is treated with DMF (20 ml) and ClCOCOCl (348 μl, 4 mmol) and stirred at room temperature for 3 hours To a mixture of toluene (10 ml) and the mixture was concentrated in vacuo. The residue added to a solution of the above 1-(1-amino-5-Florinda-3-yl)-2-methylpropan-2-ol and Na2CO3(1 g) in EtOAc/H2O (20 ml, 1:1). The mixture is stirred at room temperature for 12 hours the mixture is Then diluted with saturated is electroplated in an aqueous solution of Na 2CO3and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30%-50% EtOAc in heptane, to obtain[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid(160 mg, 50%). MS: 423 (M+H);1H NMR (300 MHz, DMSO-d6): δ 1.14 in (s, 6H), 2,77 (s, 2H), 7,03 (m, 1H), 7,33 (s, 1H), 7,35-of 7.55 (m, 3H), of 7.65 (m, 1H), 8,21 (m, 1H), at 8.36 (m, 1H), 9,43 (s, 2H).

Example 39

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Solution2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (250 mg, 1.07 mmol) in DHM (10 ml) cooled to 0°C, treated with DMF (20 ml) and ClCOCOCl (280 μl, is 3.21 mmol) and stirred for 20 minutes To a mixture of toluene (10 ml) and the mixture was concentrated in vacuo. The residue is dissolved in pyridine (10 ml) and treated with DMAP (5 mg) and 1-(1-amino-5-Florinda-3-yl)-2-methylpropan-2-I (to 0.72 mmol). The mixture is stirred at room temperature for 12 hours the Mixture is diluted with saturated aqueous Na2CO3and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20%-60% EtOAc in heptane, to obtain[5-fluoro-3-(2-hydroxy-2-meth is propyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (218 mg, 70%). MS: 437 (M+H);1H NMR (300 MHz, DMSO-d6): δ 1.14 in (s, 6H), 2,77 (s, 2H), 3,29 (s, 3H), 7,03 (m, 1H), 7,37 (s, 1H), 7,35-of 7.55 (m, 3H), of 7.65 (m, 1H), 8,19 (m, 1H), 8.34 per (m, 1H), which 9.22 (s, 1H).

Example 40

[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (748 mg, of 3.48 mmol) in DMF (30 ml) was treated with HATU (1.3 g, of 3.48 mmol) and DIPEA (1.2 ml, of 6.96 mmol) and the mixture is stirred at room temperature for 30 minutes To the mixture was added 1-(1-amino-5-Florinda-3-yl)-2-methylpropan-2-ol (2.9 mmol) and the mixture is stirred at a temperature of 80°C for 12 hours The mixture is diluted with EtOAc, washed with saturated aqueous NH4Cl and saturated aqueous Na2CO3, dried (Na2SO4), filtered and concentrated in vacuo to obtain[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(990 mg, 81%). MS: 420 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 1.13 (s, 6H), to 2.75 (s, 2H), 2,85 (s, 3H), at 6.84 (m, 1H), 7,24 (m, 1H), 7,37 (m, 1H), 7,53 (m, 1H), 7,95 (s, 1H), 7,98 (m, 1H), 8,44 (m, 1H), 8,76 (m, 1H), 9.15, with (s, 1H).

Example 41

(3-Cyano-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of (5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (300 mg, 0,82 shall mol) in THF (8 ml) cooled to 0°C, process chlorosulfonylisocyanate (86 μl, 0,99 mmol) and the mixture is stirred at room temperature for 1 h the Mixture was treated with Et3N (138 μl, 0,99 mmol) and stirred for 1 h the Mixture is diluted with brine and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 25%-35% EtOAc in heptane, to obtain(3-cyano-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(120 mg, 38%). MS: 390 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,78 (s, 3H), 7,32 (m, 1H), 7,46 (m, 1H), 7,55 (m, 1H), 7,66 (m, 1H), to 7.77 (m, 1H), to 8.20 (m, 1H), 8,35 (m, 1H), 8,65 (s, 1H), 9.28 are (s, 1H).

Example 42

[5-fluoro-3-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of (3-cyano-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (120 mg, 0.31 mmol), TMSN3(62 μl, 0,465 mmol) and TBAF (0,155 μl, 0,155 mmol, 1M in THF) in toluene (3 ml) is heated at a temperature of 80°C for 18 hours the Mixture is cooled, diluted with EtOAc and washed with 1M HCl. The organic phase is extracted with Na2CO3. The aqueous phase is acidified to pH ~3 aqueous 3n HCl solution and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtain[5-fluoro-3-(1H-tetraz is l-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (100 mg, 75%). MS: 433 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 2.81 (s, 3H), 7,28 (m, 1H), 7,47 (m, 1H), to 7.67 (m, 1H), 7,73 (m, 1H), 8,01 (m, 1H), 8,21 (m, 1H), 8,33 (m, 1H), at 8.36 (s, 1H), was 9.33 (s, 1H). IC50=5 nm.

Example 43

2-Phenylpyrimidine-5-carboxylic acid [1,2,4]triazole-4-alamid

To a solution of 2-phenylpyrimidine-5-carboxylic acid (300 mg, 1.5 mmol) in DHM (10 ml) was added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (316 mg, of 1.65 mmol) and N-hydroxybenzotriazole (223 mg, of 1.65 mmol) at room temperature and the mixture is stirred for 10 minutes To a mixture of 4-amino-4H-1,2,4-triazole (252 mg, 3 mmol) and the mixture is stirred at room temperature for 3 days. The precipitate is filtered, washed with DHM and water and dried in a vacuum oven at 40°C overnight to obtain[1,2,4]triazole-4-ylamide 2-phenylpyrimidine-5-carboxylic acid(270 mg) as a solid. MS: 267 (M+H);1H NMR (300 MHz, DMSO): δ = to 7.59 (m, 3H), and 8.50 (d, 2H), 8,84 (s, 2H), 9,36 (s, 2H). IC50= 262,5 nm.

Example 44

Piperidine-1-alamid 2-phenylpyrimidine-5-carboxylic acid

Method A: to a solution of 2-phenylpyrimidine-5-carboxylic acid (150 mg, 075 mmol) in DHM (10 ml) was added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (158 mg, 0.83 mmol) and N-hydroxybenzotriazole (112 mg, 0.83 mmol) at room temperature and the mixture is stirred for 10 minutes To the mixture was added 1-aminopiperidine (150 mg, 1.5 mmol). The mixture is stirred at room temperature overnight. The mixture was washed with aqueous 2n HCl solution (5 ml), saturated aqueous NaHCO3(5 ml) and water (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% EtOAc in heptane, to obtainpiperidine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid(125 mg) as a solid. MS: 290 (M+H).

Method B: In accordance with the methods similar to that described in example 127, but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid piperidin-1-ylamine, getpiperazin-1-alamid 2-phenylpyrimidine-5-carboxylic acid(72%) as a solid. MS: 283 (M+H);1H NMR (300 MHz, CDCl3): δ 1,35-to 1.98 (m, 6H), 2,20-of 3.60 (m, 4H), 6,60-7,17 (l, N-H), 7,52 (s, 3H), charged 8.52 (s, 2H), 9,07-9,39 (d, 2H).

Example 45

N'-(2-Forfinal)hydrazide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 44, but replacing 1-aminopiperidine (2-forfinal)hydrazine, getN'-(2-forfinal)hydrazide 2-phenylpyrimidine-5-carboxylic acidin the form of solids. MS: 309 (M+H);1H NMR (300 MHz, CDCl3): δ 6,68 (ush., 1H), 6.87 in (m, 1H),? 7.04 baby mortality (m, 3H), 7,51 (m, 3H), 8,51 (m, 2H), 9,36 (s, 2H), 10,65 (ush., 1H). IC50=12 n is.

Example 46

N'-Ethyl-N'-tolylhydrazine 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 44, but replacing 1-aminopiperidin N-ethyl-N-paratool-hydrazine, getN'-ethyl-N'-tolylhydrazine 2-phenylpyrimidine-5-carboxylicacid in the form of solids. MS: 333 (M+H);1H NMR (300 MHz, CDCl3): δ = 0,87 (t, 1H), 1,11 (t, 2H), 1.28 (in t, 3H), 2,28 (d, 3H), 3.46 in (kV, 1H), 3,65 (kV, 1H), at 6.84 (d, 1H), 6,94 (d, 1H), 7,10 (t, 2H), 7,52 (m, 3H), of 8.47 (m, 2H), 9,12 (s, 1H), 9,23 (s, 1H).

Example 47

(3-Exmortis-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 44, but replacing 1-aminopiperidin 4-aminomorpholine-3-one, get(3-exmortis-4-yl)amide 2-phenylpyrimidine-5-carboxylic acidin the form of solids. MS: 299 (M+H);1H NMR (300 MHz, DMSO): δ = 3,66 (m, 2H), 4.00 points (m, 2H), 4.26 deaths (s, 2H), 7,60 (m, 3H), of 8.47 (m, 2H), 9,29 (s, 2H), 11,27 (s, 1H). IC50= 55 nm.

Example 48

[4-(2-Hydroxyethyl)piperazine-1-yl]amide of 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid

Stage 1. To a solution of methyl ester 2-methylsulfonylamino-5-carboxylic acid 1 (1 g, 5.43 mmol) in DHM (60 ml) is added by portions MCPBA (2,81 g, 16,29 mmol) at room temperature. The resulting solution of paramashiva the t at room temperature over night. To the mixture add a solution of Na2S2O3(1.6 g) in water (60 ml). The mixture is stirred at room temperature for 20 minutes Phase is separated and the aqueous phase extracted with DHM (2×20 ml). Combined phase DHM washed with a saturated solution of NaHCO3(3×20 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester 2-methanesulfonamido-5-carboxylic acidin the form of a solid substance (of 1.05 g, 90%). MS: 217 (M+H);1H NMR (300 MHz, CDCl3): δ is 3.41 (s, 3H), 4,06 (s, 3H), 9,44 (s, 2H).

Stage 2. To a solution of methyl ester 2-methanesulfonamido-5-carboxylic acid 2 (2.5 g, to 11.56 mmol) in DHM (30 ml) is added slowly a solution of tetrabutylammonium cyanide (3.1 g, to 11.56 mmol) in water (30 ml) at room temperature. The mixture is stirred for 80 minutes, the Mixture washed with water (2×20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified column chromatography, elwira 5-60% EtOAc in heptane, to obtainmethyl ester 2-cyanopyrimidine-5-carboxylic acid(1,16 g, 61%) as a solid. MS: 164 (M+H);1H NMR (300 MHz, CDCl3): δ of 4.05 (s, 3H), 9,37 (s, 2H).

Stage 3. To a solution of methyl ester 2-cyanopyrimidine-5-carboxylic acid 3 (1 g, 6,13 mmol) in MeOH (20 ml) at room temperature add hydroxylamine hydrochloride (0.64 g, 9.2 mmol) and sodium acetate (0,76 g, 9.2 mmol). Recip is nnow the mixture is refluxed for 2 hours. The mixture is cooled to room temperature and concentrated in vacuo. To the precipitate add water (30 ml), the solid is filtered and washed with water twice. The solid is dried in a vacuum oven overnight to obtainmethyl ester of 2-(N-hydroxycarbonylmethyl)pyrimidine-5-carboxylic acid(1,09 g, 91%) as a solid. MS: 197 (M+H).

Stage 4. To a solution of methyl ester of 2-(N-hydroxycarbonylmethyl)pyrimidine-5-carboxylic acid (900 mg, 4,59 mmol) in pyridine (15 ml) added dropwise acetylchloride (432 mg, 5.5 mmol). The resulting solution was stirred at room temperature for 1 hour and refluxed for 3 hours. The solution is cooled to room temperature and concentrated in vacuo. To the precipitate add water (30 ml) and the mixture extracted with EtOAc (3×20 ml). The combined organic phase was washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester of 2-(5-methyl-[1,2,3]oxadiazol-3-yl)pyrimidine-5-carboxylic acid(900 mg, 89%) as a solid. MS: 221 (M+H).

Stage 5. To a solution of methyl ester of 2-(5-methyl-[1,2,3]oxadiazol-3-yl)pyrimidine-5-carboxylic acid (900 mg) in MeOH (20 ml) is added a solution of LiOH (100 mg) in water (20 ml) at 0°C. the ice bath is Removed and the mixture is stirred for further 10 minutes the Solvent is evaporated dobavlaut water (20 ml). The aqueous solution washed with ether (2×20 ml) and acidified with 2n. HCl to pH ~3. The precipitate is filtered, washed with water and dried in a vacuum oven overnight to obtain2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid(350 mg, 37%) as a solid. MS: 207 (M+H);1H NMR (300 MHz, DMSO-d6): δ by 2.73 (s, 3H), 9,39 (s, 2H).

Stage 6. In accordance with the methods similar to those described in example 44, but replacing 2-phenylpyrimidine-5-carboxylic acid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid, and substituting 1-aminopiperidin 2-(4-aminopiperidin-1-yl)ethanol, get[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acidin the form of solids. MS: 334 (M+H). IC50=461 nm.

Example 49

Morpholine-4-alamid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 44, but replacing 2-phenylpyrimidine-5-carboxylic acid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid, and substituting 1-aminopiperidin on morpholine-4-ylamine, getmorpholine-4-alamid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acidin the form of solids. MS: 291 (M+H).

Example 50

Morpholine-4-alamid 2-benzoylpyridine-5-carboxylic acid

Stage 1. 5-Bromo-2-chloropyrimidine (7.51 g, 38,83 mmol) dissolved in DMSO (20 ml), is added to a mixture of NaCN (1.9 grams, 38,83 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.87 g, to 7.77 mmol) in DMSO (10 ml) and water (20 ml). The mixture is stirred at room temperature over night and then add water (100 ml). The mixture is extracted with ether (3×100 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain5-bromopyrimidine-2-carbonitrile(6,28 g, 88%) as a solid. MS: 184 (M+H).

Stage 2. 5-Bromopyrimidine-2-carbonitrile (2.5 g, 13,59 mmol) dissolved in ether (30 ml) and added dropwise PhMgBr (3 the ether solution, 13,59 mmol, 4,53 ml) at room temperature. The mixture is refluxed for 3 h in a current of N2and then cooled to room temperature. To the mixture is added THF (30 ml), followed by the addition of aqueous 2n. HCl solution (10 ml). The resulting solution was stirred at room temperature for 30 min and add water (30 ml). The aqueous phase is extracted with EtOAc (3×20 ml). The combined organic phase was washed with saturated aqueous NaHCO3(15 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 70% EtOAc in heptane, to obtain(5-bromopyrimidine-2-yl)phenylmethanone(3,01 g, 84%) as a solid. MS: 264 (M+H).

stage 3. (5-Bromopyrimidine-2-yl)phenylmethanone (1.6 g, between 6.08 mmol) dissolved in dimethylacetamide (20 ml) and add the trihydrate of hexacyanoferrate(II) potassium (0,57 g of 1.34 mmol), followed by addition of Na2CO3(0.64 g, between 6.08 mmol) and palladium(II) acetate (68 mg, 0.3 mmol). The mixture is heated to 150°C in a stream of N2for 3 h and then cooled to room temperature. Add EtOAc (30 ml) and the mixture filtered. The filtrate is washed with water (2×15 ml) and 5%aqueous solution of NH4OH (15 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 70% EtOAc in heptane, to obtain2-benzoylpyridine-5-carbonitrile(0,53 g, 42%) as a solid. MS: 210 (M+H).

Stage 4. 2-Benzoylpyridine-5-carbonitrile (500 mg, 2,39 mmol) suspended in MeOH (5 ml), add one portion a solution of KOH (148 mg, 2,63 mmol) in water (5 ml) at 0°C. the Mixture is stirred at 0°C for 25 min and then acidified with aqueous 2n. HCl solution to pH ~3. MeOH is evaporated in vacuum and the residue extracted with DHM (2×5 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester 2-benzoylpyridine-5-carboxylic acid(500 mg, 86%) as oil. MS: 243 (M+H);1H NMR (300 MHz, CDCl3): δ of 4.05 (s, 3H), 7,50 (m, 2H), 7,65 (m, 1H), 8,01 (m, 2H), 9,46 (s, 2H).

Stage 5. Methyl EPE is 2-benzoylpyridine-5-carboxylic acid (420 mg, of 1.73 mmol) dissolved in THF (5 ml) and added in one portion a solution of LiOH (46 mg, at 1.91 mmol) in water (5 ml) at 0°C. the Mixture is stirred at 0°C for 60 minutes THF is evaporated in vacuo and the residue diluted with water (5 ml) and washed with ether (10 ml). The aqueous phase is acidified with aqueous 2n HCl solution to pH ~3. The precipitate is collected by filtration, washed with water three times and dried in a vacuum oven overnight to obtain2-benzoylpyridine-5-carboxylic acid (260 mg, 66%). MS: 229 (M+H);1H NMR (300 MHz, DMSO): δ 7,60 (m, 3H), 7,73 (m, 1H), a 7.85 (m, 2H), and 9.4 (s, 1H).

Stage 6. 2-Benzoylpyridine-5-carboxylic acid (50 mg, 0.22 mmol) dissolved in anhydrous DHM (5 ml) and add a solution of 2M oxalicacid (0.26 mmol, of 0.13 ml) in DHM at room temperature, followed by addition of one drop of DMF. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The residue is dissolved in DHM (5 ml) and added morpholine-4-ylamine (0.24 mmol, 25 mg)and then DIPEA (0.44 mmol, 57 mg). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira 10% MeOH in DHM to getmorpholine-4-ylamide 2-benzoylpyridine-5-carboxylic acid(42 mg) as a solid. MS: 313 (M+H). IC50=342 nm.

Example 51

[4(2-Hydroxyethyl)piperazine-1-yl]amide of 2-benzoylpyridine-5-carboxylic acid

In accordance with the methods similar to those described in example 49, step 6, but substituting morpholine-4-ylamine 2-(4-aminopiperidin-1-yl)ethanol, get[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-benzoylpyridine-5-carboxylic acidin the form of solids. MS: 356 (M+H). IC50=665 nm.

Example 52

N'-Methyl-N'-[5-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid

To a solution of 2-phenylpyrimidine-5-carboxylic acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, or 0.57 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, or 0.57 mmol) and DIPEA (or 0.57 mmol) in DHM (5 ml) is added N-methyl-N-(5-triptorelin-2-yl)hydrazine (109 mg, or 0.57 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The residue is purified by chromatography on silica gel, elwira 10-75% EtOAc in heptane, to obtainN'-methyl-N'-[5-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acidin the form of a solid (189 mg). MS: 374 (M+H);1H NMR (300 MHz, CDCl3): δ of 3.54 (s, 3H), PC 6.82 (d, 1H), 7,53-to 7.59 (m, 3H), 7,74 (d, 1H), 8,45 (d, 2H), 8,53 (d, 2H), 9,25 (s, 2H). IC50=100 nm.

Example 53

N'-Methyl-N'-[4-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 52, but replacing N-methyl-N-(5-triptorelin-2-yl)hydrazine in N-methyl-N-(4-triptorelin-2-yl)hydrazine (109 mg, or 0.57 mmol), getN'-methyl-N'-[4-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acidin the form of solids. MS: 374 (M+H);1H NMR (300 MHz, CDCl3): δ of 3.54 (s, 3H), to 6.95 (m, 2H), 7,50-to 7.68 (m, 3H), 8,35 (d, 1H), and 8.4 (s, 1H), charged 8.52 (d, 2H), 9,26 (s, 2H).

Example 54

N'-Pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 52, but replacing N-methyl-N-(5-triptorelin-2-yl)hydrazine 2-hydrazinopyridazine (54 mg, 0.52 mmol), getN'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acidin the form of a solid (56 mg). MS: 292 (M+H);1H NMR (300 MHz, DMSO-d6): δ 6,72 to 6.8 (m, 2H), 7,53 to 7.62 (m, 4H), of 8.09 (m, 2H), 8,48 (d, 2H), to 8.62 (s, 1H), 9,34 (s, 2H).

Example 55

N'-(2-Chlorophenyl)hydrazide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 52, but replacing N-methyl-N-(5-triptorelin-2-yl)hydrazine on the hydrochloride of 2-chlorophenylhydrazone (93 mg, 0.52 mmol) and using 1,14 mmol DIPEA, getN'-(2-chlorophenyl)hydrazide 2-phenylpyrimidine-5-carboxylic acidin the form of a solid (65 mg). MS: 325 (M+H);1H NMR (300 MHz, CDCl3): δ 6,65 to 6.75 (m, 2H), 6.90 to-7,05 (m, 2H),7,25 (t, 1H), 7,39 (d, 1H), 7,58 (m, 3H), 8 (s, 1H), 8,55 (d, 2H), 9,25 (s, 2H).

Example 56

N'-(2-Oxopiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

Stage 1. A mixture of methyl-5-bromovalerate (3 g, to 15.4 mmol) and hydrazine hydrate is added (55%, to 15.4 mmol) in MeOH (50 ml) was stirred at room temperature for 18 hours Add a solution of NaOMe (to 15.4 mmol) in MeOH (10 ml) and the reaction mixture was stirred at room temperature for 18 hours the Reaction mixture was concentrated in vacuo. The residue is triturated with chilled MeOH and then filtered. The filtrate was concentrated in vacuo. The residue is passed through an SCX column (10 g) and the column was washed with MeOH (3×20 ml). Product elute 7M ammonia in MeOH to obtain1-aminopiperidin-2-itin the form of oil. MS: 137 (M+Na).

Stage 2. To a solution of 2-phenylpyrimidine-5-carboxylic acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, or 0.57 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, or 0.57 mmol) and DIPEA (or 0.57 mmol) in DHM (5 ml) was added 1-aminopiperidin-2-he (64 mg, or 0.57 mmol) and the mixture is stirred at room temperature for 18 hours Add DHM (15 ml) and the mixture was washed with water 0,5h. HCl solution (25 ml) and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 50-100% EtOAc in heptane, to obtainN'-(2-oxopiperidin-1-yl)amide 2-phenyl shall eremein-5-carboxylic acid (20 mg) as a solid. MS: 297 (M+H);1H NMR (300 MHz, CDCl3): δ 1,96 is 2.10 (m, 4H), 2,60 (t, 2H), of 3.77 (t, 2H), 7,51-7,56 (m, 3H), 8,51 (d, 2H), 9,02 (USS, 1H), 9,16 (s, 2H). IC50=55 nm.

Example 57

N'-Cyclohexyl-N'-methylhydrazino 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 52, but replacing N-methyl-N-(5-triptorelin-2-yl)hydrazine on the hydrochloride of N-methyl-N-cyclohexylpiperazine (72 mg, 0.44 mmol) and using 0.88 mmol DIPEA, getN'-cyclohexyl-N'-methylhydrazino2-phenylpyrimidine-5-carboxylic acidin the form of a solid (40 mg). MS: 311 (M+H);1H NMR (300 MHz, DMSO-d6): δ 0.9 to about 1.35 (m, 5H), 1.60-to 1,95 (m, 6H), of 3.25 (s, 3H), 7,53 to 7.62 (m, 3H), of 8.09 (m, 2H), which is 9.09 (s, 2H). IC50= 146,5 nm.

Example 58

N'-Morpholine-4-alamid 2-phenoxypyridine-5-carboxylic acid

Stage 1. To a solution of methyl ester 2-methylsulfonylamino-5-carboxylic acid (1 g, 5.43 mmol) in DHM (60 ml) is added by portions MCPBA (2,81 g, 16,29 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. Add a solution of Na2S2O3(1.6 g) in water (60 ml). The mixture is stirred at room temperature for 20 minutes After the distribution of organic and aqueous phase aqueous phase is extracted with DHM (2×20 ml). Volume of the United organic phase is washed with saturated aqueous NaHCO 3(3×20 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester 2-methanesulfonamido-5-carboxylic acid(of 1.05 g, 90%) as a solid. MS: 217 (M+H);1H NMR (300 MHz, CDCl3): δ is 3.41 (s, 3H), 4,06 (s, 3H), 9,44 (s, 2H).

Stage 2. To a solution of methyl ester 2-methanesulfonamido-5-carboxylic acid (0.8 g, 3.7 mmol) in NMP (3 ml) add the trihydrate of peroxide sodium (0.68 g, 4 mmol). The mixture is heated at a temperature of 100°C in a microwave Biotage within 60 C. the Reaction mixture was poured into water and the precipitate collected by filtration and dried to obtainmethyl ester 2-phenoxypyridine-5-carboxylic acid(0.56 g, 66%) as a solid. MS: 231 (M+H);1H NMR (300 MHz, CDCl3): δ 4.75 V (s, 3H), 7,19-7,33 (m, 3H), 7,46 (t, 2H), 9,10 (s, 2H).

Stage 3. To a solution of methyl ester 2-phenoxypyridine-5-carboxylic acid (0.5 g, 2,17 mmol) in THF (10 ml) and water (5 ml) is added LiOH (105 mg, 4.35 mmol). The reaction mixture was stirred at 0°C for 1 h THF is evaporated and the aqueous residue was washed with ether, acidified with 2M aqueous HCl. The precipitate is filtered and dried to obtain2-phenoxypyridine-5-carboxylic acid (0.34 g, 73%) as a solid. MS: 217 (M+H);1H NMR (300 MHz, CDCl3): δ 7,20-7,35 (m, 3H), 7,47 (t, 2H), 9,16 (s, 2H).

Stage 4. To a solution of 2-phenoxypyridine-5-carboxylic KIS is the notes (60 mg, 0.28 mmol) in DHM (5 ml) add oxalicacid (2M in DHM, 0.15 ml, 0.29 mmol) and 1 drop of DMF. The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue is dissolved in DHM (3 ml) and DIPEA (53 μl, 0.3 mmol) and add 4-aminomorpholine (30 μl, 0.3 mmol). The reaction mixture was stirred at room temperature for 18 h and then add water and DHM. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20-100% EtOAc in heptane, to obtainN'-morpholine-4-ylamide 2-phenoxypyridine-5-carboxylic acid(20 mg) as a solid. MS: 301 (M+H);1H NMR (300 MHz, CDCl3): δ 2,85 was 3.05 (m, 4H), 3.75 to 3,95 (m, 4H), 7.18 in-7,35 (m, 3H), 7,45 (t, 2H), 8,95 (s, 2H). IC50=227 nm.

Example 59

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid

Stage 1. Methyl ester 2-methylsulfonylamino-5-carboxylic acid (323 mg, about 1.75 mmol), thiophene-2-carboxylate copper(I) (501 mg, 2,63 mmol), tetrakis(triphenylphosphine) palladium(0) (202 mg, 0,175 mmol) and 3-methoxyphenylalanine acid (400 mg, 2,63 mmol) placed in a glass test tube, vacuum, naduvath N2add anhydrous THF (6 ml) and heated overnight at 85°C, closing the lid. Reactio the ing the mixture is cooled to room temperature, diluted with EtOAc and add ammonium hydroxide. The organic phase is separated, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography on silica gel to obtainmethyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid(152 mg) in powder form. MS: 245 (M+H);1H NMR (CDCl3): δ 4,00 (s, 3H), 4,82 (d, 2H), 7,55 (m, 2H), 8,46 (m, 1H), 8,53 (s, 1H), was 9.33 (s, 2H).

Stage 2. A mixture of methyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid (145 mg, 0.59 mmol), monohydrate of lithium hydroxide (49.5 mg, 1.18 mmol), MeOH (1.5 ml), water (1.5 ml) and THF (1.5 ml) was stirred at room temperature for 3.5 hours, the Reaction mixture was concentrated and water is added (1 ml) and 1N. aqueous HCl (1.2 ml). The resulting product is filtered and dried to obtain2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid (140 mg). MS: 231 (M+H);1H NMR (DMSO-d6): δ 4,62 (s, 3H), 7,54 (m, 2H), 8,14 (s, 1H), 8.34 per (m, 1H), 8,46 (s, 1H), of 9.30 (s, 2H).

Stage 3. A mixture of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid (135 mg, of 0.58 mmol), 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazine-3-one (76 mg, of 0.58 mmol), DMTMM (171 mg, 0.6 mmol) and DMF (3 ml) was stirred at room temperature for 2 days. Add water (3 ml) and the resulting product is filtered, washed with water and dried to obtain(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid(127 mg). MS 341 (M+H); 1H NMR (DMSO-d6): δ 1.91 a (s, 3H), 4,23 (s, 3H), to 4.62 (s, 2H), 7,53 (m, 2H), 8.34 per (m, 1H), 8,46 (s, 1H), 9,27 (s, 2H), becomes 9.97 (s, 1H), 11,08 (s, 1H). IC50=of 174.5 nm.

Example 60

(2,6-Dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

Stage 1. To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-it (5,509 g, 55,0 mmol) in MeOH (40 ml) was added 25% by weight solution of NaOMe in methanol (12,7 ml, 58.8 mmol). The mixture is stirred at room temperature for 15 min and then concentrated in vacuo. The residue is added to a solution of tetrabutylammonium bromide (0,358 g at 1.08 mmol) and chloroacetone (4.6 ml, 54,9 mmol) in CHCl3(33 ml) and the mixture refluxed for 5 h in a current of N2. The mixture is cooled to room temperature and stirred over night. The resulting suspension is filtered and the filtrate concentrated in vacuo. The residue is purified through a layer of silica gel, elwira 2:1:1/heptane:EtOAc:DHM to get5-methyl-3-(2-oxopropyl)-3H-1,3,4-oxadiazol-2-it(to 7.32 g, 86%) as a crystalline solid. MS: 157 (M+H);1H NMR (300 MHz, CDCl3) δ of 4.46 (s, 2H), and 2.27 (s, 3H), of 2.21 (s, 3H).

Stage 2. To a solution of 5-methyl-3-(2-oxopropyl)-3H-1,3,4-oxadiazol-2-it (1,518 g, 9,72 mmol) in a mixture of 2-propanol (8,8 ml) and water (0,22 ml) add methylhydrazine (0,79 ml, 14.6 mmol). The reaction mixture was refluxed in a stream of N2during the 4 h and then add a solution of oxalic acid (0,273 g, of 2.92 mmol) in 2-propanol (4 ml). The obtained precipitate was separated by filtration. The filtrate was concentrated in vacuo and the residue is dissolved in 2-propanol (25 ml). The solution is cooled and added to it Et2O. the Precipitate is collected by filtration and dried to obtainN-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)ndimethylacetamide(0.96 g, 54%) as a crystalline solid. MS: 185 (M+H);1H NMR (300 MHz, DMSO-d6) δ of 8.28 (s, 1H), 4,18 (s, 2H), or 3.28 (s, 3H), 2,02 (s, 3H), 1,95 (s, 2H).

Stage 3. To a suspension of N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)ndimethylacetamide (0.34 g, 1,846 mmol) in MeOH (3 ml) is added concentrated HCl (0.25 ml, 2.9 mmol). The mixture is refluxed for 3 hours the mixture is Then cooled to 0°C, bring the acidity up to pH ~12 using a 1M aqueous solution of NaOH (2.9 ml) and concentrated in vacuo. CH3CN added to the residue in the mixing process and the mixture is filtered. The filtrate was concentrated in vacuo. CH3CN added to the residue in the mixing process and the mixture is filtered. The filtrate was concentrated in vacuo to obtain4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazine-3-one(~100%). MS: 143 (M+H);1H NMR (300 MHz, DMSO-d6) δ 4,6-3,6 (broad peak, 2H), was 4.02 (s, 2H), 3,29 (s, 3H), of 1.95 (s, 3H).

Stage 4. To a solution of 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazine-3-one (0,219 g, was 1.58 mmol) and 2-phenylpyrimidine-5-carboxylic acid (MX 0.317 g, was 1.58 mmol) in dry DMF (10 ml) in a current of the N 2add DMTMM (0,46 g of 1.66 mmol). The mixture is stirred at room temperature for 22 h, then diluted with EtOAc (70 ml) and sequentially washed with saturated aqueous NaHCO3(2×10 ml) and brine (10 ml). The organic fraction is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel by gradient elution with heptane:EtOAc to obtain(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acidin the form of a solid (0.28 g, 55%). MS: 325 (M+H);1H NMR (300 MHz, DMSO-d6) δ 9,24 (s, 2H), 8,45 (DD, J=7,7, 2.0 Hz, 2H), 7,52 to 7.62 (m, 3H), 4,25 (s, 2H), 3,18 (s, 3H), of 1.95 (s, 3H).

Example 61

(6-tert-Butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

Stage 1. To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-she (1.01 g, of 10.09 mmol) in MeOH (8 ml) was added 25% by weight solution of NaOMe in methanol (2,32 ml, about 10.8 mmol). The mixture is stirred at room temperature for 15 min and then concentrated in vacuo. The residue is added to a solution of tetrabutylammonium bromide (0.07 g, 0.22 mmol) and 1-chlorination (1.35 ml, 10,07 mmol) in CHCl3(7 ml) and the mixture refluxed for 5 h in a current of N2. The mixture is cooled to room temperature and stirred for two days at room tempera is ur. The resulting suspension is filtered and the filtrate concentrated in vacuo to obtain3-(3,3-dimethyl-2-oxobutyl)-3H-1,3,4-oxadiazol-2-it(1,876 g, 94%) as oil. MS: 199 (M+H);1H NMR (300 MHz, CDCl3) δ to 4.62 (s, 2H), and 2.26 (s, 3H), of 1.23 (s, 9H).

Stage 2. To a solution of 3-(3,3-dimethyl-2-oxobutyl)-3H-1,3,4-oxadiazol-2-it (0,91 g, 4,59 mmol) in a mixture of 2-propanol (4 ml) and water (0.1 ml) is added hydrazine monohydrate (0,34 ml, 6,89 mmol). The reaction mixture is refluxed under nitrogen atmosphere for 5 h and then to the hot solution add a solution of oxalic acid (0,13 g, 1.38 mmol) in 2-propanol (5 ml). The obtained precipitate was separated in a hot condition by filtration. The filtrate was concentrated in vacuo and the residue purified through a layer of silica gel, gradient elution with heptane:EtOAc to obtainN-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)ndimethylacetamide(0,546 g, 56%) as a solid. MC: 213 (M+H);1H NMR (300 MHz, DMSO-d6) δ 8,29 (s, 1H), to 7.64 (s, 1H), 4,22 (s, 2H), 2,04 (s, 3H)and 1.15 (s, 9H).

Stage 3. To a suspension of N-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)ndimethylacetamide (0.51 g, is 2.40 mmol) in MeOH (5 ml) is added concentrated HCl (0.33 ml, of 3.84 mmol). The mixture is refluxed for 3 hours the mixture is Then cooled to 0°C and alkalinized using 1M aqueous solution of NaOH (2.9 ml) to pH ~12, and concentrated in vacuo. EtOH added to the residue in the process displaced the air traffic management and the mixture filtered. The filtrate was concentrated in vacuo. CH3CN added to the residue in the mixing process and the mixture is filtered. The filtrate was concentrated in vacuo to obtain4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazine-3-one(0,354 g, 84%) as a solid. MS: 171 (M+H);1H NMR (300 MHz, DMSO-d6) δ 7,49 (USS, 1H), 4,22 (USS, 2H), 4,06 (s, 2H)and 1.15 (s, 9H).

Stage 4. In accordance with the methods similar to that described in example 60, step 4, but replacing 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazine-3-one 4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazine-3-one, get(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid(74%) as a solid. MS: 353 (M+H);1H NMR (300 MHz, DMSO-d6) δ 11,09 (s, 1H), there is a 10.03 (s, 1H), 9,27 (s, 2H), 8,45 (DD, J=7,7, 2.0 Hz, 2H), 7,52-of 7.60 (m, 3H), 4,29 (s, 2H), 1,13 (s, 9H).

Example 62

(6-Methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

Stage 1. To a solution of 5-methyl-3-(2-oxopropyl)-3H-1,3,4-oxadiazol-2-he (2,052 g, 13,14 mmol) in a mixture of 2-propanol (12 ml) and water (0.3 ml) is added hydrazine monohydrate (0,96 ml of 19.8 mmol). The mixture is stirred at room temperature in a stream of N2for 15 h and then refluxed for 7 hours a Solution of oxalic acid (0,363 g 4,032 mmol) in 2-propanol (6 ml) are added to the heated reaction Rast is ROS. The obtained precipitate was separated by filtration through a porous glass funnel and the filtrate was concentrated in vacuo to about 10 ml of the total volume. The concentrated solution is cooled to -12°C and the resulting crystals are collected by filtration and dried to obtainN-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)ndimethylacetamide(1,562 g, 70%). MS: 171 (M+H);1H NMR (300 MHz, CDCl3) δ 8,10 (USS, 1H), EUR 7.57 (USS, 1H), 4,20 (s, 2H), 2,04 (s, 3H), of 1.95 (s, 3H);1H NMR (300 MHz, DMSO-d6) δ 9,98 (s, 1), 9,74 (s, 1), Android 4.04 (s, 2), 1,84 (p.6).

Stage 2. In accordance with the methods similar to those described in example 35, step 4, but replacing N-[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]ndimethylacetamide N-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)acetamide", she get4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazine-3-one(92%) as a solid. MS: 129 (M+H);1H NMR (300 MHz, CD3CN) δ 8,25 (USS, 1H), 4.26 deaths (USS, 2H), 3.96 points (s, 2H), of 1.85 (s, 3H).

Stage 3. To a solution of 2-pyridine-2-Yeremey-5-carboxylic acid (0.152 g, 0.75 mmol) in dry DHM (3 ml) and DMF (0,9 ml) in a dry flask in a stream of N2add oxalicacid (74 μl, 0.86 mmol). The reaction mixture was stirred at room temperature for 1 h, the Solvent evaporated, add toluene and evaporated three times. The residue is dissolved in dry DHM (3 ml) and added to a solution of 4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazine-3-one (0,77 g, 0.6 mmol) in DHM (5 ml), with the further addition of DIPEA (0,14 ml, 0,79 mmol). The mixture is stirred at room temperature overnight and then concentrated in vacuo. The residue is diluted with water and bring the acidity up to pH ~8.5, while using saturated aqueous solution of NaHCO3. The precipitate was filtered to obtain(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(0,043 g, 23%). MS: 312 (M+H);1H NMR (300 MHz, DMSO-d6) δ 11.11 (with, 1H), 9,95 (s, 1H), 9,31 (s, 2H), 8,78 (d, 1H), 8,45 (d, 1H), 8,01 (Tr, 1H), 7,58 (DD, 1H), 4,22 (2, 2H), 1.91 a (s, 3H).

Example 63

(6-tert-Butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to that described in example 62, step 3, but replacing 2-pyridine-2-Yeremey-5-carbonylchloride 2-(3-forfinal)pyrimidine-5-carbonyl chloride replacing 4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazine-3-one 4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazine-3-one and substituting Et3N, DIPEA, get(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(0,067 g, 61%). MS: 371 (M+H);1H NMR (300 MHz, CD3OD) δ 9,26 (s, 2H), 8,35 (d, J=8,1 Hz, 1H), 8,21 (d, J=10.3 Hz), 7,55 (kV, J=10.3 Hz, 1H), 7,30 (Tr, J=8,2 Hz, 1H), 4,37 (s, 2H), 1,19 (s, 9H).

Example 64

Methyl ester of 3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid

A mixture of 2-phenylpyrimidine-5-carboxylic acid (1,17 mmol), 1-hydroxybenzotriazole (1,99 mmol) and PS-DCC (1,21 mmol/g, 2.34 mmol) in DMF (8 ml) is shaken at room temperature for 60 minutes Add methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid (1,17 mmol) and the mixture shaken at room temperature for 2-4 days. Add trisamin on the polymer carrier (PS-trisamina) (4,08 mmol/g, 3,51 mmol) and the mixture was continuously shaken at room temperature for 18 hours. The solid is filtered and washed with MeOH. The filtrate is concentrated. The residue is purified by chromatography on silica gel, elwira 10-60% EtOAc in hexane to obtainmethyl ester 3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl-propionic acid(115 mg, 25%) as a solid. MS: 397 (M+H) 397;1H NMR (300 MHz, CDCl3): δ 2.57 m) was 2.76 (m, 2H), 2,80-3,00 (m, 2H), to 3.64 (s, 3H), and 5.30 (ush. N-H), 7,37-of 7.55 (m, 3H), 8,35 (d, 2H), 9,26 (s, 2H).

Example 65

3-{2,4-Dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid

Methyl ester of 3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid (0.22 mol) hydrolyzing LiOH (0.88 mol) in MeOH/water/THF (1:1:1) at room temperature for the eyes. MeOH and THF is evaporated in vacuum. The residue is acidified with 5%aqueous HCl solution. The precipitate is collected and dried to obtain3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid(40 mg, 48%). MS: 383 (M+H);1H NMR (300 MHz, CD3OD): δ 2,68-2,77 (m, 2H), 2,98-2,90 (m, 2H), 5,49 (s, N-H)of 7.48-of 7.60 (m, 3H), to 8.41-8,56 (m, 2H), to 9.32 (s, 2H).

Example 66

(4-Methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-methylpiperazin-1-ylamine, get(4-methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid.

Example 67

The dihydrochloride (4-methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

(4-Methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid are dissolved in a solution of HCl and methanol and evaporated methanol to dryness to obtaindihydrochloride (4-methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acidin the form of solids. MS: 298 (M+H).

Example 68

Morpholine-4-alamid 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 4, but replacing the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-aminomorpholine getmorpholine-4-alamid 2-phenylpyrimidine-5-carboxylic acid(71%) as a solid. MS: 285 (M+H);1H NMR (300 MHz, CD3OD): δ 2,90-3,00 (m, 2H), 3,80-of 3.85 (m, 2H), 7,44-7,58 (m, 3H), 8,45 are 8.53 (m, 2H), 9,18 (s, 2H).

Example 69

[4-(2-Hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2-(4-aminopiperidin-1-yl)ethanol, get[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(25%) as a solid. MS: 328 (M+H);1H NMR (300 MHz, CD3OD): δ to 2.65 (t, 2H), 2,80 (ush., 2H), 3.04 from (ush., 2H), of 3.73 (t, 2H), 7.24 to 7,34 (m, H), 7,47-EUR 7.57 (m, 3H), 7,62-7,73 (m, H), 8,43-charged 8.52 (m, 2H), 9,18 (s, 2H).

Example 70

((S)-2-Methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid (S)-2-methoxypiperidine-1-ylamine, get((s)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(63%) in the form of firm is about substance. MS: 313 (M+H);1H NMR (300 MHz, CDCl3): δ 1,57-of 2.15 (m, 4H), 2,70-3,70 (m, 8H), 6,93 (ush., 0,4N-H), 7,81 (ush., 0,6N-H), to 7.50 (m, 3H), 8,48 (m, 2H), 9,10-9,38 (d, 2H).

Example 71

((R)-2-Methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid (R)-2-methoxypiperidine-1-ylamine, get((R)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(66%) as a solid. MS: 313 (M+H);1H NMR (300 MHz, CDCl3): δ 1,57-of 2.15 (m, 4H), 2.71 to 3,63 (m, 8H), 6,93 (ush., 0,4N-H), 7,71 (ush., 0,6N-H), to 7.50 (m, 3H), and 8.50 (m, 2H), 9,10-9,38 (d, 2H).

Example 72

(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylamine, get(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(34%) as a solid. MS: 389 (M+H);1H NMR (300 MHz, CD3OD): δ 7,49 to 7.62 (m, 3H), 7,98 (ush., 3H), 8,23 (s, H), 8,54 (d, 2H), 9,29 (s, 2H). IC50=107,5 nm.

Example 73

(3-Isopropyl-5-oxo-1,5-dig the draw-[1,2,4]triazole-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 3-isopropyl-5-oxo-1,5-dihydro(1,2,4)-triazole-4-ylamine, get(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazole-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid(25%) as a solid. MS: 325 (M+H).

Example 74

Pyrrol-1-alamid 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid pyrrol-1-ylamine, getpyrrol-1-alamid 2-phenylpyrimidine-5-carboxylic acid(62%) as a solid. MS: 265 (M+H);1H NMR (300 MHz, CDCl3): δ of 6.25 (d, 2H), 6,76 (d, 2H), of 7.48-7,63 (m, 3H), charged 8.52 (d, 2H), 8,95-9,60 (ush., 2H).

Example 75

(5-Morpholine-4-ylmethyl-2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 5-morpholine-4-ylmethyl-2-oxoacridine-3-ylamine, get(5-morpholine-4-ylmethyl-2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid(51%) is the form of solids. MS: 384 (M+H);1H NMR (300 MHz, CD3OD): δ 2,50-2,95 (m, 6H), 3,64-of 3.85 (m, 5H), 3,98 (t, H), 4,88 (m, H), of 7.48-of 7.60 (m, 3H), 8,49 (d, 2H), 9,16 (s, 2H), 9,37 (ush. N-H). IC50=20 nm.

Example 76

(4-Cyclopentylpropionyl-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-cyclopentylpropionyl-1-ylamine, get(4-cyclopentylpropionyl-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(67%) as a solid. MS: 352 (M+H);1H NMR (300 MHz, CDCl3): δ 1,25-2,00 (m, 8H), 2.00 in the 3.35 (m, 9H), 6,70-7,40 (m, N-H), 7,40-of 7.60 (m, 3H), and 8.50 (s, 2H), 8,86-9,38 (m, 2H).

Example 77

(2-Oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrochloride 2-oxoacridine-3-ylamine get(2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid(18%) as a solid. MS: 285 (M+H);1H NMR (300 MHz, CD3OD): δ of 3.94 (t, 2H), 4,55 (t, 2H), 7,46 to 7.62 (m, 3H), 8,53 (d, 2H), of 9.30 (d, 2H). IC50=49 nm.

Example 78

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl]amide of 4-methyl-2-phenylpyrimidine-5-carbon is Oh acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-ylamine, get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl]amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid(87%) as a solid. MS: 325 (M+H);1H NMR (300 MHz, CDCl3): δ 1,95 (s, 3H), and 3.72 (s, 3H), 4,30 (s, 2H), 7,34-7,58 (m, 4H), 7,72 (ush., H), 8,92 (ush., H), 8,43 (d, 2H), 8,87 (s, H), 9,46 (ush., H).

Example 79

Ethyl ester [N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]acetic acid

Et3N (13,15 mmol) is added to a stirred solution of chloride of 2-phenylpyrimidine-5-carboxylic acid (5,26 mmol) and hydrochloride of ethyl ether hydrazinolysis acid (5 mmol) in DHM (30 ml) at room temperature and the mixture is stirred at room temperature for 5 hours the Mixture was quenched with water and extracted with EtOAc (60 ml). The organic phase is washed with water (20 ml) and brine (15 ml), dried, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 5-50% EtOAc in heptane, to obtainethyl ester [N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]acetic acid(256 mg, 16%) as a solid. MS: 301 (M+H);1H NMR (300 MHz, CDCl3): δ of 1.35 (s, 3H) 4,20-and 4.40 (m, 4H), 4,56 (s, 2H), 7,54 (m, 3H), 8,53 (m, 2H), 9,24 (s, 2H).

Example 80

2-[N'-(2-Phenylpyrimidine-5-carbonyl)hydrazino]ndimethylacetamide

A mixture of ethyl ether [N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]acetic acid (from 0.37 mmol) in a solution of 25% ammonia (25 ml) was stirred at room temperature overnight. The solid is collected by filtration and dried to obtain2-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]ndimethylacetamide(46%). MS: 272 (M+H);1H NMR (300 MHz, CD3OD): δ of 4.45 (s, 2H), 7,45-7,56 (m, 3H), 8,40-of 8.50 (m, 2H), 9,18 (s, 2H).

Example 81

4-[3-(4-Morpholino)propyl]-1-(2-phenylpyrimidine-5-carbonyl)-3-thiosemicarbazide

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-[3-(4-morpholino)propyl]-3-thiosemicarbazide get4-[3-(4-morpholino)propyl]-1-(2-phenylpyrimidine-5-carbonyl)-3-thiosemicarbazide(32%) as a solid. MS: 401 (M+H);1H NMR (300 MHz, CD3OD): δ 1,67-of 1.97 (m, 2H), 2,27-2,84 (m, 6H), 3,40-3,86 (m, 6H), 7,34-to 7.59 (m, 3H), 8,33-to 8.57 (m, 2H), 9,24 (s, 2H).

Example 82

(2,3-Dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

Oxalicacid in DHM (2M, 1.5 ml) are added to a solution of 2-phenylpyrimidine-5-carboxylic acid (200 mg, 2 mmol) in DHM (20 is l) and stirred at room temperature for 2 hours The reaction mixture was concentrated in vacuo. The residue is dissolved in DHM (20 ml). Add N-aminoindole (268 mg, 2 mmol) and triethylamine (404 mg, 4 mmol) and stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue purified by chromatography on silikagelevye column, elwira 0-40% EtOAc in heptane, to obtain(2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(195 mg, 31%) as a solid. MS: 317 (M+H);1H NMR (300 MHz, CD3OD): δ of 3.07 (t, 2H), of 3.77 (t, 2H), 6,76 (m, H), 6,82-to 6.95 (m, H), 7,09-7,24 (m, 2H), 7,54-7,63 (m, 3H), charged 8.52 (d, 2H), 9.28 are (s, 2H) and(indol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(10 mg, 2%). MS: 315 (M+H). IC50=2 nm.

Example 83

Methyl ester {4-[2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}acetic acid

Stage 1. In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid piperazine-1-ylamine, getpiperazine-1-alamid 2-phenylpyrimidine-5-carboxylic acid.

Stage 2. Piperazine-1-alamid phenylpyrimidine-5-carboxylic acid are dissolved in a solution of HCl and methanol and evaporated methanol to dryness to obtaindihydrochloride (piperazine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acidin the form of solids.

Stage 3. The suspension is of hydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.5 mmol), methylpropanoate (0.5 mmol) and Na2CO3(2.5 mmol) in wet THF (20 ml) was stirred at room temperature for 20 hours the Mixture was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 1-5% methanol in DHM to getmethyl ester {4-[2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}acetic acid(135 mg, 76%) as a solid. MS: 356 (M+H);1H NMR (300 MHz, CDCl3): δ 2,60-3,18 (m, 8H), 3,18-to 3.35 (d, 2H), 3,74 (s, 3H), 6,67 (ush., 0.5 N-H) 7,03 (ush., 0.5 N-H), 7,46-of 7.60 (m, 3H), and 8.50 (d, 2H), of 9.21 (d, 2H).

Example 84

(4-Cinematelevision-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

A solution of dihydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.29 mmol), bromoacetonitrile (0.29 mmol) and Na2CO3(of 1.46 mmol) in wet THF (8 ml) was stirred at room temperature overnight. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 1-2% methanol in DHM to get(4-cinematelevision-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(38 mg, 40%) as a solid. MS: 323 (M+H);1H NMR (300 MHz, CDCl3): δ 2,60-3,30 (m, 8H), 3,55 (s, 2H), 6,63 (ush., 0.5 N-H), 7,14 (ush., 0.5 N-H), 7,52 (s, 3H), 8,53 (d, 2H), 9,06-9,38 (m, 2H).

Example 85

2-{4-[(2-Phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}-ethyl is the ester of acetic acid

A solution of [4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid (0.21 mmol) and acetylchloride (1.06 mmol) in pyridine (4 ml) is stirred at a temperature of 80°C during the night. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is dissolved in EtOAc (10 ml), washed with water (10 ml), 10% Na2CO3(10 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-5% methanol in DHM to get2-{4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl)ethyl ester(12 mg, 15%) as a solid. MS: 370 (M+H);1H NMR (300 MHz, CDCl3): δ of 2.08 (s, 3H), 2,42-3,20 (m, 8H), 3,20-of 3.80 (m, 3H), 4,10-to 4.52 (m, 2H) 7,42-the 7.65 (m, 3H), charged 8.52 (m, 2H), 9,07-9,38 (d, 2H).

Example 86

(4-Acetylpiperidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

A solution of dihydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.43 mmol), acetylchloride (1.28 mmol) and Et3N (1,72 mmol) in DMF (8 ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue is dissolved in EtOAc (15 ml), washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with ether to obtain(4-acetimeter the Jn-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid (98 mg, 71%) as a solid. MS: 326 (M+H);1H NMR (300 MHz, CDCl3): δ 2,12 (s, 3H), 2,92-3,10 (m, 4H), 3,40-4,10 (m, 4H), 7,43-of 7.60 (m, 3H), 7,75 (ush., N-H), charged 8.52 (m, 2H), 9,11-9,38 (ush., 2H).

Example 87

[4-(2-Oxitetraciclina-3-yl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

A solution of dihydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.45 mmol) and bradykinin-2-she (1.8 mmol) in DMF (10 ml) is stirred in a stream of N2at 0°C for 15 min, then add NaH (60%, 1.8 mmol) and the mixture is heated to room temperature and stirred over night. The mixture is quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-2% methanol in DHM to get[4-(2-oxitetraciclina-3-yl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(120 mg, 73%) as a solid. MS: 368 (M+H);1H NMR (300 MHz, CDCl3): δ was 2.34 (s, 2H), 2,50-3,30 (m, 8H), 3,42-3,70 (m, H), 4,17-4,50 (m, 2H), 7,34-to 7.68 (m, 3H), and 8.50 (d, 2H), 9,06-9,38 (d, 2H). IC50=26 nm.

Example 88

[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

A solution of dihydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.36 mmol), triperoxonane and the hydride (1,08 mmol) and Et 3N (1.44 mmol) in DMF (8 ml) is stirred in a stream of N2at room temperature over night. The reaction mixture was concentrated in vacuo. The residue is dissolved in EtOAc (15 ml), washed with water (10 ml) and brine (15 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with ether to obtain[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(136 mg, ~100%) as a solid. MS: 380 (M+H);1H NMR (300 MHz, CDCl3): δ 2.95 and is 3.40 (s, 4H), 3,60-4,10 (m, 4H), 7,41-to 7.68 (m, 3H), charged 8.52 (d, 2H), 9,03-9,40 (ush., 2H). IC50= 57 nm.

Example 89

[4-(2-Methoxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

Stage 1. To a suspension of [4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid (0.83 mmol) in DHM (8 ml) in a stream of N2add a solution of Et3N (or 2.67 mmol) in DHM (1 ml), a solution of N,N-dimethyl-4-aminopyridine (0.2 mmol) in DHM (1 ml) and a solution of di-tert-BUTYLCARBAMATE (1.48 mmol) in DHM (1 ml) at room temperature. The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 6% ethanol in EtOAc to obtaintert-butyl ester [4-(2-methoxyethyl)piperazine-1-yl]-(2-phenylpyrimidine-5-carbonyl)carbamino acid(70 mg, 20%) in the ideal solid. MS: 428 (M+H).

Stage 2. A solution of tert-butyl ester [4-(2-methoxyethyl)piperazine-1-yl]-(2-phenylpyrimidine-5-carbonyl)carbamino acid (0.21 mmol), NaH (60%, 0.66 mmol) and iodomethane (to 0.63 mmol) in DMF (8 ml) is stirred in a stream of N2at room temperature over night. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-2% methanol in DHM to get[4-(2-methoxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid(32 mg, 44%) as a solid. MS: 342 (M+H).

Example 90

[4-(2-Morpholine-4-yl-2-oxoethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid

A solution of dihydrochloride piperazine-1-ylamide 2-phenylpyrimidine-5-carboxylic acid (0.43 mmol) and NaH (60%, of 2.15 mmol) in DMF (10 ml) is stirred in a stream of N2at room temperature for 20 minutes Add 2-chloro-1-morpholine-4-ylatason (of 0.65 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-4% methanol in DHM to get[4-(2-morphol is n-4-yl-2-oxoethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid (24 mg, 14%) as a solid. MS: 411 (M+H);1H NMR (300 MHz, CDCl3): δ 2,85-3,10 (m, 2H), 3,60-4,00 (m, 12H), to 4.46 (d, 2H), 4,84 (s, 2H), 7,44 to 7.62 (m, 3H), 8.34 per-8,58 (m, 2H), 9,20-9,38 (d, 2H). IC50=831,5 nm.

Example 91

(2,3-Dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)pyrimidine-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,3-dihydroindol-1-ylamine, get(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(83%) as a solid. MS: 335 (M+H);1H NMR (300 MHz, CDCl3): δ 3,00 (s, 2H), 3,70 (s, 2H), 6,53-7,34 (m, 5H), 7,45 (s, H), 8,00 is 8.38 (m, 2H), 9,20 (s, 2H). IC50=3 nm.

Example 92

Piperazin-1-yl-amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)pyrimidine-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid piperidin-1-ylamine, getpiperazin-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid(71%) as a solid. MS: 30 (M+H); 1H NMR (300 MHz, CDCl3): δ 1,20-2,00 (m, 6H), 2,20-of 3.60 (m, 4H), 6,97-7,30 (m, H), 7,34-7,56 (m, H), 8,06 is 8.38 (m, 2H), 9,00-9,38 (d, 2H). IC50=19,5 nm.

Example 93

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid

Stage 1. In accordance with the methods similar to that described in example 59, step 1, but substituting 3-methoxyphenylalanine acid 4-methoxyphenylalanine acid, getmethyl ester of 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid.

Stage 2. In accordance with the methods similar to that described in example 59, step 2, but substituting the methyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid methyl ester 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid, get2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid.

Stage 3. In accordance with the methods similar to that described in example 59, step 3, but replacing 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid. MS: 341 (M+H);1H NMR (DMSO-d6): δ 1.91 a (s, 3H), 3,86 (s, 3H), 4,22 (s, 2H), 7,12 (d, J=8.5 Hz, 1H), 7,95 (s, 1H), 8,42 (d, J=8.6 Hz, 1H), of 9.21 (s, 2H), 9,95 (s, 1H), 11,02 (s, 1H).

Example 94

(Hexahydrotriazine[c]pyrrol-2-yl)amide 2-phenylpyrimidine-5-carbon is howling acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid of hexahydrotriazine[c]pyrrol-2-ylamine, get(hexahydrotriazine[c]pyrrol-2-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(39%) as a solid. MS: 309 (M+H);1H NMR (300 MHz, CDCl3): δ 1,20-1,90 (m, 6H), 2.40 a-3,50 (m, 6H), 6,94 (s, N-H), 7,52 (s, 3H), and 8.50 (s, 2H), remaining 9.08-9,38 (d, 2H).

Example 95

(2,3-Dihydroindol-1-yl)amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid chloride 4-methyl-2-phenylpyrimidine-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,3-dihydroindol-1-ylamine, get(2,3-dihydroindol-1-yl)amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid(80%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CDCl3): δ 2,69 (s, 3H), 2,74-3,10 (m, 2H), to 3.64 (t, 2H), 6,58-6,97 (m, 2H), 7.03 is-7,30 (m, 2H), 7,49 (s, 3H), of 7.96 (s, N-H), 8,44 (s, 2H), 8,72 (d, 2H). IC50=5,5 nm.

Example 96

Pyrrolidin-1-alamid 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in the ore 64, but replacing the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid pyrrolidin-1-ramirezrichard getpyrrolidin-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid(67%) as a solid. MS: 269 (M+H);1H NMR (300 MHz, CDCl3): δ 1.70 to of 2.20 (m, 4H), 2,70-of 3.46 (m, 4H), 7,55 (s, 3H), 8,42-8,67 (m, 2H), 9,14-9,49 (t, 2H).

Example 97

(2,6-Dimethylpiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,6-dimethylpiperidin-1-ylamine, get(2,6-dimethylpiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(69%) as a solid. MS: 311 (M+H);1H NMR (300 MHz, CDCl3): δ 0.95 to-1,24 (m, 6H), 1,24-to 1.87 (m, 6H), 1,88-of 3.60 (m, 2H), 6.35mm (ush., N-H), 7,53 (s, 3H), charged 8.52 (s, 2H), 9,10-9,73 (m, 2H).

Example 98

(4-Cyclopentylpropionyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)pyrimidine-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-cyclopentylpropionyl-1-ylamine, get(4), the CEC is pentylpyridine-1-yl-amide 2-(3-forfinal)pyrimidine-5-carboxylic acid (64%) as a solid. MS: 370 (M+H).

Example 99

(2-Methyl-2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2-methyl-2,3-dihydroindol-1-ylamine, get(2-methyl-2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(32%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CDCl3): δ of 1.05 (m, 3H), 2,50-and 2.79 (m, H), 3,03-3,24 (m, H), 3,40-to 3.58 (m, 0,5H), 3,92 (ush., 0,5H), to 6.67 (d, 0,5N-H), 6,77-7,33 (m, 4H), 7,51 (m, 3H), 7,98 (s, 0,5N-H), charged 8.52 (m, 2H), 9,23 (d, 2H). IC50=4 nm.

Example 100

(2-Methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)pyrimidine-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2-methyl-2,3-dihydroindol-1-ylamine, get(2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(31%) as a solid. MS: 349 (M+H);1H NMR (300 MHz, CDCl3): δ 1.00 and is 1.48 (m, 3H), 2,43-2,78 (m, 2H), 3,32-4,06 (m, H), 6,50-6,93 (m, 1,5H), 6,93-7,34 (m, 4H), 7,34-rate of 7.54 (d, H), 8,05-8,32 (m, 2H), 8,56 (s, 0,5NH), 9,17 (d, 2H). IC50=4 nm.

Example 101

N'-Methyl-N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid N'-methyl-N'-pyridine-2-ilkerin getN'-methyl-N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid(31%) as a solid. MS: 306 (M+H);1H NMR (300 MHz, CDCl3): δ of 3.48 (s, 3H), to 6.88 (m, 2H), 7,40-of 7.70 (m, 4H), 8,23 (s, H), charged 8.52 (m, 2H), 9,13 (ush., N-H), 9.28 are (s, 2H).

Example 102

(5-Florinda-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

Stage 1. A solution of 5-fluoro-1H-indole (to 16.9 mmol) and tert-butoxide potassium (33.8 mmol) in DMF (76 ml) was stirred at room temperature in a stream of N2within 2 hours To the solution is added dropwise 0,15M NH2Cl in ether (169,2 ml) for 15 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 h, then quenched with 10% aqueous solution of Na2S2O3and extracted with ether. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 60-80% EtOAc in heptane, to obtain5-Florinda-1-ylamine(751 mg, 30%) in the form of TV is Gogo substances. 1H NMR (300 MHz, CDCl3): δ 4,80 (ush., 2N-H), 6,38 (l, H)to 7.00 (m, H), 7,19-the 7.43 (m, 3H).

Stage 2. Diethylethanolamine (2,30 mmol) is added to a stirred solution of chloride of 2-phenylpyrimidine-5-carboxylic acid (1.15 mmol) and 5-Florinda-1-ylamine (1.15 mmol) in DHM (20 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue is dissolved in EtOAc (30 ml), then washed with 5% HCl (10 ml), water (10 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10-40% EtOAc in heptane, to obtain(5-Florinda-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(185 mg, 49%) as a solid. MS: 333 (M+H);1H NMR (300 MHz, CDCl3): δ 6,56 (s, H) 7,02 (m, H), 7,10-7,38 (m, 4H), 7,55 (s, 3H), 8,53 (s, 2H), 8,70-9,40 (ush., 2H). IC50=3 nm.

Example 103

(2,3-Dihydroindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-pyridin-2-Yeremey-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,3-dihydroindol-1-ylamine, get(2,3-dihydroindol-1-yl)amide 2-pyridin-2-Yeremey-5-carbon is th acid (98%) as a solid. MS: 318 (M+H);1H NMR (300 MHz, CDCl3): δ 2,85-3,20 (m, 2H), of 3.77 (t, 2H), 6,76 (d, 0,5N-H), 6,82-7,49 (m, 4H), 7,46 (d, H), 7,89 (d, H), 8,07 (ush., 0,5N-H), to 8.57 (m, H), 8,84 (d, H), of 9.30 (s, 2H). IC50=3 nm.

Example 104

Indol-1-alamid 2-pyridine-2-Yeremey-5-carboxylic acid

A suspension of (2,3-dihydroindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid (0.28 mmol) and MnO2(of 1.42 mmol) in DHM (8 ml) was stirred at room temperature for 2 hours, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-5% methanol in DHM to getindol-1-ylamide 2-pyridine-2-Yeremey-5-carboxylic acid(45 mg, 50%) as a solid. MS: 316 (M+H);1H NMR (300 MHz, CDCl3): δ 6.48 in (s, H), 6,72-of 7.48 (m, 5H), 7,56 (s, H), 7,88 (s, H), charged 8.52 (ush., 2H), the remaining 9.08 (ush., 2H), to 11.56 (ush., N-H). IC50=4,5 nm.

Example 105

Indol-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid

A suspension of (2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid (0,39 mmol) and MnO2(1,95 mmol) in DHM (10 ml) was stirred at room temperature for 40 minutes, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtainindol-1-Ilam is 2-(3-forfinal)pyrimidine-5-carboxylic acid (70 mg, 54%) as a solid. MS: 333 (M+H);1H NMR (300 MHz, CDCl3): δ 6,60 (s, H), 7,10 (d, H), 7,14-7,46 (m, 4H), 7,50 (ush., H)to 7.64 (d, H), of 8.37 (d, 2H), 8,60-9,40 (ush., 3H). IC50=5 nm.

Example 106

(2,3-Dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,3-dihydroindol-1-ylamine, get(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(91%) as a solid. MS: 349 (M+H);1H NMR (300 MHz, CDCl3): δ 2.77-to is 3.08 (m, 2H), 3,09-of 3.80 (m, 2H), 's 6.75 to 7.00 (m, 2H),? 7.04 baby mortality-to 7.32 (m, 3H), 7,44 (kV, H), 8,06-8,31 (m, 2H), 8,51 (d, 2H). IC50=23 nm.

Example 107

(2-Methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2-methyl-2,3-dihydroindol-1-ylamine, get(2-methyl-2,3-dihydroindol-1-yl)and the ID 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (94%) as a solid. MS: 363 (M+H);1H NMR (300 MHz, CDCl3): δ 1,00-1,50 (d, 3H), 2,30 is 2.80 (m, 4H), 3,01 (m, H), 3,26-of 3.96 (m, H), 6,45-7,00 (m, 2H), 7,00-7,30 (m, 3H), 7,41 (kV, H), 7,97-of 8.28 (m, 2H), 8,68 (d, H).

Example 108

(2-Methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

A suspension of (2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid (0.98 mmol) and MnO2(4,88 mmol) in DHM (15 ml) was stirred at room temperature for 2 hours, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain(2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(230 mg, 97%) as a solid. MS: 347 (M+H);1H NMR (300 MHz, CDCl3): δ 2,08-to 2.40 (m, 3H), 6,27 (s, H), 6,95-7,35 (m, 4H), of 7.36-the 7.65 (m, 2H), 8,20-8,44 (m, 2H), 8,49-9,20 (d, 2H). IC50=6 nm.

Example 109

Indol-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A suspension of (2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (to 0.72 mmol) and MnO2(of 3.60 mmol) in DHM (10 ml) was stirred at room temperature for 40 minutes, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain the recommended reading indol-1-ylamide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(185 mg, 75%) as a solid. MS: 347 (M+H);1H NMR (300 MHz, CDCl3): δ by 2.73 (s, 3H), 6,53 (s, H), 7,03 (d, H), 7,08 and 7.36 (m, 4H), 7,37 to 7.75 (m, 2H), 8,04-to 8.40 (m, 2H), 8,56 (ush., H), 8,81 (ush., H). IC50=10 nm.

Example 110

(2,3-Dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting 2-phenyl-4-Yeremey-5-carboxylic acid, 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid, and substituting methyl ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,3-dihydroindol-1-ylamine, get(2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(96%) as a solid. MS: 332 (M+H);1H NMR (300 MHz, CDCl3): δ 2,78 (s, 3H), to 3.09 (t, 2H), of 3.77 (t, 2H), 6,70-7,01 (m, 2H), 7,09-of 7.23 (m, 2H), was 7.36-7,46 (m, H), a 7.85 (t, H), 8,43-8,64 (m, 2H), 8,80 (d, H). IC50=3 nm.

Example 111

Indol-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A suspension of (2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (1.00 mmol) and MnO2(5.00 mmol) in DHM (10 ml) was stirred at room temperature for 60 minutes, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The rest of the sight is up by chromatography on silica gel, elwira 0-5% methanol in DHM to getindol-1-ylamide 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(196 mg, 60%) as a solid. MS: 330 (M+H);1H NMR (300 MHz, CDCl3): δ 2,77 (s, 3H), return of 6.58 (s, H), to 7.15 (s, 2H), 7,26 (m, 3H), to 7.84 (d, H), 8,44 (s, 2H), 8,73 (s, H), 10,94 (ush., N-H). IC50=5 nm.

Example 112

(5-Methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of 5-methanesulfonanilide (4,11 mmol) and MnO2(a 20.55 mmol) in DHM (20 ml) was stirred at room temperature overnight. The reaction mixture is filtered and the filtrate concentrated in vacuo to obtain5-methanesulfonyl-1H-indole(782 mg, 100%) as a solid. MS: 196 (M+H);1H NMR (300 MHz, CDCl3): δ to 3.09 (s, 3H), of 6.71 (s, H), 7,39 (s, H), 7,53 (d, H), 7,74 (m, H), 8,30 (s, H), 8,66 (ush., N-H).

Stage 2. A solution of 5-methanesulfonyl-1H-indole (4.1 mmol) and tert-butoxide potassium (8,2 mmol) in DMF (20 ml) was stirred at room temperature in a stream of N2within 2 hours is Added dropwise 0,15M NH2Cl in ether (41 ml) for 15 min at room temperature and the reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was quenched with a 10% aqueous solution of Na2S2O3and extracted with ether (3×40 ml). The combined organic phase washed with water (2×30 ml) and brine (20 ml), dried (Nasub> 2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira EtOAc and heptane to obtain5-methanesulfonamido-1-ylamine(230 mg, 32%) as a solid. MS: 211 (M+H);1H NMR (300 MHz, CDCl3): δ is 3.08 (s, 3H), 4,94 (ush., 2N-H), 6,55 (d, H), 7,34 (m, H), EUR 7.57 (d, H), 7,73 (m, H), 8,21 (m, H).

Stage 3. The solution of chloride of 2-(3-forfinal)pyrimidine-5-carboxylic acid (of 0.62 mmol) in EtOAc (10 ml) is added to a stirred solution of 5-methanesulfonamido-1-ylamine (of 0.62 mmol) and K2CO3(is 3.08 mmol) in EtOAc (10 ml) and H2O (10 ml) at 0°C and the reaction mixture is heated to room temperature and stirred over night. EtOAc is evaporated in vacuum and the resulting solid collected by filtration. The solid is triturated with DHM to get(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(85 mg, 34%) as a solid. MS: 411 (M+H);1H NMR (300 MHz, CD3OD): δ of 3.13 (s, 3H), for 6.81 (m, H), 7,25-7,39 (m, H), 7,49-to 7.67 (m, 3H), 7,72-to 7.84 (m, H), 8,21-8,32 (m, 2H), 8,39 (d, H), 9,41 (s, 2H).

Example 113

(6-Methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. A solution of 6-methanesulfonyl-1H-indole (2,66 mmol) and tert-butoxide potassium (5,32 mmol) in DMF (15 ml) was stirred at room temperature in a stream of N2within 2 hours Add p the drops 0,15M NH 2Cl in the air (to 26.6 ml) for 15 minutes at room temperature and the reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was quenched with a 10% aqueous solution of Na2S2O3and extracted with ether (3×20 ml). The combined organic phase was washed with brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc to obtain6-methanesulfonamido-1-ylamine(270 mg, 51%) as a solid. MS: 211 (M+H);1H NMR (300 MHz, CDCl3): δ to 3.09 (s, 3H), of 6.49 (d, H), 7,41 (m, H), to 7.61 (d, H), 7,71 (l, H)to 8.12 (s, H).

Stage 2. The solution of chloride of 2-(3-forfinal)pyrimidine-5-carboxylic acid (of 0.65 mmol) in EtOAc (15 ml) is added to a stirred solution of 5-methanesulfonamido-1-ylamine (of 0.65 mmol) and potassium carbonate (2,60 mmol) in EtOAc (10 ml) and H2O (10 ml) at 0°C and the reaction mixture is heated to room temperature and stirred over night. EtOAc is evaporated in vacuum and the resulting solid is collected by filtration and purified by chromatography on silica gel, elwira 20-60% EtOAc in heptane, to obtain(6-methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(85 mg, 33%) as a solid. MS: 411 (M+H);1H NMR (300 MHz, CDCl3): δ is 3.08 (s, 3H), 6,62 (d, H) 7,33-7,44 (m, 2H), 7,46-to 7.59 (m, 2H), of 7.75 (s, H), 8,29 (d, 2H), 8,39 (d, H), 9,42 (s, 2H), 10,80 (ush., H). IC50=8 nm.

Example 114

(5-Methanesulfonamido-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

Diethylethanolamine (3.54 mmol) are added to a solution of 2-pyridine-2-Yeremey-5-carboxylic acid HCl (1.18 mmol), 5-methanesulfonamido-1-ylamine (1.18 mmol) and TBTU (1.77 mmol) in anhydrous DMF (16 ml) at room temperature. The reaction mixture was stirred at 90°C overnight and then concentrated in vacuo. The residue is dissolved in EtOAc (50 ml) and water (50 ml). The organic phase is separated, washed with water (2x20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc and DHM to get(5-methanesulfonamido-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(125 mg, 27%) as a solid. MS: 394 (M+H);1H NMR (300 MHz, CD3OD): δ 3,14 (s, 3H), PC 6.82 (m, H), 7,50-7,72 (m, 3H), 7,80 (m, H), 8,07 (m, H), 8,30 (m, 2H), 8,70(d, H), 8,80 (s, H), of 9.51 (s, 2H).

Example 115

(5-Methanesulfonamido-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid

Diethylethanolamine (3,84 mmol) are added to a solution of the hydrochloride of 2-pyridine-2-Yeremey-5-carboxylic acid (1.28 mmol), 5-methanesulfonamido-1-ylamine (1.28 mmol) and TBTU (1.92 mmol) in anhydrous DMF (16 ml) at room temperature. The reaction mixture was stirred at ambient temperature the re 90°C overnight and then concentrated in vacuo. The residue is dissolved in EtOAc (60 ml) and washed with water (2×30 ml) and brine (20 ml). The organic phase is separated, washed with water (2×20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-5% MeOH in DHM to get(5-methanesulfonamido-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid(125 mg, 25%) as a solid. MS: 394 (M+H);1H NMR (300 MHz, CDCl3): δ 3,10 (s, 3H), of 6.61 (m, H), 6,98 (m, H), 7,34 (s, H), 7,51 (m, H), to $ 7.91 (s, H), 8,83 (m, 2H), 9,49 (s, H), 9,77 (s, H), 10,10 (s, N-H).

Example 116

(5-Methanesulfonamido-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

2,0M NaHMDS (bis(trimethylsilyl)amide and sodium) in THF is added to stirred solution of chloride of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (to 0.72 mmol) and 5-methanesulfonamido-1-ylamine (to 0.72 mmol) in anhydrous pyridine (10 ml) at room temperature. The reaction mixture was stirred at 90°C overnight and then concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira to 1.5% MeOH in DHM to get(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(50 mg, 8%) as a solid. MS: 425 (M+H);1H NMR (300 MHz, CDCl3): δ of 2.86 (s, 3H), to 3.02 (s, 3H), 6,55 (s, H), 6,92 (d, H), 17-7,38 (m, 3H), 7,53 (m, H), 7,78 (s, H), of 8.27 (d, H), scored 8.38 (d, H), 9,16 (s, H).

Example 117

Pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. The solution pyrrolo[2,3-b]pyridine (about 16.9 mmol) and tert-butoxide potassium (33.8 mmol) in DMF (76 ml) was stirred at room temperature in a stream of N2within 2 hours is Added dropwise 0,15M NH2Cl in ether (169,2 ml) at room temperature and the reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was quenched with a 5% aqueous solution of Na2S2O3(100 ml) and extracted with ether three times. The combined organic phase was washed with brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 60-80% EtOAc in heptane, to obtainpyrrolo[2,3-b]pyridine-1-ylamine(703 mg, 31%) as a solid. MS: 134 (M+H);1H NMR (300 MHz, CDCl3): δ 5,04 (ush., 2N-H), 6.35mm (d, H), to 7.09 (m, H), 7,35 (m, H), to $ 7.91 (m, H), a 8.34 (d, H).

Stage 2. The solution of chloride of 2-(3-forfinal)pyrimidine-5-carboxylic acid (1.13 mmol) in EtOAc (20 ml) is added to the mixed solution pyrrolo[2,3-b]pyridine-1-ylamine (1.13 mmol) and K2CO3(1.13 mmol) in EtOAc (10 ml) and H2O (20 ml) at room temperature and the reaction mixture was stirred at room temperature overnight. EtOAc of viparita the t in vacuum and the resulting solid collected by filtration to obtain pyrrolo[2,3-b]pyridine-1-ylamide 2-(3-forfinal)pyrimidine-5-carboxylic acid(305 mg, 81%) as a solid. MS: 334 (M+H);1H NMR (300 MHz, CDCl3): δ to 6.57 (d, H), 7,13-of 7.55 (m, 4H), to 7.99 (m, H), 8,10-to 8.40 (m, 3H), 9,27 (s, 2H), 12,57 (ush., N-H).

Example 118

Pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. The solution pyrrolo[3,2-b]pyridine (1,64 mmol) and tert-butoxide potassium (3,29 mmol) in DMF (7.3 ml) was stirred at room temperature in a stream of N2within 2 hours is Added dropwise 0,15M NH2Cl in ether (16,3 ml) at room temperature and the reaction mixture was stirred at room temperature for 3 hours, the Reaction mixture was quenched with a 5% aqueous solution of Na2S2O3(10 ml) and extracted with ether. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira EtOAc to obtainpyrrolo[3,2-b]pyridine-1-ylamine(136 mg, 62%) as a solid. MS: 134 (M+H);1H NMR (300 MHz, CDCl3): δ 4,89 (ush., 2N (H)of 6.61 (d, H), 7,16 (m, H), 7,38 (d, H), 7,76 (d, H), of 8.47 (d, H).

Stage 2. The solution of chloride of 2-(3-forfinal)pyrimidine-5-carboxylic acid (0.45 mmol) in EtOAc (8 ml) is added to the mixed solution pyrrolo[3,2-b]pyridine-1-ylamine (0.45 mmol) and K2CO3(0.45 mmol) in EtOA (4 ml) and H 2O (8 ml) at room temperature and the reaction mixture was stirred at room temperature for 30 minutes EtOAc is evaporated in vacuum and the resulting solid collected by filtration to obtainpyrrolo[3,2-b]pyridine-1-ylamide 2-(3-forfinal)pyrimidine-5-carboxylic acid(116 mg, 77%) as a solid. MS: 334 (M+H);1H NMR (300 MHz, CDCl3): δ 6,60 (d, H), 7,15-of 7.60 (m, 4H), 8,01 (m, H), 8,10-to 8.41 (m, 3H), 9,27 (s, 2H), 12,45 (ush., N-H). IC50=18 nm.

Example 119

(5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

The solution of chloride of 2-(3-forfinal)pyrimidine-5-carboxylic acid (1 mmol) in EtOAc (20 ml) is added to a stirred solution of 5-Florinda-1-ylamine (1 mmol) and potassium carbonate (1 mmol) in EtOAc (10 ml) and H2O (20 ml) at room temperature and the reaction mixture was stirred at room temperature overnight. EtOAc is evaporated in vacuum and the resulting solid collected by filtration to obtain(5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(148 mg, 42%) as a solid. MS: 351 (M+H);1H NMR (300 MHz, CDCl3): δ 6,56 (m, H), 7,02 (m, H), 7,12-7,34 (m, 3H), 7,51 (m, H), 8,24 (e, H), a 8.34 (s, H), 8,92 (ush., H), 9,24 (ush., 2H).

Example 120

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid

Stage 1. In accordance with the methods similar to that described in example 59, step 1, but substituting 3-methoxyphenylalanine acid 2-methoxyphenylalanine acid, getmethyl ester 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid.

Stage 2. In accordance with the methods similar to that described in example 59, step 2, but substituting the methyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid methyl ester 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid, get2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid.

Stage 3. In accordance with the methods similar to that described in example 59, step 3, but replacing 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid. MS: 341 (M+H);1H NMR (DMSO-d6): δ 1.91 a (s, 3H), 3,79 (s, 2H), 4,22 (s, 2H), to 7.09 (m, 1H), 7,19 (d, J=8,2 Hz, 1H), 7,52 (m, 1H), 7,65 (m, 1H), 9,24 (s, 2H), 9,96 (s, 1H), 11,06 (s, 1H). IC50=199 nm.

Example 121

Pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

The solution of chloride of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (0.45 mmol) in EtOAc (8 ml) is added to the mixed solution pyrrolo[3,2-b]pyridine-1-ylamine (0.45 mmol) and potassium carbonate (0.45 mmol) in EOAc (4 ml) and H 2O (8 ml) at room temperature and the reaction mixture was stirred at room temperature overnight. EtOAc is evaporated in vacuum and the resulting solid collected by filtration. The solid is purified by chromatography on silica gel, elwira 20-80% EtOAc in heptane, to obtainpyrrolo[3,2-b]pyridine-1-ylamide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(38 mg, 24%) as a solid. MS: 348 (M+H);1H NMR (300 MHz, CDCl3): δ was 2.76 (s, 3H), 6,59 (m, H), 7,07-to 7.64 (m, 4H), of 7.96 (m, H)8,23 (m, H), 8,32 (m, 2H), 9,12 (s, H), 10,01 (ush., N-H).

Example 122

Pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

The solution of chloride of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1 mmol) in EtOAc (10 ml) is added to the mixed solution pyrrolo[2,3-b]pyridine-1-ylamine (1 mmol) and K2CO3(1 mmol) in EtOAc (20 ml) and H2O (20 ml) at room temperature, then stirred at room temperature overnight. EtOAc is evaporated in vacuum and the resulting solid collected by filtration. The solid is purified by chromatography on silica gel, elwira 20-80% EtOAc in heptane, to obtainpyrrolo[2,3-b]pyridine-1-ylamide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(162 mg, 47%) as a solid. MS: 348 (M+H);1H NMR (300 MHz, CDCl3): δ 2,78 (s, 3H), 6,59 (m, H); 7.9-7,58 (m, 4H), of 7.96 (m, H), by 8.22 (m, H), 8,31 (d, 2H), 9,14 (s, 2H). IC50=12 nm.

Example 123

(5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

The solution of chloride 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (1 mmol) in EtOAc (20 ml) is added to a stirred solution of 5-Florinda-1-ylamine (1.20 mmol) and K2CO3(2 mmol) in EtOAc (10 ml) and H2O (20 ml) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-10% MeOH in DHM to obtain a solid phase. The solid is triturated with EtOAc/heptane to obtain(5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(122 mg, 35%) as a solid. MS: 348 (M+H);1H NMR (300 MHz, CD3OD): δ 2,77 (s, 3H), 6,55 (m, H), 7,06 (m, H), 7,32-7,66 (m, 4H), 8,02 (m, H), to 8.45 (d, H), 8,79 (s, H), 9,26 (s, H)12,00 (s, N-H). IC50=17 nm.

Example 124

(5-Florinda-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid

Saline (2-pyridin-2-Yeremey-5-carboxylic acid (1 mmol) in EtOAc (20 ml) is added to a stirred solution of 5-Florinda-1-ylamine (1 mmol) and K CO3(2 mmol) in EtOAc (10 ml) and H2O (20 ml) at room temperature and the reaction mixture was stirred at room temperature overnight. EtOAc is evaporated in vacuum and the resulting solid collected by filtration. The solid is purified by chromatography on silica gel, elwira 0-10% MeOH in DHM to get(5-Florinda-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(65 mg, 20%) as a solid. MS: 334 (M+H);1H NMR (300 MHz, CD3OD): δ 6,56 (m, H),? 7.04 baby mortality (m, H), 7,28-7,79 (m, 3H), of 8.04 (m, H), 8,49 (m, H), 8,81 (m, H), 9,48 (s, 2H), 12,22 (s, N-H). IC50=18 nm.

Example 125

Pyrrolo[2,3-b]pyridine-1-alamid 2-pyridine-2-Yeremey-5-carboxylic acid

Diethylethanolamine (1.13 mmol) are added to a solution of 2-pyridine-2-Yeremey-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU in anhydrous DMF (7 ml) at room temperature and the reaction mixture is stirred at a temperature of 80°C during the night. The reaction mixture was concentrated in vacuo. The residue is dissolved in EtOAc, washed with water twice, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM to obtain the crude product. Product vykristallizovyvalas from EtOAc to obtainpyrrolo[2,3-b]pyridine-1-ylamide 2-pyridine-2-Yeremey-5-carb is new acid (78 mg, 25%) as a solid. MS: 317 (M+H);1H NMR (300 MHz, CD3OD): δ 6,56 (m, H), from 7.24 (m, H), 7,53 (m, H), to 7.61 (m, H), 8,01-8,17 (m, 2H), 8,27 (d, H), 8,69 (m, H), 8,78(m, H), of 9.51 (s, 2H).

Example 126

Pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Diethylethanolamine (1.13 mmol) are added to a solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 ml) at room temperature and the reaction mixture is stirred at a temperature of 80°C during the night. The reaction mixture was concentrated in vacuo. The residue is dissolved in EtOAc, washed with saturated aqueous Na2CO3and water, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% CH3CN in DHM to obtain the crude product. The crude product vykristallizovyvalas from EtOAc to obtainpyrrol[2,3-b]pyridine-1-ylamide 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(95 mg, 38%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CD3OD): δ 2,89 (s, 3H), of 6.65 (d, H), of 7.23 (m, H), of 7.48-7,66 (m, 2H), 8,01-of 8.15 (m, 2H), 8,29 (m, H)8,64 (d, H), 8,77 (d, H), was 9.33 (s, 2H).

Example 127

Pyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Diethylethanolamine (1.88 mmol) are added to a solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (0.75 mmol), pyrrolo[3,2-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 ml) at room temperature and the reaction mixture is stirred at a temperature of 80°C for 8 h, the Reaction mixture was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-10% MeOH in DHM to getpyrrolo[3,2-b]pyridine-1-ylamide 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(155 mg, 63%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CD3OD): δ 2,89 (s, 3H), 7,01 (d, H), of 7.64-to 7.77 (m, 2H), 8,15 (m, H), of 8.25 (m, H), 8,59-8,76 (m, 3H), 8,82 (d, H), 9,31 (s, 2H). IC50=13 nm.

Example 128

Pyrrolo[2,3-c]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. The solution pyrrolo[2,3-c]pyridine (of 8.47 mmol) and tert-butoxide potassium (about 16.9 mmol) in DMF (38 ml) was stirred at room temperature in a stream of N2within 2 hours is Added dropwise 0,15M NH2Cl in ether (84,6 ml) at room temperature and the reaction mixture was stirred at room temperature for 2 h, quenched with 5% aqueous solution of Na2S2O3(10 ml) and extracted with ether. The organic phase is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Statomat chromatography on silica gel, elwira 0-10% MeOH in DHM to getpyrrolo[2,3-c]pyridine-1-ylamine(226 mg, 11%) as a solid. MS: 134 (M+H);1H NMR (300 MHz, CDCl3): δ 4,96 (ush., 2N-H), to 6.43 (d, H), 7,29 (m, H), 7,50 (d, H), 8,29 (d, H)8,89 (s, H).

Stage 2. Diethylethanolamine (1.13 mmol) are added to a solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-c]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 ml) at room temperature and the reaction mixture is stirred at a temperature of 80°C during the night. Water is added and the mixture extracted with EtOAc. The organic phase is separated, washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 40-100% MeOH in DHM to getpyrrolo[2,3-c]pyridine-1-ylamide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(117 mg, 45%) as a solid. MS: 348 (M+H);1H NMR (300 MHz, CD3OD): δ 2,84 (s, 3H), 6,72 (d, H), 7,29 (m, H), 7,55 (m, H), 7,71 (m, H), 8,14-8,29 (m, 2H), at 8.36 (d, 3), is 8.75 (s, H), 9,17 (s, H). IC50=28,5 nm.

Example 129

Pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

In accordance with the methods similar to that described in example 127, but substituting pyrrolo[3,2-b]pyridine-1-ylamine on pyrrolo[2,3-c]pyridin-1-ylamine, getpyrrol[2,3-c]pyridine-1-alamid 4-methyl-2-is iridin-2-Yeremey-5-carboxylic acid (46%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CD3OD): δ and 2.79 (s, 3H), only 6.64 (d, H), 7,53-the 7.65 (m, 2H), 7,78 (d, H), 8,02 (m, H), by 8.22 (m, H), 8,46 (m, H), 8,80 (d, H), 8,87 (s, H), of 9.30 (s, H).

Example 130

Pyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid

In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid, 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid getpyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(40%) as a solid. MS: 331 (M+H);1H NMR (300 MHz, CD3OD): δ of 2.86 (s, 3H), 6,74 (m, H), 7,31 (m, H), to 7.61 (m, H), 7,71 (d, H), 7,92 (d, H), to 8.41 (d, H)8,71 (d, H), 8,91 (d, H), 9,20 (s, H), for 9.64 (s, H). IC50= 14 nm.

Example 131

(5-Florinda-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid

In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid, 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid, and substituting pyrrolo[3,2-b]pyridine-1-ylamine for 5-Florinda-1-ylamine, get(5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(34%) as a solid. MS: 348 (M+H);1H NMR (300 MHz, CD3OD): δ 2,85 (s, 3H), to 6.57 (m, H), 7,02 (m, H), 7.23 percent-7,46 (m, 2H), 7.62mm (m, H), and 8.0 (d, H), 8,91 (d, H), 9,17 (s, H), 9,63 (s, H).

Example 132

(5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Method A: In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting pyrrolo[3,2-b]pyridine-1-ylamine for 5-Florinda-1-ylamine, get(5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(17%) as a solid. MS: 365 (M+H);1H NMR (300 MHz, CD3OD): δ 6,56 (d, H), 7,02 (m, H), 7,22-7,44 (m, 4H), 7,55 (m, H), by 8.22 (d, H), at 8.36 (d, H), 9,13 (s, H).

Method B: a Solution of chloride of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1 mmol) in EtOAc (20 ml) is added to a stirred solution of 5-Florinda-1-ylamine (1 mmol) and K2CO3(1 mmol) in EtOAc (10 ml) and H2O (20 ml) at room temperature, then stirred at room temperature overnight. EtOAc is evaporated in vacuum and the resulting solid collected by filtration. The solid is crystallized from EtOAc/heptane to obtain(5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(62 mg, 17%) as a solid. MS: 365 (M+H);1H NMR (300 MHz, CDCl3): δ 2.82 from (s, H), 6,55 (s, H), 6.90 to-7,41 (m, 4H), 7,49 (m, H), compared to 8.26 (d, 2H), 8,57 (ush., H), 8,96 (ush., H). IC50=19 nm.

Example 33

(5-Methoxyindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 5-methoxy-1H-indole (to 16.9 mmol) and tert-butoxide potassium (33.8 mmol) in DMF (76 ml) was stirred at room temperature in a stream of N2within 2 hours is Added dropwise 0,15M NH2Cl in ether (169,2 ml) for 15 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched with 5% aqueous solution of Na2S2O3(100 ml) and stirred at room temperature overnight. The mixture is extracted with ether. The organic phase is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-20% EtOAc in heptane, to obtain5-methoxyindol-1-ylamine(388 mg, 14%) as a solid.1H NMR (300 MHz, CDCl3): δ 4,78 (ush., 2N-H), 6.35mm (d, H)6,94 (d, H), was 7.08 (d, H), 7,17 (d, H), 7,30-7,39 (d, H).

Stage 2. In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting pyrrolo[3,2-b]pyridine-1-ylamine for 5-methoxyindol-1-ylamine, get(5-methoxyindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(43%) in the form of solid substances is A. MS: 377 (M+H);1H NMR (300 MHz, CD3OD): δ and 2.83 (s, 3H), of 3.84 (s, 3H), 6,50 (d, H), 6.90 to (m, H), 7,12 (d, H), 7,22 and 7.36 (m, 3H), 7,55 (m, H), by 8.22 (d, H), at 8.36 (d, H), 9,11 (s, H). IC50=6 nm.

Example 134

(5-Cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. NaH (60%, 60 mmol) is added by portions to a solution of 5-cyano-1H-indole (20 mmol) in NMP (35 ml) and the temperature of the reaction mixture support 0°C for 1 h a Solution of HOSA (60 mmol) in NMP (14 ml) is added dropwise at 0°C. the Reaction mixture is heated to room temperature and stirred overnight, then quenched with water and extracted with EtOAc. The organic phase is separated, washed with water three times and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 20-40% EtOAc in heptane, to obtain5-cyanoindole-1-ylamine(531 mg, 16%) as a solid.1H NMR (300 MHz, CDCl3): δ 4,88 (ush., 2N-H), 6,53 (d, H), 7,32 (d, H), 7,54 (kV, 2H), 7,98 (d, H).

Stage 2. In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting pyrrolo[3,2-b]pyridine-1-ylamine for 5-cyanoindole-1-ylamine, get(5-cyanoindole-1-yl)amide2-(3-forfinal)-4-methylpyrimidin-5-carboxylic key is lots (39%) as a solid. MS: 372 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,77 (s, 3H), 6.73 x (l, H), was 7.45 (m, H), 7,53-of 7.82 (m, 4H), 8,08-8,23 (m, 2H), 8,32 (d, H), 9,27 (s, H), 12,15 (ush., N-H).

Example 135

(4-Cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods similar to those described in example 134, step 1, but substituting 5-cyano-1H-indole 4-cyano-1H-indol get4-cyanoindole-1-ylamine(33%) as a solid.1H NMR (300 MHz, CDCl3): δ 4,1 (ush., 2N-H), to 6.88 (d, H), 7,22-7,40 (m, 2H), 7,51 (d, H), 7,72 (d, H).

Stage 2. In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, and substituting pyrrolo[3,2-b]pyridine-1-ylamine for 4-cyanoindole-1-ylamine, get(4-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(29%) as a solid. MS: 372 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,77 (s, 3H), of 6.71 (s, H), 7,32-7,51 (m, 2H), EUR 7.57-of 7.69 (m, 2H), 7,88 (m, 2H), 8,16 (d, H), 8,31 (d, H), a 9.25 (s, H).

Example 136

[4-(1H-Tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Solution (0.5 mmol), ammonium chloride (6 mmol) and sodium azide (6 mmol) in anhydrous DMF (6 ml) is heated in a microwave oven when the temperature is f 200°C for 1 h The reaction mixture was quenched with saturated aqueous Na2CO3and washed with EtOAc. The aqueous phase is separated, acidified with a concentrated aqueous solution to adjust the pH to ~1 and extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 3% MeOH in DHM to get[4-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(18 mg, 9%) as a solid. MS: 415 (M+H);1H NMR (300 MHz, CD3OD): δ 2,85 (s, 3H), 7,20-7,35 (m, 2H), 7,44 (m, H), 7,52-to 7.59 (m, 2H), 7,65 (m, H), to 7.77 (d, H)8,23 (d, H), of 8.37 (d, H), 9,18 (s, H).

Example 137

Methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid

Stage 1. In accordance with the methods similar to that described in example 133, step 1, but replacing 5-methoxy-1H-indol on methyl ester 1H-indole-4-carboxylic acid, getmethyl ester of 1-amino-1H-indole-4-carboxylic acid(10%) as a solid.1H NMR (300 MHz, CDCl3): δ 4,88 (ush., 2N-H), 7,03 (d, H), 7,33 (m, 2H), 7,49 (d, H), 7,94 (d, H).

Stage 2. In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, replace pyrrolo[3,2-b]pyrid the n-1-ylamine for methyl ester of 1-amino-1H-indole-4-carboxylic acid and the reaction mixture is stirred at a temperature of 150°C for 45 minutes, getmethyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid(33%) as a solid. MS: 405 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,77 (s, 3H), 3,92 (s, 3H), 7,44 (m, H), 7,63 (m, H), 7,72 (m, H), 7,76-7,88 (m, 2H), 8,17 (d, H), 8,31 (d, H), 9,26(s, H), 12,06 (ush., N-H).

Example 138

1-{[2-(3-Forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid

A solution of methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid (0.48 mmol) and LiOH (1,91 mmol) in methanol/THF/H2O (1:1:1, 6 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and washed DHM. The aqueous phase is distributed and acidified with 10%aqueous HCl solution to adjust the pH to ~1. The mixture is extracted with ether twice. The organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid (186 mg, 99%) as a solid. MS: 391 (M+H);1H NMR (300 MHz, CD3OD): δ 2,85 (s, 3H), 7,20 (m, H), 7.24 to 7,40 (m, 2H), 7,46-to 7.61 (m, 2H), 7,66 (d, H), 7,92 (d, H)8,23 (d, H), of 8.37 (d, H), 9,16 (s, H).

Example 139

(3-Cyanomethyl-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. In accordance with the methods and the logic described in example 133, stage 1, but replacing 5-methoxy-1H-indol on 1H-indol-3-ylacetonitrile get(1-amino-1H-indol-3-yl)-acetonitrile(17%) as a solid.1H NMR (300 MHz, CDCl3): δ a 3.83 (s, 2H), 4,80 (ush., 2N-H), 7,17-7,25 (m, 2H), 7,33 (t, H), 7,46 (d, H), to 7.59 (d, H).

Stage 2. In accordance with the methods similar to that described in example 127, but substituting 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, replace pyrrolo[3,2-b]pyridine-1-ylamine for 3-cyanomethylene-1-ylamine and the reaction mixture is stirred at a temperature of 150°C for 1 h, get(3-cyanomethyl-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(42%) as a solid. MS: 386 (M+H);1H NMR (300 MHz, CD3OD): δ 2,84 (s, 3H), a 4.03 (s, 2H), 7,15-of 7.48 (m, 5H), 7,55 (m, H), of 7.70 (d, H)8,23 (d, H), of 8.37 (d, H), 9,14 (s, H).

Example 140

(5-Methoxyindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

In accordance with the methods similar to that described in example 127, but substituting pyrrolo[3,2-b]pyridine-1-ylamine for 5-methoxyindol-1-ylamine, the reaction mixture is stirred at a temperature of 150°C for 1 h, get(5-methoxyindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid(22%) as a solid. MS: 360 (M+H);1H NMR (300 MHz, CD3OD): δ is 2.88 (s, 3H), of 3.84 (s, 3H), 6,50 (d, H), 6.90 to (m, H), 7,13 (d, H), 7,25-7,34 (m, 2), of 7.60 (m, H), with 8.05 (m, H), 8,65 (d, H), 8,79 (d, H), 9,20 (s, 2H).

Example 141

[3-(1H-Tetrazol-5-ylmethyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

In accordance with the methods similar to those described in example 136, but substituting (4-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (3-cyanomethyl-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid, get[3-(1H-tetrazol-5-ylmethyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(12%) as a solid. MS: 429 (M+H);1H NMR (300 MHz, CD3OD): δ 2,85 (s, 3H), to 4.52 (s, 2H), 7,15 (m, H), 7.24 to 7,35 (m, 2H), was 7.36-to 7.50 (m, 2H), 7,55 (m, H)8,23 (d, H), of 8.37 (d, H)to 9.15 (s, H).

Example 142

2-(2-Phenylpyrimidine-5-carbonyl)-1-hydrazinecarboxamide

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrochloride semicarbazide get2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazinecarboxamide(62%) as a solid. MS: 258 (M+H).

Example 143

2-(2-Phenylpyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetr hydropyridine-5-propionic acid thiosemicarbazide, get2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide(27%) as a solid. MS: 274 (M+H).

Example 144

(2,4-Dioxoimidazolidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 2,4-dioxoimidazolidin-1-ylamine, get(2,4-dioxoimidazolidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid(8%) as a solid. MS: 298 (M+H).

Example 145

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-ylamine, get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid(39%) as a solid. MS: 311 (M+H);1H NMR (300 MHz, CD3OD): δ to 1.98 (s, 3H), 4,32 (s, 2H), 7,45-7,63 (m, 3H), and 8.50 (d, 2H), 9,24 (s, 2H).

Example 146

N'-Phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting methyl is a new ester 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid N'-phenylhydrazine, getN'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid(18%) as a solid. MS: 291 (M+H);1H NMR (300 MHz, CDCl3): δ 6,34 (s, N-H), 6,82? 7.04 baby mortality (m, 2H), 7,15-7,39 (m, 3H), 7,40-7,63 (m, 3H), 7,94 (s, N-H), 8,51 (d, 2H), 9,20 (s, 2H).

Example 147

N'-(2-Phenylpyrimidine-5-carbonyl)hydrazide pyridine-2-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrazide 2-pyridine-2-carboxylic acid, getN'-(2-phenylpyrimidine-5-carbonyl)hydrazide pyridine-2-carboxylic acid(52%) as a solid. MS: 320 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 7.75 (m, 4H), 7,98-to 8.14 (m, 2H), 8,46 (d, 2H), 8,73 (d, H), to 9.32 (s, 2H), 10,81 (s, N-H), 10,96 (ush., N-H).

Example 148

4-[N'-(2-Phenylpyrimidine-5-carbonyl)hydrazino]benzosulfimide

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid 4-hydrazinobenzothiazole get4-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]benzosulfimide(36%) as a solid. MS: 370 (M+H).

Example 149

N'-(2-Phenylpyrimidine-5-carbonyl)hydrazide 3-hydroxybenzoic acid

In the accordance with the methods similar to that described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrazide 3-hydroxybenzoic acid, getN'-(2-phenylpyrimidine-5-carbonyl)hydrazide 3-hydroxybenzoic acid(56%) as a solid. MS: 335 (M+H).

Example 150

N'-(Phenylpyrimidine-5-carbonyl)hydrazide benzo[1,3]dioxo-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrazide benzo[1,3]dioxo-5-carboxylic acid, getN'-(phenylpyrimidine-5-carbonyl)hydrazide benzo[1,3]dioxo-5-carboxylic acid(83%) as a solid. MS: 363 (M+H).

Example 151

N'-(Phenylpyrimidine-5-carbonyl)hydrazide of 3,4-dimethoxybenzoic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid hydrazide of 3,4-dimethoxybenzoic acid, getN'-(phenylpyrimidine-5-carbonyl)hydrazide3,4-dimethoxybenzoic acid(76%) as a solid. MS: 379 (M+H).

Example 152

N'-Methyl-N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 64 but substituting the methyl ester of 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-propionic acid N'-methyl-N'-phenylhydrazine, getN'-methyl-N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid(80 mg, 88%) as a solid. MS: 305 (M+H).

Example 153

(5-Methoxy-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of tert-butoxide potassium (5,23 g, 46,62 mmol) and 5-methoxy-3-methylindole (3,41 g to 21.15 mmol) in DMF (20 ml) was stirred at room temperature for 45 minutes a Solution of monochloramine in ether (400 ml, 60 mmol) is added through an additional funnel over 15 minutes the mixture is stirred for 2 hours the Solvent is removed and the residue partitioned between EtOAc and water. The organic fraction is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified column chromatography, elwira 10% EtOAc in heptane, to obtain5-methoxy-3-methylindol-1-ylamine(1.42 g, 38%) as a solid. MS: 176 (M+H);1H NMR (300 MHz, CDCl3): δ 7,26-of 7.23 (m, 1H), 6,98-6,97 (m, 1H), 6,91-6,87 (m, 2H), with 4.64 (USS, 2H), 3,86 (s, 3H), 2.26 and was 2.25 (m, 3H).

Stage 2. In a microwave vial (20 ml) was placed 2-(3-forfinal)4-methylpyrimidin-5-carboxylic acid (657 mg, of 2.83 mmol), HOTT (1,16 g, 3.11 mmol), DIPEA (1.35 ml, 7,73 mmol) and DMF (6 ml). The mixture is stirred at 23°C in a stream of N2within 15 minutes Add 5-methoxy-3-methylindol-1-ylamine (456 mg, at 2.59 mmol) and the vial lid. The resulting mixture was heated in a microwave oven (Biotage-Initiator) at a temperature of 150°C for 6 minutes, the Mixture was partitioned between EtOAc and water. The organic fraction is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified column chromatography, elwira 45% EtOAc in heptane, to obtain(5-methoxy-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(327 mg, 32%) as a solid. MS: 391 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 11.75 (s, 1H), 9,19 (s, 1H), 8,32 (d, 1H), 8,18-8,16 (m, 1H), 7,66 to 7.62 (m, 1H), 7,45 (TD, 1H), 7,30 (d, 1H), 7,22 (s, 1H), 7,05 (d, 1H), 6,85 (DD, 1H), 3,81 (s, 3H), was 2.76 (s, 3H), and 2.27 (s, 3H).

Example 154

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid

Stage 1. In accordance with the methods similar to that described in example 59, step 1, but substituting 3-methoxyphenylalanine acid 3-hydroxyphenylarsonic acid, getmethyl ester 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid.

Stage 2. In accordance with the methods similar to that described in example 59, stage 2, but substituting the methyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid methyl ester 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid, get2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid.

Stage 3. In accordance with the methods similar to that described in example 59, step 3, but replacing 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid. MS: 327 (M+H);1H NMR (DMSO-d6): δ 1.91 a (s, 3H), 4,22 (s, 2H), of 5.75 (s, 1H), 6,98 (m, 1H), was 7.36 (m, 1H), of 7.90 (m, 1H), 9,25 (s, 2H), 9,71 (s, 1H), 9,95 (s, 1H), 11,05 (s, 1H). IC50=21 nm.

Example 155

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid

Stage 1. In accordance with the methods similar to that described in example 59, step 1, but substituting 3-methoxyphenylalanine acid 2-hydroxyphenylarsonic acid, getmethyl ester 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid.

Stage 2. In accordance with the methods similar to that described in example 59, step 2, but substituting the methyl ester of 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid methyl ester 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid, get2-(2-hydroxyphenyl)pyrim the DIN-5-carboxylic acid .

Stage 3. In accordance with the methods similar to that described in example 59, step 3, but replacing 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid get(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid. MS: 327 (M+H);1H NMR (DMSO-d6): δ = 1.91 a (s, 3H), 4,22 (s, 2H), 7,02 (m, 2H), 7,50 (m, 1H), 8,46 (m, 1H), to 9.32 (s, 2H), becomes 9.97 (s, 1H), 11,12 (s, 1H), 12,95 (s, 1H).

Example 156

(6-Methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-hydroxyphenyl)pyrimidine-5-carboxylic acid

A mixture of (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid (100 mg, 0.29 mmol), methanethiol sodium (206 mg, 2.9 mmol) and DMF (2 ml) is stirred at 110°C for 6 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the residue purified HPLC on a reversed-phase column to retrieve(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-hydroxyphenyl)pyrimidine-5-carboxylic acid(32 mg). MS: 327 (M+H);1H NMR (DMSO-d6): δ of 1.87 (s, 3H), 4,17 (s, 2H), 6,74 (m, 2H), 8,21 (d, J=6,9 Hz, 2H), remaining 9.08 (s, 2H), at 9.53 (s, 1H).

Example 157

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

Stage 1. The flask containing 2-C is anoperation (16.6 g, 158 mmol), ammonium acetate (14.6 g, 189,6 mmol), N-acetylcysteine (2.58 g, 15.8 mmol) and ethanol (160 ml), refluxed. After 1.25 h, the reaction mixture was slightly cooled (approximately 50°C) and add tert-piperonyl sodium (15,18 g, 158 mmol) and ethanol (160 ml). After stirring for 10 minutes, add ethyl ester 2-dimethylaminomethylene-3-oxomalonate acid (33.6 g, 181,7 mmol). The reaction mixture is then refluxed for a further 2 hours the Reaction mixture is then cooled to room temperature and add sodium hydroxide (12,6 g, 316 mmol) in water (50 ml). After 2 h the reaction mixture was cooled in an ice bath and the pH of the reaction adjusted to ~3, using an aqueous solution of ~12M HCl. The reaction mixture was then concentrated in vacuo to ~100 ml Pour in additional water (100 ml) and the suspension cooled in an ice bath, filtered and the precipitate washed with a minimum amount of cooling water. The precipitate is then dried in vacuum to obtain4-methyl-[2,2']bipyridinyl-5-carboxylic acid(85%).

MS: 217 (M+H);1H NMR (300 MHz, CDCl3): δ = 2,80 (s, 3H), 7,66 (t, 1H), 9,01 (d, 2H), 9,14 (s, 1H).

Stage 2. 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (0.5 g, 2,31 mmol) combine with chloride of 5-fluoro-3-methylindol-1 ramonia (464 mg, 2,31 mmol), N-methylmorpholine (233 mg, 2,31 mmol) and DMF (10 ml). The suspension is stirred for 5 minutes at room t is mperature, then add the chloride of 4-(4,6-dimethoxy-[1,3,5]triazine-2-yl)-4-methylmorpholin-4-s (640 mg, 2,31 mmol). The reaction mixture is heated to 50°C for 4 h, the Reaction mixture was then poured into water (50 ml), the suspension is cooled for 2 hours in the refrigerator and then filtered. The precipitate is then suspended in acetonitrile at 50°C for 4 h, cooled, then filtered to obtain(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(60%). MS: 363 (M+H);1H NMR (300 MHz, CDCl3): δ=, and 2.27 (s, 3H), 2,77 (s, 3H), 7,07 (dt, 1H), was 7.36 (DD, 1H), 7,38 (s, 1H), 7,44-of 7.48 (m, 1H), of 7.70 (t, 1H), 9,05 (d, 2H), 9,29 (s, 1H), 11,9 (s, 1H). IC50=4,5 nm.

Example 158

(5-fluoro-3-methylindol-1-yl)amide 2-thiazol-2-Yeremey-5-carboxylic acid

Stage 1. In flask 2-cenotesa (6.7 g, 60,9 mmol), ammonium acetate (5,63 g, 73 mmol), N-acetylcysteine (993 mg, 6,09 mmol) and methanol (60 ml). The reaction mixture was then refluxed overnight. The reaction mixture was concentrated in vacuo to obtain a residue used in the next stage without additional modifications.

Stage 2. The crude residue obtained in stage 1, are suspended in DMF (100 ml). To it add 2-etoxycarbonyl-3-exabot-1-EN-1-Olathe sodium (13,86 g, 70 mmol). The reaction mixture was then heated to 100°C for 1.5 h and then cooled to CONTROLTEMPLATES. The reaction mixture was then poured into ice water (1 liter). The suspension is filtered and the filtrate is successively extracted with DHM (100 ml) and EtOAc (200 ml). The organic phase is dried (Na2SO4), filtered and concentrated to obtain a residue (10,31 g).

Stage 3. The residue from stage 2 (of 6.26 g, weighing 28.32 mmol) are combined with sodium hydroxide solution (of 2.26 g, 56,65 mmol) in water (90 ml) and methanol (90 ml) and stirred at room temperature overnight. The solution volume is reduced by half in vacuo and the pH adjusted to 3 with aqueous HCl (approx 12M). The solid is collected by filtration and dried in vacuum to obtain2-thiazol-2-Yeremey-5-carboxylic acid (56% for 3 stages). MS: 208 (M+H);1H NMR (300 MHz, CDCl3): δ = 8,11 (d, 1H), 8,16 (d, 1H), to 9.32 (s, 2H).

Stage 4: a Mixture of 2-thiazol-2-Yeremey-5-carboxylic acid (50 mg, 0,244 mmol), chloride 5-fluoro-3-methylindol-1 ramonia (49 mg, 0,244 mmol), diisopropylethylamine (31.5 mg, 0,244 mmol) in DMF (1 ml) was stirred at room temperature for 5 minutes To the mixture of the chloride of 4-(4,6-dimethoxy-[1,3,5]triazine-2-yl)-4-methylmorpholin-4-s (37 mg, mmol 0,244). The reaction mixture is heated to 50°C for 1.5 h and then concentrated in vacuo. The residue is transferred in DMSO-d6then HPLC purified on reverse-phase C18 column, elwira water and acetonitrile, with a buffer of 0.1% TFU, to get(5-fluoro-3-mutilin the ol-1-yl)amide 2-thiazol-2-Yeremey-5-carboxylic acid (58%). MS: 354 (M+H);1H NMR (300 MHz, CDCl3): δ=, and 2.27 (s, 3H), 7,05 (dt, 1H), 7,32 (s, 1H), 7,32-7,44 (m, 2H), 8,11 (d, 1H), 8,19 (d, 1H), 9,42 (s, 2H), 12,12 (s, 1H).

Example 159

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

Stage 1. A solution of 2-canadiate (1.55 g, of 14.2 mmol) in MeOH (12 ml) is treated with N-acetylcysteine (234 mg, of 1.42 mmol), ammonium acetate (1.5 g, 18.5 mmol) and heated in a microwave oven at a temperature of 120°C for 15 minutes the Mixture was then treated with ethyl ether 2-dimethylaminomethylene-3-oxomalonate acid (3.2 g, 17,0 mmol) and KOt-Bu (2.2 g, 20 mmol) and heated in a microwave oven at a temperature of 120°C for another 15 minutes the Mixture is then treated with a solution KOH (1.2 g, 20 mmol) in H2O (5 ml) and refluxed for 1 h, the Mixture is neutralized with a concentrated aqueous solution of HCl. The precipitate is collected by filtration and dried to obtain4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (1,95 g, 62%). MS: 222 (M+H);1H NMR (300 MHz, DMSO-d6): δ 13,77 (s, OH, 1H), 9,18 (s, 1H), 8,13 (d, 1H), 8,07 (d, 1H), 2,81 (s, 3H).

Stage 2. A mixture of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (221 mg, 1 mmol), chloride 5-fluoro-3-methylindol-1-yl-ammonium (200 mg, 1 mmol) and N-methylmorpholine (101 mg, 1 mmol) in DMF (5 ml) was stirred at room temperature for 5 minutes Add the chloride of 4-(4,6-dimethoxy-[1,3,5]triazine-2-yl)-4-m is hilmarton-4-s (277 mg, 1 mmol) and the reaction mixture is heated to 50°C for 4 h, the Reaction mixture was then poured into water (50 ml). The precipitate is collected by filtration and dried in vacuum to obtain(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(68%). MS: 368 (M+H);1H NMR (300 MHz, CDCl3): δ=, and 2.27 (s, 3H), was 2.76 (s, 3H), 7,06 (dt, 1H), 7,35-7,38 (m, 2H), 7,42-7,47 (m, 1H), 8,07 (d, 1H), 8,14 (d, 1H), which 9.22 (s, 1H), 11,9 (s, 1H).

Example 160

(5-fluoro-3-methylindol-1-yl)amide [2,2']bipyridinyl-5-carboxylic acid

Stage 1. In an autoclave was placed 2-cyanopyrimidine (7,88 g, 75 mmol), N-acetylcysteine (1.22 g, 7.5 mmol), ammonium acetate (6,93 g, 90 mmol) and MeOH (75 ml). The autoclave is sealed and heated at 110°C for 1.5 h and then cooled to room temperature. To the reaction mixture are added 2-etoxycarbonyl-3-exabot-1-EN-1-Olathe sodium (17 g, 86,25 mmol) and MeOH (75 ml). The mixture is refluxed for 1.5 h and then cooled to room temperature. To the mixture is added NaOH (6 g, 150 mmol) and water (80 ml). The mixture is stirred for 30 min or until LC-MS signal of the completion of the hydrolysis of the intermediate ester. the pH of the reaction mixture was adjusted to ~3 concentrated (~12M) aqueous solution of HCl. MeOH is evaporated in vacuum and the precipitate is collected by filtration and washed with a minimum amount of cooling water is to get [2,2']bipyridinyl-5-carboxylic acid (59%). MS: 203 (M+H);1H NMR (300 MHz, CDCl3): δ = 7,71 (t, 1H), 9,06 (d, 2H), 9,40 (s, 2H).

Stage 2. A mixture of [2,2']bipyridinyl-5-carboxylic acid (166 mg, 0.82 mmol), chloride 5-fluoro-3-methylindol-1 ramonia (164 mg, 0.82 mmol) and DIPEA (106 mg, 0.82 mmol) in DMF (5 ml) was stirred at room temperature for 5 minutes To the mixture of the chloride of 4-(4,6-dimethoxy-[1,3,5]triazine-2-yl)-4-methylmorpholin-4-s (226 mg, 0.82 mmol). The reaction mixture is heated to 50°C for 1.5 h and then concentrated in vacuo. The residue is transferred in DMSO-d6and then HPLC purified on reverse-phase C18 column, elwira water and acetonitrile, with a buffer of 0.1% TFU, to get(5-fluoro-3-methylindol-1-yl)amide [2,2']bipyridinyl-5-carboxylic acid(56%). MS: 349 (M+H);1H NMR (300 MHz, CDCl3): δ=, and 2.27 (s, 3H), 7,05 (dt, 1H), 7,33 (s, 1H), was 7.36 (DD, 1H), 7,42-7,46 (m, 1H), 7,72 (t, 1H), 9,07 (d, 2H), 9,51 (s, 2H), 12,17 (s, 1H).

Example 161

(3-Chloro-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of (5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (300 mg, 0,824 mmol) in MeCN (20 ml) was treated with NCS (185 mg, of 1.42 mmol) and the mixture is stirred at 60°C in a sealed flask for 2 hours the Mixture was then concentrated, diluted with 10%aqueous solution of Na2S2O8(20 ml) and extracted with EtOA (3×20 ml). The combined organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10%-20% EtOAc in heptane, to obtain(3-chloro-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(160 mg, 49%). MS: 399 (M+H);1H NMR (300 MHz, CDCl3): δ 8,79 (s, 1H), 8,04 (d, 1H), 7,92 (d, 1H), 7,18 (m, 1H),? 7.04 baby mortality (s, 1H), 7,00 (m, 3), 6,76 (m, 1), 2,52 (s, 3H).

Example 162

Amide 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-3-carboxylic acid

A solution of (5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (300 mg, 0.82 mmol) in 2-Me-THF (7 ml) is treated chlorosulfonylisocyanate (CSI) (85 μl, 2.0 mmol) at 0°C and the mixture is heated to room temperature within 2 h the Mixture was then cooled to 0°C, treated with 1M NaOH (1 ml), diluted with brine (20 ml) and extracted with EtOAc (3×20 ml). The combined organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtainamide 5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-3-carboxylic acid(275 mg, 83%). MS: 408 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,27 (s, 1H), 8,35 (d, 1H), compared to 8.26 (s, 1H), to 8.20 (d, 1H), 7,95 (d, 1H), to 7.59 (m, 3H), 7,15 (m, 1H), 2,78 (s, 3H). IC50=8 nm.

Example 163

2-{5-fluoro-1-[(4-methyl-2-pyridine-2-illerimi the in-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionate acid

Stage 1. A solution of methyl ester (5-fluoro-1H-indol-3-yl)acetic acid (3 g, of 14.8 mmol) in MeCN (25 ml) is treated with Boc2O (4.3 g, 16.3 mmol) and DMAP (200 mg, and 1.63 mmol) and the mixture is stirred at room temperature for 1 h the Mixture was diluted with saturated aqueous NH4Cl (50 ml) and extracted with DHM (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 8% EtOAc in heptane, to obtaintert-butyl ester 5-fluoro-3-methoxycarbonylmethylene-1-carboxylic acid(1.6 g, 35%). MS: 371 (M+Na+ACN);1H NMR (300 MHz, CDCl3): δ of 8.09 (m, 1H), to 7.59 (s, 1H), 7,17 (m, 1H),? 7.04 baby mortality (m, 1H), and 3.72 (s, 3H), to 3.67 (s, 2H), of 1.55 (s, 9H).

Stage 2. A solution of tert-butyl ester 5-fluoro-3-methoxycarbonylmethylene-1-carboxylic acid (1.6 g, 5.2 mmol) in 2-Me-THF (50 ml) at -78°C is treated with LDA (5,7 ml, 1.8m in THF, 10.4 mmol) and stirred for 0.5 hours Add MeI (of 1.02 ml, 15.6 mmol) and the mixture is heated to 0°C for 2 hours the Mixture is diluted with saturated aqueous NH4Cl (50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtaintert-butyl ester 5-fluoro-3-(1-methoxycarbonyl-1-methylethyl)indole-1-carboxylic acidused the next stage without additional purification.

Stage 3. A solution of tert-butyl ester 5-fluoro-3-(1-methoxycarbonyl-1-methylethyl)indole-1-carboxylic acid (5.2 mmol) in MeOH (25 ml) is treated with K2CO3(720 mg, 5.2 mmol) and refluxed for 2 hours the Mixture is diluted with brine (50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester of 2-(5-fluoro-1H-indol-3-yl)-2-methylpropionic acid(650 mg, 53%, stage 2), which is used in the next stage without additional purification. MS: 236 (M+H);1H NMR (300 MHz, DMSO-d6): δ 7,35 (m, 1H), 7,30 (m, 1H), 7,14 (m, 1H), 6,91 (m, 1H), 3,54 (s, 3H), of 1.57 (s, 6H).

Stage 4. A suspension of NaH (1,02 g, 25.5 mmol, 60% in mineral oil) in DMF (25 ml) at 0°C is treated with methyl ether of 2-(5-fluoro-1H-indol-3-yl)-2-methylpropionic acid (400 mg, 1.7 mmol) and stirred at 0°C for 0.5 h the Mixture was treated with portions of HOSA (960 mg, 8.5 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×100 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylpropionic acidthat is used in the next stage without additional about isdi.

Stage 5. A solution of methyl ester of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylpropionic acid (0.85 mmol) and 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (201 mg, 0,935 mmol) in DMF (8.5 ml) is stirred at 40°C for 0.5 hours, the Mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60°C for 1 h the Mixture was concentrated in vacuo, diluted with saturated aqueous a solution of Na2CO3(20 ml) and extracted with EtOAc (3×20 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester 2-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionic acidthat is used in the next stage without additional purification.

Stage 6. A solution of methyl ester 2-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionic acid (0.85 mmol) in MeOH (5 ml) is treated with 10%aqueous NaOH solution (2 ml) and stirred at room temperature overnight. The mixture was then concentrated, diluted with EtOAc (50 ml) and extracted with 10%aqueous NaOH solution (3×50 ml). The aqueous phase is acidified with 12M aqueous HCl and extracted with DHM (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated. The residue is triturated with Et2O to get2-{5-fluoro-1-[(4-methyl-2-feast of the DIN-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionic acid (100 mg, 27%, 3 phase). MS: 434 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,26 (s, 1H), 8,79 (m, 1H), 8,44 (d, 1H), 8,03 (t, 1H), to 7.59 (m, 1H), 7,53 (s, 1H), 7,49 (m, 1H), 7,35 (d, 1H), was 7.08 (t, 1H), and 2.79 (s, 3H), of 1.59 (s, 6H).

Example 164

2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionate acid

Stage 1. A solution of methyl ester of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylpropionic acid (0.85 mmol) and 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (217 mg, 0,935 mmol) in DMF (8.5 ml) is stirred at 40°C for 0.5 hours, the Mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60°C for 1 h the Mixture was concentrated in vacuo, diluted with saturated aqueous a solution of Na2CO3(20 ml) and extracted with EtOAc (3×20 ml). The combined organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ester of 2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionic acidthat is used in the next stage without additional purification.

Stage 2. A solution of methyl ester of 2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionic acid (0.85 mmol) in MeOH (5 ml) is treated with 10%aqueous NaOH solution (2 ml) and stirred at room temperature during the night is. The mixture was then concentrated, diluted with EtOAc (50 ml) and extracted with 10%aqueous NaOH solution (3×50 ml). The aqueous phase is acidified with 12M HCl and extracted with DHM (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated. The residue is treated with Et2O to get2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionic acid(139 mg). MS: 451 (M+H);1H NMR (300 MHz, DMSO-d6): δ which 9.22 (s, 1H), with 8.33 (d, 1H), 8,18 (d, 1H), 7,63 (m, 1H), 7,50 (m, 3H), 7,33 (m, 1H), 7,07 (m, 1H), 2,78 (s, 3H), of 1.59 (s, 6H). IC50=7 nm.

Example 165

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 5-farindola (10.5 g, 78 mmol) in MeCN (150 ml) at 0°C is treated with methyl vinyl ketone are in 9.5 ml, 117 mmol) and Sc(OTf)3(383 mg, 0.78 mmol) and stirred for 1 h the Mixture was then stirred for further 6 h at room temperature. The mixture was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10%-50% EtOAc in heptane, to obtain4-(5-fluoro-1H-indol-3-yl)butane-2-it(11.1 g, 70%).

Stage 2. A solution of 4-(5-fluoro-1H-indol-3-yl)butane-2-she (11.1 g, 54.1 mmol) in THF (200 ml) at 0°C is treated with MeMgBr (54,1 ml, 3M in THF, 162,3 mmol), stirred at 0°C for 2 h and warmed to room temperature in the course is their night. The mixture was then poured on ice, treated with NH4Cl (3 g) in the solid state and extracted with EtOAc (3×120 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10-60% EtOAc in heptane, to obtain4-(5-fluoro-1H-indol-3-yl)-2-methylbutane-2-ol(of 3.07 g, 26%). MS: 222 (M+H);1H NMR (300 MHz, CDCl3): δ 7,94 (s, NH, 1H), 7,22 (m, 2H), 7,03 (s, 1H), 6,93 (m, 1H), 2,81 (m, 2H), 1,90 (m, 2H), 1,33 (s, 6H).

Stage 3. A suspension of NaH (8,1 g, 204 mmol, 60% in mineral oil) in DMF (100 ml) at 0°C is treated with 4-(5-fluoro-1H-indol-3-yl)-2-methylbutane-2-I (3 g, to 13.6 mmol) and stirred at 0°C for 0.5 h the Mixture was treated with portions of HOSA (7.7 g, 68 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×100 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by filtration through a thin layer of silica gel to obtain4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylbutane-2-olthat is used in the next stage without additional purification. MS: 237 (M+H);1H NMR (300 MHz, CDCl3): δ 7,30 (m, 1H), 7,22 (m, 1H), 6,98 (m, 2H), 4,71 (s, NH2, 2H), 2,75 (m, 2H), to 1.86 (m, 2H), 1,31 (s, 6H).

Stage 4. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (278 mg, 1.2 mmol) and 4-(1-and the Ino-5-fluoro-1H-indol-3-yl)-2-methylbutane-2-ol (1.2 mmol) in DMF (10 ml) is stirred at 50°C for 1 h The mixture is treated with DMTMM (331 mg, 1.2 mmol) and stirred at 50°C for 1 h the Mixture was concentrated in vacuo, diluted with saturated aqueous Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 50% EtOAc in heptane, to obtain[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(330 mg, 61%). MS: 451 (M+H);1H NMR (300 MHz, CD3OD): δ 9,10 (s, 1H), at 8.36 (d, 1H), 8,23 (d, 1H), 7,55 (m, 1H), 7,32 (m, 3H), 7,18 (s, 1H), 7,03 (m, 1H), 3,91 (s, OH, 1H), 2,84 (s, 3H), 2,82 (m, 2H), 1.91 a (m, 2H), 1,31 (s, 6H).

Example 166

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (516 mg, 4 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylbutane-2-ol (566 mg, 4 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (662 mg, 4 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous a solution of Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silicagel is, elwira 4%-10% MeOH in DHM to get[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(450 mg, 44%). MS: 434 (M+H);1H NMR (300 MHz, DMSO-d6): δ a 9.25 (s, 1H), 8,81 (d, 1H), of 8.47 (d, 1H), 8,02 (m, 1H), 7,58 (m, 1H), 7,43 (m, 3H), 7,06 (m, 1H), 4,29 (s, OH, 1H), 2,78 (s, 3H), of 2.72 (m, 2H), 1.77 in (m, 2H), 120 (s, 6H).

Example 167

[5-fluoro-3-(2-pyridin-3-retil)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 5-pergamena (576 mg, 3 mmol) and pyridine-3-carboxaldehyde (531 mg, 3 mmol) in MeCN (6 ml) is treated with Bu3P (1,12 ml, 4.5 mmol) and stirred at 90°C for 24 h the Mixture is concentrated and filtered through a layer of silica gel, elwira 30% EtOAc in heptane, to obtain5-fluoro-3-(2-pyridin-3-elwenil)-1H-indolein the form of a mixture of olefin isomers, which is used in the next stage without additional purification.

Stage 2. A solution of 5-fluoro-3-(2-pyridin-3-elwenil)-1H-indole (3 mmol) in MeOH (10 ml) is treated with Pd/C (200 mg) and shaken in a Parr apparatus at a pressure of 40 ATM of H2within 18 hours the Mixture is filtered through celite and the filtrate concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-10% MeOH in DHM, to get5-fluoro-3-(2-pyridin-3-retil)-1H-indole(360 mg, 50%, stage 2).

Stage 3. A suspension of NaH (600 mg, 15 mmol, 60% in mineral oil) in DMF (10 ml) and a temperature of 0°C is treated with 5-fluoro-3-(2-pyridin-3-retil)-1H-indol(240 mg, 1 mmol) and stirred at 0°C for 0.5 h the Mixture was treated with portions of HOSA (565 mg, 5 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×1050 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain5-fluoro-3-(2-pyridin-3-retil)indol-1-ylaminethat is used in the next stage without additional purification.

Stage 4. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (232 mg, 1 mmol) and 5-fluoro-3-(2-pyridin-3-retil)indol-1-ylamine (255 mmol) in DMF (10 ml) is stirred at 50°C for 10 minutes the Mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50°C for 0.5 h the Mixture was diluted with saturated aqueous Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by treatment in MeOH:H2O (2:1) to obtain a[5-fluoro-3-(2-pyridin-3-retil)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(6 mg, 1%). MS: 470 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 9.21 (s, 1H), 8,51 (m, 1H), 8,40 (m, 1H), with 8.33 (d, 1H), 8,19 (d, 1H), 7,74 (d, 1H), 7,63 (m, 1H), 7,45 (m, 4H), 7,33 (m, 1H), 7,06 (m, 1H), 3,29 (s, 2H), 3,01 (s, 2H), 2,77 (s, 3H).

Example 168

(5-fluoro-3-formylindole-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of (5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (250 mg, 0.55 mmol) in H2O (5.5 ml) is treated with DDQ (369 mg, 1.6 mmol) in EtOAc (0.5 ml) and stirred at room temperature for 2 hours the Mixture is diluted with EtOAc (50 ml), washed with brine (50 ml) and extracted with saturated aqueous NaHCO3(3×50 ml). The aqueous phase is acidified to pH 2 with concentrated HCl and washed with Et2O (50 ml). The aqueous phase is neutralized 10%aqueous NaOH solution and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by treatment in Et2O to get(5-fluoro-3-formylindole-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(87 mg, 43%). MS: 376 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 12.53 (s, NH, 1H), 10,00 (s, 1H), 9,34 (m, 1H), 8,81 (m, 1H), 8,66 (s, 1H), 8,48 (m, 1H), 8,04 (m, 1H), 7,86 (m, 1H), 7,72 (m, 1H), to 7.61 (m, 1H), 7,27 (m, 1H), 2,80 (s, 3H).

Example 169

5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid

Stage 1. A solution of methyl ester 5-fluoro-1H-indole-3-carboxylic acid (510 mg, 2.6 mmol) in NMP (6.5 ml) at room temperature is treated with KOt-Bu (342 mg, 2.9 mmol) and peremeci is up at room temperature for 0.5 H. Add a solution of O-amino-4-nitrobenzoic acid (558 mg, 3.0 mmol) in NMP (2.5 ml) and the mixture is stirred for 3 hours the Mixture is diluted with EtOAc (50 ml) and washed with 10%aqueous solution of NaHCO3(50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtainmethyl ether1-amino-5-fluoro-1H-indole-3-carboxylic acidthat is used in the next stage without additional purification.

Stage 2. A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (559 mg, 2.6 mmol) and methyl ester of 1-amino-5-fluoro-1H-indole-3-carboxylic acid (540 mg, 2.6 mmol) in DMF (25 ml) is stirred at 50°C for 0.5 hours, the Mixture is treated with DMTMM (718 mg, 2.6 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 1-10% MeOH in DHM, to getmethyl ether

-5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid.

Stage 3. A solution of methyl ester of 5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid (2.6 mmol) in MeOH (10 ml) is treated with an aqueous solution of KOH (500 mg, 8.9 mm is l) in H 2O (200 ml) and refluxed for 2 hours the Mixture is diluted with EtOAc (50 ml) and extracted with 1%aqueous solution of KOH (3×50 ml). The combined aqueous phase is neutralized with concentrated HCl and the precipitate collected by filtration and dried in vacuum to obtain5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid (195 mg, 19%, 3 phase). MS: 392 (M+H);1H NMR (300 MHz, DMSO-d6): δ to 12.44 (s, OH, 1H), 12,31 (s, NH, 1H), 9,31 (s, 1H), 8,81 (d, 1H), 8,48 (d, 1H), 8,35 (s, 1H), 8,03 (m, 1H), to 7.77 (m, 1H), 7.62mm (m, 2H), 7,19 (m, 1H), and 2.79 (s, 3H).

Example 170

(5-fluoro-3-hydroxymethylene-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of (5-fluoro-3-formylindole-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (230 mg, 0,614 mmol) in MeOH (10 ml) was treated with NaBH4(233 mg, 6,14 mmol) and stirred at room temperature for 1 h the Mixture was diluted with EtOAc (50 ml) and H2O, neutralized with concentrated HCl and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified HPLC on a medium with inverse phase, elwira 20-100% MeCN in H2O, to obtain(5-fluoro-3-hydroxymethylene-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(90 mg, 8%). MS: 378 (M+H);1H NMR (300 MHz, DMSO-d6): δ 11,92 (s, NH, 1H),9,27 (s, 1H), 8,81 (d, 1H), of 8.47 (d, 1H), with 8.05 (m, 1H), to 7.61 (m, 1H), 7,44 (m, 3H), 7,10 (m, 1H), 5,00 (t, OH, 1H), of 4.66 (d, 2H), 2,78 (s, 3H).

Example 171

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (300 mg, 1.38 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylbutane-2-ol (325 mg, 1.38 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (380 mg, 1.38 mmol) and stirred at 50°C for 2 hours the Mixture is diluted with saturated aqueous Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-7% MeOH in DHM, to get[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(200 mg, 33%). MS: 435 (M+H);1H NMR (300 MHz, CD3OD): δ 9,26 (s, 1H), which is 9.09 (d, 2H), of 7.70 (t, 1H), 7,29 (m, 2H), 7,22 (s, 1H), 7,01 (m, 1H), 2,90 (s, 3H), 2,82 (m, 2H), 1.91 a (m, 2H), 1,31 (s, 6H).

Example 172

[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (300 mg, about 1.36 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methylbutane-2-ol (325 mg, 1.38 mmol) in DMF ( ml) is stirred at 50°C for 1 h The mixture is treated with DMTMM (380 mg, 1.38 mmol) and stirred at 50°C for 2 hours the Mixture is diluted with saturated aqueous Na2CO3(50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-7% MeOH in DHM, to get[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(155 mg, 26%). MS: 440 (M+H);1H NMR (300 MHz, DMSO-d6): δ which 9.22 (s, 1H), 8,14 (d, 1H), 8,08 (d, 1H), 7,40 (m, 3H), 7,06 (m, 1H), or 4.31 (s, OH, 1H), was 2.76 (s, 3H), 2,71 (m, 2H), 1.77 in (m, 2H), 1,20 (s, 6H). IC50=5 nm.

Example 173

(3-Ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 2-iodine-4-triptoreline (10 g, 34.8 mmol) in DHM (100 ml) is treated with TFAA (5,55 ml of 41.8 mmol) and pyridine (3.4 ml, compared with 41.8 mmol) and stirred at room temperature for 1 h the Mixture was diluted with H2O (150 ml) and extracted with DHM (3×150 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with MeCN (100 ml), treated with bromide TRANS-krotala (5,4 ml, at 52.2 mmol) and K2CO3(9.6 g, to 69.6 mmol) and refluxed for 2 hours the Mixture is cooled, filtered through a layer of the whole is the focus. The residue is purified by chromatography on silica gel, elwira 0-10% EtOAc in heptane, to obtainN-but-2-enyl-2,2,2-Cryptor-N-(2-iodine-4-triptoreline)ndimethylacetamide(12.7 g, 84%). MS: 438 (M+H);1H NMR (300 MHz, CDCl3): δ 8,18 (s, 1H), to 7.67 (s, 1H), 7,26 (m, 1H), 5,52 (m, 2H), 4,88 (m, 1H), 3,51 (m, 1H), 1,68 (d, 3H).

Stage 2. A solution of N-but-2-enyl-2,2,2-Cryptor-N-(2-iodine-4-triptoreline)ndimethylacetamide (12.7 g, 29 mmol) in DMF (60 ml) is treated with n-Bu4NCl (8.8 g, 32 mmol), Pd(OAc)2(131 mg, of 0.58 mmol) and stirred at 100°C for 2 hours the Mixture is cooled to room temperature, diluted with EtOAc (150 ml), filtered through a layer of silica gel and washed with 1M HCl (150 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10-30% EtOAc in heptane, to obtain3-ethyl-5-trifluoromethyl-1H-indole(2.6 g, 42%). MS: 214 (M+H);1H NMR (300 MHz, CDCl3): δ 8,08 (s, NH, 1H), 7,89 (s, 1H), 7,41 (m, 2H), 7,07 (m, 1H), 2,81 (kV, 2H), of 1.34 (t, 3H).

Stage 3. A suspension of NaH (7 g, 176 mmol, 60% in mineral oil) in DMF (50 ml) at 0°C is treated with 3-ethyl-5-trifluoromethyl-1H-indole (2.4 g, 11.3 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (6.6 g, 59 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×150 ml). The combined organic the second phase is dried (Na 2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10-50% EtOAc in heptane, to obtain3-ethyl-5-cryptomaterial-1-ylamine(1.3 g, 50%). MS: 229 (M+H);1H NMR (300 MHz, CDCl3): δ to 7.84 (s, 1H), 7,45 (s, 2H), 7,02 (s, 1H), 4,74 (s, NH2, 2H), 2,77 (kV, 2H), 1,31 (t, 3H).

Stage 4. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (232 mg, 1.0 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (228 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50°C for 2 hours the Mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(240 mg, 54%). MS: 443 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,24 (s, 1H), 8.34 per (d, 1H), compared to 8.26 (d, 1H), 8,19 (s, 1H), 7,58 (m, 2H), 7,42 (m, 3H), 2,84 (kV, 2H), 2,78 (s, 3H), of 1.31 (t, 3H).

Example 174

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (215 mg, 1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (228 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1 is the mole) and stirred at 50°C for 2 hours The mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(235 mg, 55%). MS: 426 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9.28 are (s, 1H), 8,81 (d, 1H), 8,48 (d, 1H), 8,03 (m, 1H), to 7.99 (s, 1H), 7,60 (m, 4H), 2,82 (kV, 2H), and 2.79 (s, 3H), of 1.31 (t, 3H).

Example 175

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (221 mg, 1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (228 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50°C for 2 hours the Mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(250 mg, 58%). MS: 432 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,07 (s, NH, 1H), 9,25 (s, 1H), 8,15 (d, 1H), of 8.09 (d, 1H), to 7.99 (s, 1H), 7,68 (d, 1H), 7,51 (m, 2H), 2,77 (s, 3H), 2,74 (kV, 2H), of 1.29 (t, 3H).

Example 176

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (216 mg, 1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (228 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50°C for 2 hours the Mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum. The solid is triturated with Et2O to get(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(100 mg, 23%). MS: 427 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,11 (s, NH, 1H), to 9.32 (s, 1H), 9,07 (d, 2H), 8,00 (s, 1H), 7,69 (m, 2H), 7,53 (m, 2H), 2,80 (kV, 2H), and 2.79 (s, 3H), of 1.31 (t, 3H). IC50=8 nm.

Example 177

(3-Ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 2-bromo-4-triphtalocyaninine (7.6 g, 29.7 mmol) in DHM (60 ml) is treated with TFAA (5 ml, of 35.6 mmol) and pyridine (2,87 ml of 35.6 mmol) and stirred at room temperature overnight. The mixture was diluted with H2O (150 ml) and extracted with DHM (3×150 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with MeCN (60 ml), treated with bromide TRANS-krotala (4.6 ml of 44.5 mmol) and K2CO3(8.1 g, 59 mmol), to patat under reflux for 1 h and then stirred at room temperature for 2 hours The mixture is filtered through a layer of celite and the filtrate concentrated. The residue is purified by chromatography on silica gel, elwira 0-15% EtOAc in heptane, to obtainN-(2-bromo-4-trifloromethyl)-N-but-2-enyl-2,2,2-trifurcated(10.5 g, 87%). MS: 406 (M+);1H NMR (300 MHz, CDCl3): δ 7,56 (s, 1H), 7,22 (m, 2H), 5,52 (m, 2H), a 4.86 (m, 1H), only 3.57 (m, 1H), 1,65 (d, 3H).

Stage 2. SolutionN-(2-bromo-4-trifloromethyl)-N-but-2-enyl-2,2,2-trifurcated(10 grams of 24.7 mmol) in DMF (50 ml) is treated with n-Bu4NCl (7.5 g, to 27.2 mmol), Pd(OAc)2(221 mg, 0.98 mmol) and stirred at 100°C for 1 h Add H2O (10 ml) and the mixture is cooled to room temperature, filtered through a layer of silica gel. The filtrate is extracted with heptane (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0%-25% EtOAc in heptane, to obtain3-ethyl-5-triptoreline-1H-indole(3.1 g, 55%). MS: 230 (M+H);1H NMR (300 MHz, CDCl3): δ of 7.97 (s, NH, 1H), 7,44 (s, 1H), 7,29 (m, 1H), 7,07 (m, 2H), 2,77 (kV, 2H), 1,32 (t, 3H).

Stage 3. A suspension of NaH (7.9 g, 197 mmol, 60% in mineral oil) in DMF (60 ml) at 0°C is treated with 3-ethyl-5-triptoreline-1H-indole (3 g, of 13.1 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (7,4 g, 65,5 mmol) and warmed to room temperature for 2 hours the Mixture ZAT is poured on ice and filtered through a layer of celite. The filtrate is extracted with heptane (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10%-30% EtOAc in heptane, to obtain3-ethyl-5-cryptomaterial-1-ylamine(2,05 g, 64%). MS: 245 (M+H);1H NMR (300 MHz, CDCl3): δ 7,37 (m, 2H), 7,11 (m, 1H), 7,00 (s, 1H), 4.72 in (s, NH2, 2H), by 2.73 (q, 2H), of 1.29 (t, 3H).

Stage 4. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (244 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(270 mg, 59%). MS: 459 (M+H);1H NMR (300 MHz, CDCl3): δ 11,51 (s, NH, 1H), remaining 9.08 (s, 1H), 8,35 (d, 1H), 8,24 (d, 1H), of 7.48 (m, 2H), 7,22 (m, 2H), 7,11 (m, 2H), 2,85 (s, 3H), 2,80 (kV, 2H), of 1.35 (t, 3H).

Example 178

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (250 mg, 1,mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (244 mg, 1.0 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(300 mg, 68%). MS: 442 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,27 (s, 1H), 8,81 (d, 1H), of 8.47 (d, 1H), 8,03 (m, 1H), EUR 7.57 (m, 3H), 7,47 (s, 1H), 7,21 (d, 1H), 2,78 (s, 3H), 2,74 (kV, 2H), of 1.29 (t, 3H).

Example 179

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (244 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(130 mg, 29%). MS: 443 (M+); 1H NMR (300 MHz, DMSO-d6): δ a 9.25 (s, 1H), 9,05 (d, 2H), 7,69 (t, 1H), to 7.64 (s, 1H), 7,54 (m, 2H), 7,14 (d, 1H), 2,80 (s, 3H), was 2.76 (q, 2H), of 1.29 (t, 3H).

Example 180

(3-Ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-cryptomaterial-1-ylamine (244 mg, 1.0 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(250 mg, 56%). MS: 448 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,23 (s, 1H), 8,15 (m, 1H), 8,09 (m, 1H), 7,55 (m, 2H), of 7.48 (s, 1H), 7,19 (d, 1H), 2,78 (s, 3H), 2,71 (m, 2H), of 1.29 (t, 3H).

Example 181

(6-Cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A suspension of NaH (6.5 g, 162 mmol, 60% in mineral oil) in DMF (54 ml) at 0°C is treated with 6-triptoreline (2.0 g, a 10.8 mmol) and stirred at 0°C for 0.5 h the Mixture was treated with p is rceme HOSA (6,1 g, 54 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice and filtered through a layer of celite. The filtrate is extracted with Et2O (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10%-30% EtOAc in heptane, to obtain6-cryptomaterial-1-ylamine(1,79 g, 83%). MS: 201 (M+H);1H NMR (300 MHz, CDCl3): δ 7,74 (s, 1H), to 7.67 (d, 1H), 7,35 (d, 1H), 7,30 (m, 1H), 6,45 (d, 1H), a 4.83 (s, NH2, 2H).

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (278 mg, 1.2 mmol) and 6-cryptomaterial-1-ylamine (200 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 0.5 hours, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane during the night. The precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(6-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(180 mg, 44%). MS: 415 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,09 (s, NH, 1H), was 9.33 (s, 1H), 8,35 (d, 1H), to 8.20 (d, 1H), of 7.90 (s, 1H), 7,79 (m, 2H), 7,65 (m, 1H), 746 (m, 2H), 6,74 (d, 1H), and 2.79 (s, 3H).

Example 182

(6-Cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (258 mg, 1.2 mmol) and 6-cryptomaterial-1-ylamine (200 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 0.5 hours, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane during the night. The precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(6-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(160 mg, 40%). MS: 398 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,13 (s, NH, 1H), 9,36 (s, 1H), 8,82 (d, 1H), 8,48 (d, 1H), 8,04 (m, 1H), 7,83 (m, 3H), 7,60 (m, 1H), 7,44 (d, 1H), 6,74 (d, 1H), 2,80 (s, 3H).

Example 183

(6-Cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (265 mg, 1.2 mmol) and 6-cryptomaterial-1-ylamine (200 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C more than the s 0.5 hours The mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane during the night. The precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(6-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(160 mg, 40%). MS: 404 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,12 (s, NH, 1H), was 9.33 (s, 1H), 8,15 (d, 1H), with 8.05 (d, 1H), to $ 7.91 (s, 1H), 7,79 (m, 2H), 7,44 (m, 1H), 6.73 x (d, 1H), 2,77 (s, 3H).

Example 184

(6-Cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (259 mg, 1.2 mmol) and 6-cryptomaterial-1-ylamine (200 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 0.5 hours, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane during the night. The precipitate is collected what filtrowanie, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(6-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(100 mg, 25%). MS: 399 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,16 (s, NH, 1H), 9,39 (s, 1H), 9,06 (d, 2H), 7,92 (s, 1H), 7,81 (m, 2H), of 7.70 (t, 1H), 7,44 (d, 1H), 6,74 (d, 1H), and 2.79 (s, 3H).

Example 185

(3-Ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 2-iodine-6-triptorelin-3-ylamine (5,09 g of 17.7 mmol) in DHM (50 ml) is treated with TFAA (3 ml and 21.2 mmol) and pyridine (1.7 ml and 21.2 mmol) and stirred at room temperature for 1 h the Mixture was diluted with H2O (150 ml) and extracted with DHM (3×150 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with MeCN (50 ml), treated with bromide TRANS-krotala (2,8 ml of 26.6 mmol) and K2CO3(4.7 grams of 34.4 mmol) and refluxed for 2 hours the Mixture is filtered through a layer of celite. The filtrate was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0%-25% EtOAc in heptane, to obtainN-but-2-enyl-2,2,2-Cryptor-N-(2-iodine-6-triptorelin-3-yl)ndimethylacetamide(5.5 g, 71%). MS: 439 (M+H);1H NMR (300 MHz, CDCl3): δ 7,71 (d, 1H), 7,53 (d, 1H), 5,52 (m, 2H), to 4.98 (m, 1H), to 3.58 (m, 1H), 1,68 (d, 3H).

Stage 2. A solution of N-buta--Anil-2,2,2-Cryptor-N-(2-iodine-6-triptorelin-3-yl)ndimethylacetamide (5,2 g, to 11.9 mmol) in DMF (24 ml) is treated with n-Bu4NCl (3.6 g, 13,1 mmol), Pd(OAc)2(107 mg, 0.48 mmol) and stirred at 100°C for 1 h Add H2O (10 ml) and the mixture is cooled to room temperature and filtered through a layer of silica gel. The filtrate is extracted with EtOAc/heptane (3×50 ml) (1:1). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 5-50% EtOAc in heptane, to obtain3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine(2.2 g, 86%). MC: 215 (M+H);1H NMR (300 MHz, CDCl3): δ 8,24 (s, NH, 1H), 7,73 (d, 1H), 7,50 (d, 1H), 7,34 (d, 1H), 2,93 (kV, 2H), of 1.36 (t, 3H).

Stage 3. A suspension of NaH (4,65 g, 116 mmol, 60% in mineral oil) in DMF (40 ml) at 0°C is treated with 3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2 g, of 7.75 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (4.4 g, to 38.8 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, treated with NH4Cl in the solid state (3 g) and filtered through a layer of celite. The filtrate is extracted with Et2O (3×150 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30-50% EtOAc in heptane, to obtain3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-ylamine(1, g, 84%). MS: 230 (M+H);1H NMR (300 MHz, DMSO-d6): δ of 7.97 (d, 1H), to 7.59 (d, 1H), 7,54 (s, 1H), 6,12 (s, NH2, 2H), 2,78 (kV, 2H), 1.28 (in t, 3H).

Stage 4. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (278 mg, 1.1 mmol) and 3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-ylamine (230 mg, 1 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C during the night. The mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(195 mg, 44%). MS: 444 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,16 (s, NH, 1H), 9.28 are (s, 1H), 8.34 per (d, 1H), 8,18 (m, 2H), 7,86 (s, 1H), 7,65 (m, 2H), 7,45 (m, 1H), and 2.83 (q, 2H), 2,78 (s, 3H), of 1.35 (t, 3H).

Example 186

(3-Ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-(2-pyridyl)-4-methylpyrimidin-5-carboxylic acid (258 mg, 1.1 mmol) and 3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-ylamine (230 mg, 1.0 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C during the night. A mixture of p is izbavlyayut saturated aqueous Na 2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(175 mg, 41%). MS: 427 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,18 (s, NH, 1H), 9,31 (s, 1H), 8,80 (d, 1H), 8,45 (d, 1H), 8,16 (d, 1H), 8,01 (m, 1H), 7,88 (s, 1H), 7,72 (d, 1H), to 7.59 (m, 1H), 2,81 (kV, 2H), and 2.79 (s, 3H), of 1.35 (t, 3H).

Example 187

(3-Ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (88 mg, 0.40 mmol) and 3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-ylamine (89 mg, 0.40 mmol) in DMF (5 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (113 mg, 0.41 mmol) and stirred at 50°C during the night. The mixture is diluted with saturated aqueous Na2CO3(5 ml) and stirred for 10 minutes the Precipitate is collected by filtration, washed with H2O (50 ml) and heptane (50 ml) and dried in vacuum to obtain(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(75 mg, 40%). MS: 433 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,19 (s, NH, 1H), 9.28 are (s, 1H), 8,15 (m, 2H), 8,08 (d, 1H), 7,87 (s, 1H), 7,72 (d, 1H), and 2.83 (q, 2H), 2,77 (s, 3H), of 1.35 (t, 3H).

the example 188

(3-Ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (259 mg, 1.2 mmol) and 3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-ylamine (230 mg, 1.0 mmol) in DMF (5 ml) is stirred at 50°C for 0.5 hours, the Mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50°C during the night. The mixture is diluted with saturated aqueous Na2CO3(5 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified HPLC on a reversed-phase column, elwira 20-100% MeCN in H2O, to obtain(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(230 mg, 54%). MS: 428 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9.28 are (s, 1H), 9,05 (d, 2H), 8,11 (d, 1H), 7,98 (s, 1H), 7,69 (t, 1H), to 7.64 (d, 1H), and 2.83 (q, 2H), 2,80 (s, 3H), of 1.34 (t, 3H).

Example 189

(5-Methoxy-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A suspension of NaH (1.25 g, 51 mmol, 60% in mineral oil) in DMF (47 ml) at 0°C is treated with 5-methoxy-2-methylindole (500 mg, 3.1 mmol) and stirred at 0°C for 0.5 h the Mixture was treated with portions of HOSA (1.92 g, 17,0 shall mol) and warmed to room temperature over 2 hours The mixture was then poured on ice and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain5-methoxy-2-methylindol-1-ylaminethat is used in the next stage without additional purification.

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (719 mg, 3.1 mmol) and 5-methoxy-2-methylindol-1-ylamine (550 mg, 3.1 mmol) in DMF (4 ml) is stirred at 50°C for 15 minutes the Mixture is treated with DMTMM (856 mg, 3.1 mmol) and stirred at 50°C for 1 h the Mixture was concentrated in vacuo, diluted with EtOAc (50 ml) and washed with saturated aqueous Na2CO3(50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30% EtOAc in heptane, to obtain(5-methoxy-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(180 mg, 15%, stage 2). MS: 391 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,23 (s, 1H), 8.34 per (d, 1H), 8,18 (d, 1H), 7,63 (m, 1H), 7,46 (m, 1H), 7,31 (d, 1H), 7,02 (d, 1H), 6,77 (m, 1H), and 6.25 (s, 1H), 3,76 (s, 3H), 2,77 (s, 3H), of 2.34 (s, 3H).

Example 190

N',N'-Diphenylhydrazine 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (500 mg, 2.2 mmol) and N,N-defen is hydrazine (422 mg, 2.2 mmol) in DMF (3 ml) is stirred at 50°C for 15 minutes the Mixture is treated with DMTMM (633 mg, 2.2 mmol) and stirred at 50°C for 3 hours the Mixture is diluted with EtOAc (50 ml) and washed with saturated aqueous Na2CO3(50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 75% EtOAc in heptane, to obtainN',N'-diphenylhydrazine 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(60 mg, 7%). MS: 399 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,04 (s, 1H), 8.30 to (d, 1H), 8,15 (m, 1H), to 7.61 (m, 1H), 7,44 (m, 1H), 7,35 (m, 4H), 7,22 (m, 4H),? 7.04 baby mortality (m, 2H), 2,64 (s, 3H). IC50=16 nm.

Example 191

(7-Fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A suspension of NaH (805 mg, 20,1 mmol, 60% in mineral oil) in DMF (5 ml) at 0°C is treated with 7-fluoro-3-methylindole (200 mg, of 1.34 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (757 mg, 6.7 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice and extracted with EtOAc (3×100 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain7-fluoro-3-methylindol-1-ylaminethat is used in the next stage without to anitelea cleanup.

Stage 2. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1,34 mmol) and 7-fluoro-3-methylindol-1-ylamine (342 mg, about 1.47 mmol) in DMF (15 ml) is stirred at 50°C for 1 h, the Mixture is treated with DMTMM (407 mg, about 1.47 mmol) and stirred at 50°C for 4 h the Mixture was concentrated in vacuo, diluted with Et2O (50 ml) and washed with saturated aqueous Na2CO3(50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-100% DHM in EtOAc to obtain(7-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(241 mg, 48%). MS: 379 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,05 (s, 1H), 8,32 (d, 1H), 8,18 (d, 1H), to 7.64 (m, 1H), 7,45 (m, 1H), 7,40 (m, 1H), 7,31 (s, 1H), 7,05 (m, 2H), 2,74 (s, 3H), to 2.29 (s, 3H).

Example 192

(5-Methanesulfonyl-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of allyl-(2-iodine-4-methanesulfonyl)amine (1,43 g, 4.1 mmol) in DMF (20 ml) is treated with n-Bu4NCl (1.47 g, 5,32 mmol), Pd(OAc)2(56.6 mg, 0.2 mmol) and stirred at 100°C for 1 h Add HCl (5.3 ml, 3M) and the mixture is cooled to room temperature, filtered through a layer of celite and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4 ), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 60% EtOAc in heptane, to obtain5-methanesulfonyl-3-methyl-1H-indole(370 mg, 43%).

Stage 2. A suspension of NaH (1.06 g, to 26.6 mmol, 60% in mineral oil) in DMF (15 ml) at 0°C is treated with 5-methanesulfonyl-3-methyl-1H-indole (370 mg, 1.77 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (1 g, cent to 8.85 mmol) and warmed to room temperature over night. The mixture was then poured on ice and extracted with EtOAc (3×100 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo to obtain5-methanesulfonyl-3-methylindol-1-ylaminethat is used in the next stage without additional purification.

Stage 3. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1.77 mmol) and 5-methanesulfonyl-3-methylindol-1-ylamine (452 mg, of 1.95 mmol) in DMF (15 ml) was stirred at room temperature for 1 h, the Mixture is treated with DMTMM (538 mg, of 1.95 mmol) and stirred at 60°C for 1.5 h the Mixture was diluted with EtOAc (50 ml) and washed with saturated aqueous Na2CO3(50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-100% EtOAc in heptane, and then treatment is with Et 2O to get(5-methanesulfonyl-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(106 mg, 14%). MS: 439 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9.15, with (s, 1H), of 8.37 (d, 1H), 8,24 (m, 2H), 7,82 (m, 1H), to 7.59 (d, 1H), 7,54 (m, 1H), 7,34 (s, 1H), 7,29 (m, 1H), 3,13 (s, 3H), and 2.83 (s, 3H), 2,42 (s, 3H).

Example 193

Triperoxonane acid salt (3-acylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. (See: J. Org. Chem. 2002, 67, 6226-6227) To a stirred suspension of AlCl3(22,6 g, 169 mmol) in DHM (300 ml) is added 7-azaindole (5 g, of 42.3 mmol). After stirring at room temperature for 1 hour and added dropwise to acetylchloride (13.3 g, 169 mmol) and the resulting mixture stirred for 18 hours the Mixture is cooled to 0°C, quenched with MeOH (150 ml) and stirred for 1 hour To the mixture of the silica gel, the solvent is removed in vacuo and the residue purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get1-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanone(1.6 g).1H NMR (300 MHz, CH3OD): δ 8,93 (d, 1H), 8,45 (s, 2H), 7,50 (t, 1H), 3,30 (s, 3H).

Stage 2. To a solution of 1-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanone (1,34 g scored 8.38 mmol) in TFA (25 ml) add triethylsilane (6,09 g, a 52.4 mmol) and stirred at room temperature for 18 hours the Mixture is concentrated, diluted with aqueous 2n. a solution of KOH and extracted three times DHM. Unite the military the organic phase is dried (Na 2SO4), filtered and evaporated. The resulting residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-ethyl-1H-pyrrolo[2,3-b]pyridine(0,91 g). MS: 147 (M+H);1H NMR (300 MHz, CDCl3): δ 9,23 (USS, 1H), 8,32 (d, 1H), 7,94 (s, 1H), 7,05-7,14 (m, 2H), 2,80 (kV, 2H), of 1.35 (t,3H).

Stage 3. 3-ethyl-1H-pyrrolo[2,3-b]pyridine (0,91 g, 6.2 mmol) and KOtBu (1.39 g, 12.4 mmol) was dissolved in DMF (28 ml) and stirred for 2 h at room temperature. In the process of energetic ozonation nitrogen added in several portions NH2Cl (92 ml 0,15M in the air). The reaction mixture was stirred at room temperature for 2 hours the Mixture is cooled to 0°C and then quenched with Na2S2O3(2.7 g) in water (50 ml). After keeping at room temperature for 18 h the mixture is concentrated and treated DHM and filtered. The filtrate is concentrated and purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-acylpyrrole[2,3-b]pyridine-1-ylamine(380 mg). MS: 162 (M+H);1H NMR (300 MHz, CDCl3): δ 8,32 (d, 1H), of 7.90 (d, 1H),? 7.04 baby mortality-7,13 (m, 2H), 4,96 (USS, 2H), was 2.76 (q, 2H), 1,33 (t, 3H).

Stage 4. A mixture of 3-acylpyrrole[2,3-b]pyridine-1-ylamine (126 mg, 0.78 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (168 mg, 0.78 mmol), HATU (356 mg, 0,936 mmol) and DIPEA (302 mg, 2.34 mmol) in DMF (4 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAC. The organic phase is tub (Na 2SO4), filtered and concentrated. The residue is initially purified by chromatography on silica gel, elwira 10% MeOH in DHM. The resulting product is again purified HPLC on a reversed-phase column, elwira 0.1% solution TFU in water and acetonitrile, to obtaintriperoxonane acid salt (3-acylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(29 mg). MS: 359 (M+H);1H NMR (300 MHz, CD3OD): δ of 9.45 (s, 1H), 9,04 (d, 1H), 8,93 (d, 1H), 8,67 (t, 1H), 8,31 (d, 1H), 8,19-8,08 (m, 2H), 7,34 (s, 1H), 7,27 (DD, 1H), 2,96 (s, 3H), 2,85 (kV, 2H), 1.39 in (t, 3H).

Example 194

(3-Acylpyrrole[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of 3-acylpyrrole[2,3-b]pyridine-1-ylamine (126 mg, 0.78 mmol), 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (180 mg, 0.78 mmol), HATU (356 mg, being 0.036 mmol) and DIPEA (302 mg, 2.34 mmol) in DMF (4 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-100% ethyl acetate in heptane, to obtain(3-acylpyrrole[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(128 mg). MS: 376 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,10 (s, 1H), 8,25-of 8.33 (m, 2H), 8,16 (d, 1H), with 8.05 (d, 1H), 7.62mm (kV, 1H), 7,39-of 7.48 (m, 2H), 7,16 (DD, 1H), 278 (, 3H), a 2.75 (q, 2H), of 1.29 (t, 3H).

Example 195

(3-Acylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of 3-acylpyrrole[2,3-c]pyridine-1-ylamine (93 mg, 0,577 mmol), 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (134 mg, 0,757 mmol), HATU (263 mg, 0,692 mmol) and DIPEA (223 mg, at 1.73 mmol) in DMF (3 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified column chromatography on silica gel, elwira 0-100% ethyl acetate in heptane, to obtain(3-acylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(86 mg). MS: 376 (M+H);1H NMR (300 MHz, CD3OD): δ 9.15, with (s, 1H), 8,69 (s, 1H), of 8.37 (d, 1H), 8,15 compared to 8.26 (m, 2H), of 7.70 (d, 1H), 7,55 (kV, 1H), 7,49 (s, 1H), 7,29 (m, 1H), 2,80-2,90 (m, 5H), to 1.38 (t, 3H). IC50=7 nm.

Example 196

Triperoxonane acid salt (3-acylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. (See: J. Org. Chem. 2002, 67, 6226-6227) To a stirred suspension of AlCl3(11.3 g, of which 84.5 mmol) in CH2Cl2(150 ml) is added 6-azaindole (2.5 g, each holding 21.25 mmol). After stirring at room temperature for 1 hour and added dropwise to acetylchloride (6,65 g, of which 84.5 mmol) and the resulting semipermissive within 18 PM The mixture is cooled to 0°C, quenched with MeOH (75 ml) and stirred for 1 hour To the mixture silica gel (40 ml), MeOH and DHM, the solvents are removed in vacuo and the residue purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get1-(1H-pyrrolo[2,3-c]pyridine-3-yl)ethanone(1.52 g, 45%). MS: 161 (M+H);1H NMR (300 MHz, CD3OD): δ 9,20 (s, 1H), 8,95 (s, H), of 7.82 (d, 1H), 8,72 (d, 1H), 8,43 (d, 1H), 2,64 (s, 3H).

Stage 2. To a solution of 1-(1H-pyrrolo[2,3-c]pyridine-3-yl)ethanone (1,53 g of 9.55 mmol) in TFA (29 ml) add triethylsilane (6,88 g, 59,21 mmol) and stirred at room temperature for 18 hours the Mixture is concentrated and extracted with EtOAc. The organic phase is washed with aqueous 2n. the KOH solution, dried (Na2SO4), filtered and evaporated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-ethyl-1H-pyrrolo[2,3-c]pyridine(1.35 g, 97%). MS: 147 (M+H);1H NMR (300 MHz, CDCl3): δ 13.3-inch (ush., N-H) 9,46 (s, 1H), 8,04 (s, 1H), 7,71-7,88 (m, 2H), 2,88 (kV, 2H), 1.39 in (t, 3H).

Stage 3. 3-ethyl-1H-pyrrolo[2,3-c]pyridine (1,21 g, 8,29 mmol) and KOtBu (1.86 g, 16,57 mmol) dissolved in DMF (47 ml) and stirred for 2 h at room temperature. During vigorous blowing nitrogen added in several portions NH2Cl (101 ml 0,15M in the air). The reaction mixture was stirred at room temperature for 1 h the Mixture was then cooled to 0°C and quenched with Na2S2O3(4.3 g) in water (80 ml). After veterianary room temperature for 2 days split phase. To the aqueous phase add saline solution and then extracted with EtOAc. The combined organic phases are dried (Na2SO4) to obtain a mixture of 3-acylpyrrole[2,3-c]pyridine-1-ylamine and source material. This mixture is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-acylpyrrole[2,3-c]pyridine-1-ylamine(93 mg). The remaining mixture of starting material and product are collected and dissolved in DHM. The resulting solution was cooled to 0°C and add the BOC2O (164 mg, 0.75 mmol). The resulting mixture was purified by chromatography on silica gel, elwira 10% MeOH in DHM for more3-acylpyrrole[2,3-c]pyridine-1-ylamine(145 mg).1H NMR (300 MHz, CDCl3): δ cent to 8.85 (s, 1H), of 8.25 (d, 1H), of 7.48 (d, 1H), 7,10 (s, 1H), 4,88 (s, 2H), 2,75 (kV, 2H), of 1.35 (t, 3H).

Stage 4. A mixture of 3-acylpyrrole[2,3-c]pyridine-1-ylamine (122 mg, 0,757 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (163 mg, 0,757 mmol), HATU (356 mg, 0,936 mmol) and DIPEA (294 mg, of 2.27 mmol) in DMF (4 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and then extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM. The resulting product is again purified HPLC on a reversed-phase column, elwira 0.1% solution TFU in water and acetonitrile, to obtaintriperoxonane acid is th salt (3-acylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (42 mg, 9.5 per cent). MS: 359 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,43 (s, 1H), 9,37 (s, 1H), 8,80 (d, 1H), 8,45 (t, 2H), compared to 8.26 (s, 1H), they were 8.22 (d, 1H), 8,03 (t, 1H), to 7.59 (t, 1H), 2,86 (kV, 2H), 2,80 (s, 3H), of 1.32 (t, 3H).

Example 197

(3-Methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of 3-methylpyrrole[3,2-b]pyridine-1-ylamine (75% purity) (240 mg, <1,63 mmol), 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (379 mg, and 1.63 mmol), HATU (744 mg, a 1.96 mmol) and DIPEA (388 mg, 4,89 mmol) in DMF (5 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM. The resulting product is recrystallized from ether to obtain(3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(197 mg, 44%). MS: 362 (M+H);1H NMR (300 MHz, CD3OD): δ 9,14 (s, 1H), 8,40 (d, 1H), at 8.36 (d, 1H), they were 8.22 (d, 1H), a 7.85(d, 1H), 7,55 (kV, 1H), 7,47 (s, 1H), 7,25-7,34 (m, 2H), and 2.83 (s, 3H), 2,42 (s, 3H). IC50=2 nm.

Example 198

(3-Methyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Step 1: To a mixture of 2-iodine-4-triptorelin (5 g, of 17.4 mmol), KOt-Bu (2,05 g, and 18.3 mmol) and THF (200 ml) at -78°C add allylbromide (2,21 g,and 18.3 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours, water is Added and the mixture extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-50% EtOAc in heptane, to obtainallyl-(2-iodine-4-triptoreline)Amin(1,9 g, 33%). MC 328 (M+H);1H NMR (300 MHz, CDCl3): δ of 7.90 (s, 1H), 7,45 (d, 1H), 5,88-of 6.02 (m, 1H), 5,33 (d, 1 H), 5.25 in (d, 1H), 4.72 in (USS, 1H), 3,90 (s, 2H).

Stage 2. A mixture of allyl-(2-iodine-4-triptoreline)amine (1.75 g, to 5.35 mmol), tetrabutylammonium chloride (1.68 g, to 5.35 mmol), palladium acetate (120 mg, 0.54 mmol) and potassium carbonate (2,22 g, 16.0 mmol) in DMF (50 ml) is heated at a temperature of 80°C for 1.5 h, the Reaction mixture was quenched with water and extracted three times DHM. The combined organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain3-methyl-5-trifluoromethyl-1H-indole(401 mg).1H NMR (300 MHz, CDCl3): δ = 8,09 (USS, 1H), of 7.90 (s, 1H), 7,44 (s, 1H), 7,10 (s, 1H), of 2.38 (s, 3H).

Stage 3. 60% NaH (1,21 g, 30.2 mmol) is added in portions to a stirred solution of 3-methyl-5-trifluoromethyl-1H-indole (400 mg, a 2.01 mmol) in DMF (6 ml) at 0°C. the Mixture is stirred at 0°C for 1 h To the mixture portions HOSA (1,14 g, 10.0 mmol) at 0°C and the mixture naked is ewout to room temperature within 2 hours The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times DHM. The combined organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain3-methyl-5-cryptomaterial-1-ylamine(223 mg, 52%). MC: 215 (M+H);1H NMR (300 MHz, CDCl3): δ = 7,84 (s, 1H), of 7.48 (s, 2H),? 7.04 baby mortality (s, 1H), of 4.77 (s, 2H), 2,34 (s, 3H).

Stage 4. A mixture of 3-methyl-5-cryptomaterial-1-ylamine (223 mg, 1.04 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (224 g, 1.04 mmol), HATU (475 mg, 1.25 mmol), DIPEA (404 mg, of 3.13 mmol) is stirred in DMF at 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get(3-methyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(122 mg, 28%). MS: 412 (M+H);1H NMR (300 MHz, CD3OD): δ which 9.22 (s, 1H), 8,79 (d, 1H), 8,66 (d, 1H), of 8.06 (t, 1H), to $ 7.91 (s, 1H), 7,60 (DD, 1H), 7,51 (s, 2H), 7,29 (s, 3H), 2,88 (s, 3H), 2.40 a (s, 3H).

Example 199

(3-Methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. To a solution of 3-amino-2-chloropyridine (5 g, for 38.9 mmol) in THF (35 ml) is added 2M NaHMDS in THF (38,9 ml, 77,8 mmol)After stirring at room temperature for 15 min add one portion a solution of BOC 2O (7,7 g of 35.6 mmol) in THF (20 ml) and then stirred for 5 h at room temperature. To the mixture of 0.1%aqueous HCl solution. The mixture is extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-50% EtOAc in heptane, to obtaintert-butyl ether (2-chloropyridin-3-yl)carbamino acid(7,18 g, 89%). MS: 229 (M+H);1H NMR (300 MHz, CDCl3): δ charged 8.52 (d, 1H), with 8.05 (DD, 1H), 7.23 percent (DD, 1H), 7,02 (USS, 1H), 1.55V (s, 9H).

Stage 2. A mixture of tert-butyl methyl ether (2-chloropyridin-3-yl)carbamino acid (7 g, 30.7 mmol), allylbromide (5,26 g and 40.8 mmol) and cesium carbonate (20,8 g, to 63.8 mmol) in DMF (280 ml) is heated at 60°C for 1 h, the Reaction mixture was quenched with water, extracted with EtOAC. The organic phase is dried (Na2SO4), filtered and concentrated to obtaintert-butyl ether allyl-(2-chloropyridin-3-yl)carbamino acid(8,03 g, 98%), which is used in the next stage without additional purification.

Stage 3. A mixture of tert-butyl methyl ether allyl-(2-chloropyridin-3-yl)carbamino acid (8,03 g, 30 mmol), tetrabutylammonium chloride (9.4 g, 30 mmol), palladium acetate (673 mg, 3 mmol) and potassium carbonate (12.4 g, 3 mmol) in DMF (300 ml) is heated at a temperature of 80°C for 1.5 h, the Reaction mixture was quenched DHM and washed with water. The organic phase is dried (Na SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtaintert-butyl ester 3-methylpyrrole[3,2-b]pyridine-1-carboxylic acid tert-butyl ester 3-methylene-2,3-dihydropyrrolo[3,2-b]pyridine-1-carboxylic acid(1,58 g).

Stage 4. The above mixture was then stirred DHM (10 ml) and TFU (10 ml) at room temperature for 3 hours, the Reaction mixture was concentrated and added dropwise an aqueous solution of 2M KOH and DHM. The precipitate is collected by filtration to obtainpotassium salt of 3-methyl-1H-pyrrolo[3,2-b]pyridine(1 g, 20%). MS: 133 (M+H);1H NMR (300 MHz, CD3OD): δ compared to 8.26 (d, 1H), of 7.75 (d, 1H), 7,33 (s, 1H), 7,12 (DD, 1H), a 2.36 (s, 3H).

Stage 5. A mixture of potassium salt of 3-methyl-1H-pyrrolo[3,2-b]pyridine (1 g, 5,88 mmol), KOtBu (660 mg, 5,88 mmol) in DMF (26 ml) blow N2and stirred at room temperature for 2 hours To the mixture chloramine in ether (0,15M, 29 ml) and the mixture is stirred for 45 minutes, the Reaction mixture was cooled to 0°C, add Na2S2O3(3.4 g) in water (70 ml) and the mixture is stirred for 15 minutes the Mixture was concentrated in vacuo. The residue is treated DHM and then filtered. The filtrate was washed with 2M aqueous KOH, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to obtain a mixture of the source material is material and 3-methylpyrrole[3,2-b]pyridine-1-ylamine(839 mg, ~64%, ~66% mol. purity), which is used in the next stage without additional purification.

Stage 6. A mixture of 3-methylpyrrole[3,2-b]pyridine-1-ylamine (839 mg, <5,71 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (1,32 g, 6,13 mmol), HATU (2.6 g, 6,85 mmol), DIPEA (of 2.21 g of 17.1 mmol) in DMF (17 ml) is stirred at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and ether. The aqueous phase was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira mixture DHM, MeOH and triethylamine (9,5:0,5:0,05), to obtain(3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(134 mg). MS: 345 (M+H);1H NMR (300 MHz, CD3OD): δ which 9.22 (s, 1H), 8,79 (d, 1H), 8,64 (d, 1H), 8,40 (d, 1H), with 8.05 (t, 1H), 7,87 (d, 1H), 7,60 (t, 1H), 7,49 (s, 1H), 7,30 (DD, 1H), 2,87 (s, 3H), 2,42 (s, 3H).

Example 200

(3-Methylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. 60% sodium hydride (6,69 g, 167 mmol) is added in portions to a stirred solution of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.47 g, and 11.2 mmol) in DMF (33 ml) at 0°C for 1 h To the mixture portions hydroxylamine-O-sulfonic acid (6.3 g and 55.8 mmol) at 0°C and stirred for 2 h at 0°C. the Reaction mixture was quenched at 0°C water, the oxygen is their in vacuum, to remove DMF. The residue is treated DHM. The solid is filtered off and the filtrate was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM to get3-methylpyrrole[2,3-c]pyridine-1-ylamine(1 g, 61%). MS: 148 (M+H);1H NMR (300 MHz, CDCl3): δ cent to 8.85 (s, 1H), 8,27 (d, 1H), 7,46 (d, 1H), to 7.09 (s, 1H), 2,30 (s, 3H).

Stage 2. A mixture of 3-methylpyrrole[2,3-c]pyridine-1-ylamine (224 mg, 1.53 mmol), 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (354 mg, 1.53 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4,59 mmol) in DMF (8 ml) is stirred at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-100% EtOAc in heptane, to obtain(3-methylpyrrole[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(55 mg). MS: 362 (M+H);1H NMR (300 MHz, CD3OD): δ 9.15, with (s, 1H), 8,69 (s, 1H), of 8.37 (d, 1H), 8,24 (s, 1H), to 8.20 (d, 1H), 7,68 (d, 1H), 7,55 (kV, 1H), 7,47 (s, 1H), 7,29 (m, 1H), 2,84 (s, 3H), 2,39 (s, 3H).

Example 201

(3-Methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. To a solution of 3-amino-4-chloropyridine (6,56 g, 51 mmol) in THF (46 ml) is added 2M NaHMDS in THF (50 ml, 100 mmol). After stirring at room temperature during the 15 min add one portion a solution of BOC 2O (10,1 g of 46.4 mmol) in THF (26 ml) and the mixture stirred for 3 h at room temperature. To the mixture of 0.1%aqueous solution of HCl (590 ml). The mixture is extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-50% EtOAc in heptane, to obtaintert-butyl ester (4-chloropyridin-3-yl)carbamino acid(of 6.78 g, 76%). MS: 229 (M+H);1H NMR (300 MHz, CDCl3): δ 9,38 (MC, 1H), 8,23 (d, 1H), 7,30 (DD, 1H), 6,85 (USS, 1H), 1.57 in (s, 9H).

Stage 2. A mixture of tert-butyl methyl ether (4-chloropyridin-3-yl)carbamino acid (of 6.78 g, 29.7 mmol), allylbromide (5,1 g and 40.8 mmol) and cesium carbonate (20,1 g, to 61.8 mmol) in DMF (200 ml) is heated at 60°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified column chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtaintert-butyl ether allyl-(4-chloropyridin-3-yl)carbamino acid(5,66 g, 71%). MS: 269 (M+H);1H NMR (300 MHz, CDCl3): δ 8,42 (d, 1H), 7,40 (d, 1H), 5,80 is 5.98 (m, 1H), 4,35-4,51 (m, 1H), 3,90-4,07 (m, 1H).

Stage 3. A mixture of tert-butyl methyl ether allyl-(4-chloropyridin-3-yl)carbamino acid (of 7.68 g, 28.7 mmol), tetrabutylammonium chloride (9.0 g, 28.7 mmol), palladium acetate (643 mg, 2,87 mmol) and potassium carbonate (11.9 g, 86,0 mmol) in DMF (200 ml) n is grebaut at a temperature of 80°C for 1.5 hours The reaction mixture was diluted with DHM and washed three times with water. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified column chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain a mixturetert-butyl ester 3-methylpyrrole[2,3-c]pyridine-1-carboxylic acidandtert-butyl ester 3-methylene-2,3-dihydropyrrolo[2,3-c]pyridine-1-carboxylic acid(only 3.1 g).

Stage 4. The above mixture was then stirred DHM (10 ml) and TFU (10 ml) at room temperature for 18 h and then concentrated in vacuo. Add 2M aqueous solution of KOH. The mixture is extracted with EtOAC. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified column chromatography on silica gel, elwira 10% MeOH in DHM, to get3-methyl-1H-pyrrolo[2,3-c]pyridine(1.98 g, 69%). MS: 133 (M+H);1H NMR (300 MHz, CDCl3): δ 9,10 (USS, 1H), 8,79 (s, 1H), 8,28 (d, 1H), 7,52 (d, 1H), 7,20 (s, 1H) 2,36 (s, 2H).

Stage 5. A mixture of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1,21 g, 9,16 mmol), KOtBu (2,05 g, and 18.3 mmol) in DMF (41 ml) blow N2and stirred at room temperature for 2 hours To the mixture chloramine in ether (0,15M, 92 ml) and the mixture is stirred for 20 minutes, the Reaction mixture was cooled to 0°C. and add a solution of Na2S2O3(5 g) in water (80 ml). The mixture is stirred for 10 min and then the concentration of irout in vacuum. The residue is treated DHM and filtered. Add DHM, cooled to 0°C and add BOC2O (541 mg, 2.48 mmol). The resulting mixture was separated by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-methylpyrrole[2,3-c]pyridine-1-ylamine(468 mg, 35%). MS: 148 (M+H);1H NMR (300 MHz, CDCl3): δ cent to 8.85 (s, 1H), 8,27 (d, 1H), 7,46 (d, 1H), to 7.09 (s, 1H), 2,30 (s, 3H).

Stage 6. A mixture of 3-methylpyrrole[2,3-c]pyridine-1-ylamine (467 mg, 3,18 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (683 g, 3,18 mmol), HATU (1.45 g, 3,81 mmol), DIPEA (1,23 g, 9,54 mmol) in DMF (10 ml) is stirred at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and add NaHCO3(320 mg, 3,81 mmol) and EtOAC. The obtained solid is collected by filtration and then treated with hot water. The mixture is again filtered and the solid dried in vacuum to obtain(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(484 mg). MS: 345 (M+H);1H NMR (300 MHz, CD3OD): δ 9,24 (s, 1H), 8,79 (d, 2H), 8,65 (d, 1H), 8,21 (d, 1H), with 8.05 (t, 1H), 7,72 (d, 1H), 7,60 (s, 1H), EUR 7.57 (s, 1H), 2,88 (s, 3H), 2.40 a (s, 3H).

Example 202

(3-Methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. To a solution of 4-amino-3-chloropyridine (15 g, of 116.7 mmol) in THF (60 ml) was added NaHMDS in THF (1M, 233 ml, 233 mmol). After stirring at room te is the temperature for 30 min add one portion a solution of BOC 2O (23,2 g, 106 mmol) in THF (45 ml) and the mixture stirred for 3 h at room temperature. Add a further quantity of BOC2O (2 g, 9.0 mmol) in THF (40 ml) and the reaction mixture stirred for 18 h at room temperature. To the mixture of 0.1%aqueous HCl solution (1.35 l). The mixture is extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is recrystallized from ether to obtaintert-butyl methyl ether (3-chloropyridin-4-yl)carbamino acid(4 g). The mother liquor is purified by chromatography on silica gel, elwira 0-50% EtOAc in heptane. The assembled product is crystallized from ether to obtain additional 4.5 gtert-butyl methyl ether (3-chloropyridin-4-yl)carbamino acid(total yield 8.5 g). MS: 229 (M+H);1H NMR (300 MHz, CDCl3): δ 8,48 (s, 1H), scored 8.38 (d, 1H), 8,17 (d, 1H), 7,18 (USS, 1H), 1.57 in (s, 9H).

Stage 2. A mixture of tert-butyl methyl ether (3-chloropyridin-3-yl)carbamino acid (8,4 g, to 36.8 mmol), allylbromide (7,46 g, 39,1 mmol) and cesium carbonate (24,9 g, to 76.4 mmol) in DMF (100 ml) is heated at 60°C for 1 h, the Reaction mixture was quenched with water and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtaintert-butyl ether allyl-(3-chloropyridin-3-yl)to raminosoa acid (8,4 g, 85%). MS: 269 (M+H);1H NMR (300 MHz, CDCl3): δ = 8,66 (s, 1H), 8,49 (d, 1H), 7,18 (d, 1H), 5,80-5,96 (m, 1H), 5,15 (s, 1H), 5,10 (d, 1H), 4.2V (USS, 1H), USD 1.43 (s, 9H).

Stage 3. A mixture of tert-butyl methyl ether allyl-(3-chloropyridin-4-yl)carbamino acid (8,25 g, 30,8 mmol), tetrabutylammonium chloride (9,67 g, 30,8 mmol), palladium acetate (691 mg, is 3.08 mmol) and potassium carbonate (12.8 g, 92,3 mmol) in DMF (100 ml) is heated at a temperature of 80°C for 1.5 h, the Reaction mixture was diluted with DHM and washed three times with water. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain a mixturetert-butyl ester 3-methylpyrrole[3,2-c]pyridine-1-carboxylic acidandtert-butyl ester 3-methylene-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylic acid(just 4,21 g).

Stage 4. The mixture obtained in stage 3, stirred DHM (10 ml) and TFU (10 ml) at room temperature for 18 hours, the Reaction mixture was concentrated. Add 2M aqueous solution of KOH and the mixture is extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get3-methyl-1H-pyrrolo[3,2-c]pyridine(1,91 g, 47%). MS: 133 (M+H);1H NMR (300 MHz, CDCl3): δ 8,89 (s, 1H), 8,24 (d, 1H), 7,37 (d, 1H), 7,11 (s, 1H) 2,40 (s, 3H).

Stage 5. A mixture of 3-methyl-1H-pyrrolo[3,2-a]pyridine (1,91 g, 14,47 mmol) and KOtBu (3.25 g, of 28.9 mmol) in DMF (65 ml) blow N2and stirred at room temperature for 2 hours To the mixture chloramine in ether (0,15M, 145 ml) and the mixture is stirred for 20 minutes, the Reaction mixture was cooled to 0°C. and add a solution of Na2S2O3(800 mg) in water (130 ml). The mixture is stirred for 10 min at 0°C and then concentrated in vacuo. The residue is treated DHM and filtered. To the filtrate add DHM, cooled to 0°C and treated with BOC2O (793 mg, 3.6 mmol). The mixture was concentrated in vacuo and the residue purified by chromatography on silica gel, elwira 10% MeOH in DHM to get3-methylpyrrole[3,2-c]pyridine-1-ylamine(842 mg, 35%). MS: 148 (M+H);1H NMR (300 MHz, CDCl3): δ cent to 8.85 (s, 1H), at 8.36 (d, 1H), 7,32 (d, 1H), 6,95 (s, 1H) 4,77 (s, 2H), is 2.37 (s, 3H).

Stage 6. A mixture of 3-methylpyrrole[3,2-c]pyridine-1-ylamine (223 mg, of 1.52 mmol), 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (329 mg, of 1.52 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4,59 mmol) in DMF (8 ml) is stirred at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water and NaHCO3(168 mg, 2 mmol). The mixture was concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10% MeOH in DHM, to get(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(91 mg, 17%). MS: 345 (M+H);1H NMR (300 MHz, DMSO-d6): δ = 9,34 (s, 2H) 8,79 (d, 1H), 8,53 (d, 1H), 8,45 (d, 1H), 8,13 (d, 1H), 8,02 (t, 1H), 7,86 (s, 1H), to 7.59 (t, 1H), 2,77 (s, 3H), 2,43 (s, 3H).

Example 203

(3-Methylpyrrole[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of 3-methylpyrrole[3,2-c]pyridine-1-ylamine (224 mg, of 1.52 mmol), 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (354 mg, of 1.52 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4,59 mmol) in DMF (8 ml) is heated at a temperature of 150°C for 1 h, the Reaction mixture was quenched with water, add NaHCO3(168 mg, 2 mmol) and the mixture extracted with EtOAc. The organic phase is separated, dried (Na2SO4), filtered and concentrated. The residue is initially purified column chromatography on silica gel, elwira 10% MeOH in DHM, and then recrystallized from EtOAc to obtain2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (3-methylpyrrole[3,2-c]pyridin-1-yl)amide(198 mg). MS: 362 (M+H);1H NMR (300 MHz, CD3OD): δ 9,12 (s, 1H), 8,86 (s, 1H), 8,35 (d, 1H), 8,15-8,31 (m, 2H), 7,47-of 7.60 (m, 2H), 7,35 (s, 1H), 7,29 (m, 1H), 2,84 (s, 3H), of 2.44 (s, 3H).

Example 204

(5-Nitroindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. NaH (60%, 421,5 mmol) is added by portions to a solution of 5-nitro-1H-indole (28.1 mmol) in anhydrous DMF (80 ml) at 0°C and the mixture is stirred at 0°C in a stream of N2within 10 minutes To the mixture until ablaut portions HOSA (to 140.5 mmol) for 30 minutes and the mixture is stirred at 0°C for 2 hours The reaction mixture was quenched with water. Add a further quantity of water (250 ml) and the mixture extracted with EtOAc (3×100 ml). The combined organic phase washed with water (2×30 ml), brine (30 ml), dried (Na2SO4), filtered and concentrated. The residue was washed with heptane (2×20 ml) and recrystallized from EtOAc to obtain5-nitroindole-1-ylamine(4,84 g, 97%) as a solid. MS: 178 (M+H);1H NMR (300 MHz, CDCl3): δ 4,93 (ush., 2N-H), 6,62 (d, H), 7,30 (d, H), 7,52 (d, H), 8,17 (d, H), 8,58 (s, H).

Stage 2. DIPEA (12,65 mmol) are added to a solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (4,22 mmol), 5-nitroindole-1-ylamine (4,22 mmol) and HOTT (hexaphosphate S-(1-oxido-2-pyridyl)-thio-N,N,N',N'-tetramethylurea) (7.6 mmol) in anhydrous DMF (15 ml) and the mixture is heated at 80-90°C during the night. After evaporation of the solvent the residue is dissolved in EtOAc (150 ml), washed with water (20 ml), 5% sodium sulfate (20 ml), water (ml) and brine (20 ml). The organic phase is dried (Na2SO4), filtered and concentrated. The residue was kept at room temperature overnight to obtain(5-nitroindole-1-yl)amide of 4-methyl-2-(3-forfinal)pyrimidine-5-carboxylic acid(730 mg, 44%) as a solid. MS: 392 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,78 (s, 3H), to 6.88 (d, H), 7,38-7,53 (m, H), EUR 7.57-7,76 (m, 2H), 7,81 (d, H), 8,06-8,32 (m, 2H), 8.34 per (l, H), 8,65 (d, H), 9,27 (s, 2H).

u> Example 205

(5-Aminoindan-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of (5-nitroindole-1-yl)amide of 4-methyl-2-(3-forfinal)pyrimidine-5-carboxylic acid (1,64 mmol) in MeOH (45 ml) and 10% Pd/C (0.16 mmol) gidrogenit in a Parr shaker 500 ml under a pressure of 50 psi at room temperature overnight. Pd/C is filtered off. The filtrate is concentrated to obtain(5-aminoindan-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(545 mg, 92%) as a solid. MS: 362 (M+H);1H NMR (300 MHz, CD3OD): δ of 3.84 (s, H), 6,37 (d, H), for 6.81 (DD, H), 7,01 (d, H), 7,16 and 7.36 (m, 3H), 7,55 (m, H)8,23 (d, H), at 8.36 (d, H), 9,50 (s, H).

Example 206

[5-(Dimethanesulfonate)aminoindan-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of (5-aminoindan-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (0.43 mmol) and methanesulfonamide (0.52 mmol) in anhydrous DHM (10 ml) is stirred at 0°C and add triethylamine (1,29 mmol). The reaction mixture was stirred at 0°C for 1 h and then warmed to room temperature and stirred for 30 minutes. Add DHM (20 ml) and the mixture was washed with 4% HCl (15 ml), water (10 ml) and brine (15 ml). The organic phase is dried (Na2SO4), filtered and the concentration of irout. The residue is purified by chromatography using silica gel, elwira 0-60% EtOAC in DHM, to get[5-(dimethanesulfonate)aminoindan-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(85 mg, 38%) as a solid. MS: 518 (M+H);1H NMR (300 MHz, CDCl3): δ of 2.75 (s, 3H), 2,90 (s, 3H), 3,66 (s, 3H), 6,51 (s, H),? 7.04 baby mortality-7,53 (m, 6H), 8,03 (l, H)to 8.12 (d, H), at 8.60 (s, H).

Example 207

(5-Benzoylamino-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of benzoyl chloride (0.85 mmol) in anhydrous DHM (2 ml) is added dropwise to a solution of (5-aminoindan-1-yl)amide of 4-methyl-2-(3-forfinal)pyrimidine-5-carboxylic acid (0.47 mmol) and triethylamine (1,41 mmol) in anhydrous DHM (16 ml) and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue is dissolved in EtOAc (25 ml) and washed with water (2×20 ml) and brine (10 ml). The organic phase is dried (Na2SO4), filtered and concentrated. The residue is treated with EtOAc to obtain(5-benzoylamino-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(95 mg, 43%) as a solid. MS: 466 (M+H);1H NMR (300 MHz, DMSO-d6): δ 2,99 (s, 3H), 6,72 (d, H), 7,38-of 7.48 (m, H), of 7.48-7,80 (m, 6H), 7,83-8,016 (m, 3H), 8.07-a to 8.20 (m, H), 8,23-8,35 (m, 2H), 9,24 (s, H), of 10.25 (ush., H).

Example 208

Dichlorinated [5-fluoro-3-(1,2,3,6-tetrahydropyrido the Jn-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. A mixture of 5-farindola (6,65 g, and 49.2 mmol) and hydrochloride of 4-piperidineacetate (18,9 g, 123 mmol) in methanol solution 2n. KOH (90 ml) is refluxed for 6 hours After cooling to room temperature, add water (150 ml) and stirred at room temperature for 30 minutes. The precipitate is filtered, washed with water (10 ml) and ether (15 ml) and dried in vacuum to obtain5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)indole(6,34 g, 60%). MS: 217 (M+H);1H NMR (300 MHz, CDCl3): δ 8,40 (ush., H), EUR 7.57 (DD, H), 7.24 to 7,37 (m, H), of 7.23 (s, H), 6,98 (t, H), of 6.20 (s, H), 3,62 (m, 2H), and 3.16 (m, 2H), 2,50 (s, 2H).

Stage 2. A solution of di-tert-BUTYLCARBAMATE (504 mg, 2,31 mmol) in DHM (10 ml) is added to a stirred solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)indole (500 mg, 2,31 mmol) in DHM (20 ml) at room temperature and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to obtaintert-butyl ester 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid(730 mg). MS: 317 (M+H);1H NMR (300 MHz, CDCl3): δ 8.17 and (ush., H), 7,56 (d, H), 7,31 (m, H), 7,26 (s, H), 6,99 (t, H), 6,13 (s, H)to 4.17 (m, 2H), 3,70 (m, 2H), 2.57 m (s, 2H), and 1.54 (s, 9H).

Stage 3. A solution of tert-butyl ester 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (730 mg, 2,31 mmol) in anhydrous DMF is added slowly to the mix is a solution of 60% NaH (1108 mg, 27,72 mmol) in anhydrous DMF (20 ml) at 0°C in a stream of N2and stirred at room temperature for one hour. Add HOSA (1305 mg, 11,55 mmol) in portions at 0°C, stirred at 0°C for 5 hours, poured on ice/water (350 ml) and extracted with ether (3×35 ml). The combined organic extract was washed with water (2×20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with heptane (3×5 ml) to obtain atert-butyl methyl ether4-(1-amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid(715 mg, 94%) as a solid. MS: 332 (M+H);1H NMR (300 MHz, CDCl3): δ 7,52 (d, H), of 7.36 (m, H), 7,20 (s, H),? 7.04 baby mortality (t, H), the 6.06 (s, H), 4,78 (s, 2H), 4,15 (m, 2H), 3,69 (t, 2H), 2,54 (s, 2H), of 1.55 (s, 9H).

Stage 4. The triethylamine (2.6 mmol) is added to a stirred solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (1,30 mmol) and isobutylphthalate (1,95 mmol) in anhydrous DHM (20 ml) at room temperature in a stream of N2and stirred at room temperature for 2 hours, the Reaction mixture was concentrated in vacuo. The residue is dried in vacuum and add THF (30 ml). The mixture is filtered and the filtrate concentrated to obtainisobutyl-[1-(4-methyl-2-pyridine-2-Yeremey-5-yl)]carbonate(350 mg, 85%).

Stage 5. Bis(trimethylsilyl)amide, sodium (2H.) in THF (0,83 ml) we use the t to a stirred solution of tert-butyl ester 4-(1-amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (367 mg, 1.11 mmol) in anhydrous DMF (20 ml) at room temperature in a stream of N2then stirred at room temperature for 15 minutes a Solution of isobutyl-[1-(4-methyl-2-pyridine-2-Yeremey-5-yl)]-carbonate (350 mg, 1.11 mmol) in anhydrous DMF (5 ml) is added slowly at room temperature and stirred at 60°C for 18 hours in a stream of N2. DMF is evaporated. The residue is dissolved in EtOAc (60 ml), washed with water (3×20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-20% MeOH in DHM, to gettert-butyl methyl ether4-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid(158 mg, 28%).

Stage 6. A solution of tert-butyl ester 4-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (158 mg) in DHM (15 ml) was bubbled gaseous HCl for 10 min at room temperature, then stirred at room temperature for 18 hours DHM is evaporated and the residue treated with MeOH (2 ml). The solid is collected by filtration and dried to obtaindichloride [5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(81 mg, 54%). MS: 429 (M+H);1H NMR (300 MHz, CD OD): δ =2,89 (m, 2H), 2,96 (s, 3H), 3,53 (t, 2H), 3,94 (m, H), 6,27 (s, H), 7,12 (t, H), 7,46 (kV, H), to 7.59-7,71 (m, H)8,28 (t, H), cent to 8.85 (t, H), 8,99 (l, H)to 9.15 (d, H), 9,41 (s, H).

Example 209

(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-yl-4-cryptomaterial-5-carboxylic acid

A solution of 2-pyridin-2-yl-4-cryptomaterial-5-carboxylic acid (219 mg, 0.81 mmol), 5-fluoro-3-methylindol-1-ylamine (0.98 mmol), DIPEA (158 mg, of 1.23 mmol) and HATU (1.06 mmol) in anhydrous DMF (8 ml) is stirred at a temperature of 80°C during the night. The reaction mixture was diluted with EtOAc (40 ml) and washed with water (4×20 ml) and brine (20 ml). The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 1%-50% EtOAc in DHM. The assembled product is recrystallized from DHM to get(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-yl-4-cryptomaterial-5-carboxylic acid(105 mg, 31%) as a solid. MS: 416 (M+H);1H NMR (300 MHz, CD3OD): δ =2,32 (s, 3H),? 7.04 baby mortality (t, H), 7,16 (s, H), 7,25 (DD, H), 7,34 (kV, H), to 7.67 (DD, H), 8,11 (t, H), to 8.70 (d, H), 8,82 (l, H)to 9.57 (s, H). IC50=8 nm.

Example 210

(2-Methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A mixture of (2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (246 mg, of 0.68 mmol) and MnO2(296 mg, 3 mmol) in DHM (10 ml) was stirred at room temperature for 1.5 hours The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is treated with ether to obtain(2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(158, 65%). MS: 361 (M+H);1H NMR (300 MHz, CDCl3): δ 2,39 (s, 3H), and 2.83 (s, 3H), 6,36 (s, H), 7,10-7,29 (m, 3H), 7,44 to 7.62 (m, H), 8,17 (s, H), of 8.25 (d, H), 8,35 (d, H), 8,97 (s, H).

Example 211

(6-Fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid

Stage 1. LiAlH4(14.7 mmol, 1 M solution in THF) are added to a solution of 6-fluoro-4H-benzo[1,4]oxazin-3-one (1.23 g, 7,35 mmol) in THF at room temperature and refluxed for 2 hours. The reaction mixture was quenched with a few drops of water followed by gradual addition of ethyl acetate (10 ml). The solid is filtered off and washed with EtOAc. The filtrate was concentrated in vacuo to obtain6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine(1 g). MS: 154 (M+H).

Stage 2. To a solution of 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g) in DHM (15 ml) add soliditet and refluxed over night. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel, elwira 10% EtOAc in heptane to obtain6-fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine(0,83 g).

Stage 3. LiAlH4in THF (1M, to 6.58 ml) was added to a solution of 6-ft is R-4- nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (0.8 g) in THF (10 ml) at 0°C and then stirred at room temperature overnight. The reaction mixture was quenched with a few drops of water followed by addition of EtOAc (10 ml). The solid is filtered off and washed with EtOAc (15 ml). The filtrate was concentrated in vacuo and the residue purified by chromatography on a column of silica gel, elwira 15% EtOAc in heptane, to obtain6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-ylamine(0,44 mg).

Stage 4. DIPEA (174 μl) are added to a mixture of 2-(3-forfinal)pyrimidine-5-carboxylic acid (218 mg), HATU (380 mg) and 6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-ylamine (220 mg) in DMF (15 ml) and then heated at a temperature of 80°C during the night. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on a column of silica gel, elwira 30% EtOAc in heptane, to obtain(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid(81 mg). MS: 369 (M+H);1H NMR (300 MHz, DMSO-D6): δ 11,05 (s, 1H), 9,35 (s, 2H), 8,32 (DD, 1H), 8,18 (DD, 1H), 7,65 (m, 1H), 7.5 (m, 1H), 6,8-6,7 (m, 2H), 6,52-of 6.45 (m, 1H), 4,36-to 4.33 (m, 2H), 3,65 (m, 2H). IC50=12 nm.

Example 212

(6-Fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 211, step 4, but substituting 2-(3-forfinal)pyrimido the-5-carboxylic acid 2-phenylpyrimidine-5-carboxylic acid, get(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid in the form of a solid substance. MS: 351 (M+H);1H NMR (300 MHz, DMSO-D6): δ 11,03 (s, 1H), was 9.33 (s, 2H), 8,49-8,46 (m, 2H), to 7.61-of 7.55 (m, 3H), 6,8-6,7 (m, 2H), 6,52-of 6.45 (m, 1H), 4,36-to 4.33 (m, 2H), 3,65 is 3.25 (m, 2H). IC50=21 nm.

Example 213

(3-Ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. A solution of 5-fluoro-3-iodopyridine-2-ylamine (3 g, 12.6 mmol) in DHM (40 ml) is treated with TFAA (2.1 ml, 15.1 mmol) and pyridine (1.2 ml, 15.1 mmol) and stirred at room temperature for 2 hours the Mixture is diluted with H2O (150 ml) and extracted with DHM (3×150 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with MeCN (40 ml), treated with bromide TRANS-krotala (2 ml, of 18.9 mmol) and K2CO3(3.5 g, 25,2 mmol) and refluxed for 2 hours the Mixture is cooled, filtered through a layer of celite and concentrate. The residue is purified by chromatography on silica gel, elwira 5-30% EtOAc in heptane, to obtainN-but-2-enyl-2,2,2-Cryptor-N-(5-fluoro-3-iodopyridine-2-yl)ndimethylacetamide(2.5 g, 51%). MS: 389 (M+H);1H NMR (300 MHz, CDCl3): δ at 8.36 (m, 1H), 7,98 (s, 1H), 5,55 (m, 2H), to 4.62 (m, 1H), 3.96 points (m, 1H), 1,61 (m, 3H).

Stage 2. A solution of N-but-2-enyl-2,2,2-Cryptor-N-(5-fluoro-3-iodopyridine-2-yl)ndimethylacetamide (to 2.57 g, 6.5 mm is l) in DMF (10 ml) is treated with n-Bu 4NCl (2 g, 7,15 mmol), Pd(OAc)2(59 mg, 0.26 mmol) and stirred at 100°C for 2 hours the Mixture is cooled to room temperature, diluted with EtOAc (50 ml), filtered through a layer of silica gel and washed with 1M HCl (50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 25-70% EtOAc in heptane, to obtain3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine(0.75 g, 70%). MS: 165 (M+H);1H NMR (300 MHz, CDCl3): δ 9,62 (s, NH, 1H), 8,17 (m, 1H), 7,60 (m, 1H), 7,16 (s, 1H), 2,74 (kV, 2H), 1,31 (t, 3H).

Stage 3. A suspension of NaH (2.7 g, 68 mmol, 60% in mineral oil) in DMF (20 ml) at 0°C is treated with 3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (745 mg, 4.5 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (2.5 g, to 22.5 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30-50% EtOAc in heptane, to obtain3-ethyl-5-fererro[2,3-b]pyridine-1-ylamine(685 mg, 84%). MS: 180 (M+H);1H NMR (300 MHz, CDCl3): δ is 8.16 (s, 1H), 7,56 (m, 1H), 7,14 (s, 1H), is 4.93 (s, NH2, 2H), 2,697 (kV, 2H), 1.28 (in t, 3H).

Stage 4. A solution of 4-methyl-2-pyridine-2-Yeremey-5-carb is new acid (490 mg, 2.28 mmol) and 3-ethyl-5-fererro[2,3-b]pyridine-1-ylamine (340 mg, 1.9 mmol) in DMF (6 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(427 mg, 60%). MS: 377 (M+H);1H NMR (300 MHz, DMSO-d6): δ 11,94 (s, NH, 1H), 9,14 (s, 1H), 8,81 (d, 1H), of 8.47 (d, 1H), 8.30 to (s, 1H), 8,03 (m, 2H), to 7.61 (m, 2H), of 2.81 (s, 3H), of 2.75 (q, 2H), of 1.29 (t, 3H).

Example 214

(3-Ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (509 mg, 2.28 mmol) and 3-ethyl-5-fererro[2,3-b]pyridine-1-ylamine (340 mg, 1.9 mmol) in DMF (6 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(481 mg, 66%). MS: 383 (M+H) 1H NMR (300 MHz, DMSO-d6): δ 11,95 (s, NH, 1H), 9,10 (s, 1H), 8,29 (s, 1H), 8,14 (d, 1H), 8,08 (d, 1H), 8,00 (m, 1H), EUR 7.57 (s, 1H), and 2.79 (s, 3H), of 2.75 (q, 2H), of 1.29 (t, 3H).

Example 215

(5-Fererro[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

Stage 1. A solution of 5-fluoro-3-iodopyridine-2-ylamine (4 g, a 16.8 mmol) in THF (50 ml) and trimethylsilylacetamide (of 4.7 ml, 33.6 mmol) is treated with PdCl2(PPh3)4(353 mg, 0.5 mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 ml, of 50.4 mmol) and stirred at room temperature for 2 hours the Mixture is filtered through celite and concentrated. The residue is purified by chromatography on silica gel, elwira 10-35% EtOAc in heptane, to obtain5-fluoro-3-trimethylsilylethynyl-2-ylamine(3.3 g, 94%). MS: 209 (M+H);1H NMR (300 MHz, CDCl3): δ of 7.90 (d, 1H), 7,30 (m, 1H), 4,89 (s, NH2, 2H), and 0.25 (s, 9H).

Stage 2. A solution of 5-fluoro-3-trimethylsilylethynyl-2-ylamine (3.2 g, to 15.4 mmol) in MeOH (77 ml) and K2CO3(1.1 g, 7.7 mmol) was stirred at room temperature for 0.5 hours the Mixture is filtered through celite and concentrated. The residue is purified by chromatography on silica gel, elwira 15-55% EtOAc in heptane, to obtain3-ethinyl-5-herperidin-2-ylamine(1.55 g, 74%). MS: 137 (M+H);1H NMR (300 MHz, CDCl3): δ 7,94 (d, 1H), 7,35 (m, 1H), 4,91 (s, NH2, 2H), 3,44 (s, 1H).

Stage 3. A solution of 3-ethinyl-5-herperidin-2-ylamine (1,25g, 9.2 mmol) in DMF (20 ml) is treated with (Rh(cod)2Cl)2(23 mg, is 0.023 mmol) and Tris-(4-forfinal)Fofana (115 mg, 0,368 mmol) and stirred at 85°C for 0.5 h the Mixture was then poured into brine (50 ml) and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 35-75% EtOAc in heptane, to obtain5-fluoro-1H-pyrrolo[2,3-b]pyridine(1,05 g, 84%). MS: 137 (M+H);1H NMR (300 MHz, CDCl3): δ 9.15, with (s, NH, 1H), to 7.99 (s, 1H), 7,44 (d, 1H), 7,18 (s, 1H), 6,28 (s, 1H).

Stage 4. A suspension of NaH (4.4 g, 110 mmol, 60% in mineral oil) in DMF (37 ml) at 0°C is treated with 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 7.4 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (4,2 g, 37 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30-70% EtOAc in heptane, to obtain5-fererro[2,3-b]pyridine-1-ylamine(980 mg, 88%). MS: 152 (M+H);1H NMR (300 MHz, CDCl3): δ to 8.20 (s, 1H), 7,60 (m, 1H), 7,42 (m, 1H), 6,36 (s, 1H), free 5.01 (s, NH2, 2H).

Stage 5. A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid the (529 mg, 2.28 mmol) and 5-fererro[2,3-b]pyridine-1-ylamine (288 mg, 1.9 mmol) in DMF (6 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(5-fererro[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(475 mg, 68%). MS: 366 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,12 (s, 1H), 8.30 to (m, 2H), 8,18 (d, 1H), of 7.97 (d, 1H), 7,82 (d, 1H), to 7.59 (m, 1H), 7,44 (m, 1H), 6,59 (d, 1H), 2,80 (s, 3H).

Example 216

(5-Fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid (440 mg, 2.28 mmol) and 5-fererro[2,3-b]pyridine-1-ylamine (288 mg, 1.9 mmol) in DMF (6 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(343 mg, 52%). MS: 349 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,1 (s, 1H), 8,81 (d, 1H), 8,53 (d, 1H), of 8.27 (s, 1H), 8,01 (m, 1H), of 7.90 (m, 1H), to 7.77 (d, 1H), EUR 7.57 (m, 1H), 6,60 (d, 1H), 2,84 (s, 3H).

Example 217

(2-Cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

Stage 1. A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 ml) and cyclopropylacetylene (1,4 ml and 16.9 mmol) is treated with PdCl2(PPh3)4(177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 ml, of 25.2 mmol) and stirred at room temperature for 2 hours the Mixture is filtered through celite and concentrated. The residue is purified by chromatography on silica gel, elwira 0-35% EtOAc in heptane, to obtain2-cyclopropylamino-4-ftorhinolona(1.1 g, 74%). MS: 176 (M+H);1H NMR (300 MHz, CDCl3): δ 6,93 (m, 1H), for 6.81 (m, 1H), 6,59 (m, 1H), 4.00 points (s, NH2, 2H), 1,49 (m, 1H), 0,82 (m, 4H).

Stage 2. A solution of 2-cyclopropylamino-4-ftorhinolona (0,80 g, 4.5 mmol) in PhMe (16 ml) is treated with InBr3(80 mg, 0.23 mmol) and stirred at 110°C for 0.5 h the Mixture was then poured into brine (20 ml) and extracted with EtOAc (3×20 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-25% EtOAc in heptane, to obtain2-cyclopropyl-5-fluoro-1H-indole(610 mg, 78%). MS: 176 (M+H);1H NMR (300 MHz, CDCl3): δ 7,88 (s, NH, 1H), 7,12 (m, 2H), 6,83 (m, 1H), 6,09 (s, 1H), 1,90 (m, 1), of 0.95 (m, 2H), 0,77 (m, 2H).

Stage 3. A suspension of NaH (1.9 g, 47 mmol, 60% in mineral oil) in DMF (20 ml) at 0°C is treated with 2-cyclopropyl-5-fluoro-1H-indole (550 mg, 3.14 mmol) and stirred at 0°C for 1 h the Mixture was treated with portions of HOSA (1.8 g, 15.7 mmol) and warmed to room temperature for 2 hours the Mixture is then poured on ice, filtered through a layer of celite and extracted with EtOAc (3×50 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 5-35% EtOAc in heptane, to obtain2-cyclopropyl-5-Florinda-1-ylamine(420 mg, 70%). MS: 191 (M+H);1H NMR (300 MHz, CDCl3): δ 7,30 (m, 1H), 7,11 (m, 1H), 6,92 (m, 1H), 5,90 (s, 1H), 4,57 (s, NH2, 2H), 2,07 (m, 1H), 1,02 (m, 2H), 0.75 in (m, 2H).

Stage 4. A solution of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid (184 mg, 0.85 mmol) and 2-cyclopropyl-5-Florinda-1-ylamine (135 mg, 0.71 mmol) in DMF (3 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (235 mg, 0.71 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(35 mg, 13%). MS: 389 (M+H);1H NMR (300 MHz, DMSO-d6 ): δ 11,93 (s, NH, 1H), 9,31 (s, 1H), 9,06 (d, 2H), of 7.70 (m, 1H), 7,42 (m, 1H), 7,26 (m, 1H), 6,97 (m, 1H), 6,16 (s, 1H), and 2.79 (s, 3H), of 1.97 (m, 1H), 1,01 (m, 2H), 0.74 and (m, 2H).

Example 218

(2-Cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid

A solution of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid (188 mg, 0.85 mmol) and 2-cyclopropyl-5-Florinda-1-ylamine (135 mg, 0.71 mmol) in DMF (3 ml) is stirred at 40°C for 1 h, the Mixture is treated with DMTMM (235 mg, 0.71 mmol) and stirred at 40°C for 1 h the Mixture was diluted with saturated aqueous Na2CO3(5 ml) and stirred for 5 minutes the Precipitate is collected by filtration and dried in vacuum to obtain(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid(60 mg). MS: 394 (M+H);1H NMR (300 MHz, DMSO-d6): δ 9,26 (s, 1H), 8,15 (d, 1H), 8,08 (d, 1H), 7,43 (m, 1H), 7,24 (m, 1H), 6,97 (m, 1H), 6,18 (s, 1H), 2,77 (s, 3H), of 1.95 (m, 1H), 1,01 (m, 2H), 0,73 (m, 2H).

Example 219

(5-Methoxyindol-1-yl)amide 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid

A solution of 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid (496 mg, 2,30 mmol) and 5-methoxyindol-1-ylamine (0.98 mmol) in anhydrous DMF (10 ml) is stirred at 50°C for 30 minutes To the mixture DMTMM (555 mg, a 2.01 mmol) and stirred at 50°C is about an hour. DMF is evaporated. The residue is mixed with water (40 ml) and stirred at room temperature for 20 minutes. The solid is collected by filtration, washed with water (3×5 ml) and dried in vacuum to obtain(5-methoxyindol-1-yl)amide 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid(410 mg) as a solid. MS: 361 (M+H);1H NMR (300 MHz, CD3OD): δ of 2.93 (s, 3H), 4,84 (s, 3H),? 7.04 baby mortality (t, H), of 6.50 (d, H), 6,92 (d, H), 7,14 (s, H), 7,26-7,37 (m, 2H), 7,72 (t, H), which is 9.09 (d, 2H), 9,27 (s, H).

Example 220

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid

Stage 1. Bromine (1,96 g, 12.2 mmol) is added to a mixture of 2-fluoro-5-aminopyridine (1,37 g, 12.2 mmol) and sodium acetate (2 mg, 24.4 mmol) in acetic acid (30 ml) and stirred at room temperature for 4 hours. Acetic acid is evaporated in a vacuum. The residue is dissolved in EtOAc (50 ml), washed with saturated aqueous Na2CO3(10 ml), water (20 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtain2-bromo-3-amino-6-herperidin(2.1 g) as a solid. MS: 190 (M+H);1H NMR (300 MHz, CDCl3): δ Android 4.04 (ush., 2H), 6,77 (DD, H), 7,17 (DD, H).

Stage 2. TFAA (8,31 g, 39,57 mmol) is added dropwise to a stirred solution of 2-bromo-3-amino-6-herperidin (6,30 g, 33.0 mmol) and pyridine (3,91 g, 49,46 mm is l) in DHM (80 ml) at room temperature and stirred at room temperature for one hour. Add water (40 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtainN-(2-bromo-6-herperidin-3-yl)-2,2,2-trifurcated(9,37 g, >99%) as a solid.1H NMR (300 MHz, CDCl3): δ 7,06 (m, H), 8,40 (ush., N-H), 9,75 (DD, H).

Stage 3. A solution of N-(2-bromo-6-herperidin-3-yl)-2,2,2-trifurcated (9,16 g, 31.9 per mmol), allylbromide (6,18 g, or 47.9 mmol) and sodium carbonate (8,82 g, to 63.8 mmol) in CH3CN (80 ml) is stirred at a temperature of 80°C for 2 h, the Reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel, elwira 0-60% DHM in heptane, to obtainN-allyl-N-(2-bromo-6-herperidin-3-yl)-2,2,2-trifurcated(9,05 g) in the form of butter.1H NMR (300 MHz, CDCl3) δ 3,68 (kV, H), 5,01 (kV, H)to 5.17 (d, H), from 5.29 (d, H), 6,85 (m, H), of 7.00 (DD, H), of 7.64 (t, H).

Stage 4. A solution of N-allyl-N-(2-bromo-6-herperidin-3-yl)-2,2,2-trifurcated (3,41 g, 10,43 mmol), palladium acetate (94 mg, 0.42 mmol), chloride, Tetra(n-butylamine) (3,19 g, 11,47 mmol) and triethylamine (2.37 g, and 23.4 mmol) in anhydrous DMF (20 ml) is stirred at a temperature of 100°C in a stream of N2within hours. DMF is evaporated and the residue is mixed with water (12 ml) and stirred at room temperature for one hour. To this mixture EtOAc (15 ml) and stirred at room temperature overnight. The organic phase is separated and the aqueous phase extracted with EtOA (35 ml). The combined organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 10-60% EtOAc in heptane, to obtain5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine(1.5 g) as a solid. MS: 151 (M+H);1H NMR (300 MHz, CDCl3) δ of 2.38 (s, 3H), 6,77 (d, H), 7,28 (s, H), 7,74 (DD, H).

Stage 5. A solution of 5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine (10,7 mmol) in anhydrous DMF (15 ml) is added dropwise to a stirred solution of NaH (60%, 160 mmol) in anhydrous DMF (25 ml) in a stream of N2at 0°C for 20 min and stirred at 0°C in a stream of N2within 30 minutes. Add HOSA (of 53.5 mmol) in portions over 30 minutes at 0°C and stirred at 0°C for 1.5 h the Mixture was quenched with ice water (400 ml) and extracted with ether (3×60 ml). The combined organic phase washed with water (2×30 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira 0-60% EtOAc in heptane, to obtain5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-ylamine(570 mg). MS: 166 (M+H);1H NMR (300 MHz, CDCl3) δ 2,32 (s, 3H), 4,82 (ush., 2N-H)6,76 (d, H), 7,17 (s, H), to 7.77 (DD, H).

Stage 6. A solution of 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid (1,41 mmol), 5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-ylamine (1,41 mmol), DIEA (158 mg, 4,22 mmol) and HATU (1,69 mmol) in anhydrous DMF (8 ml) was stirred at 90°C for 16 hours. DMF is evaporated under vacuum. The residue is dissolved in EtOAc (40 ml), washed with water (3×10 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 1-20% MeOH in DHM, to get(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid(125 mg) as a solid. MS: 364 (M+H);1H NMR (300 MHz, CD3OD): δ 2,31 (s, 3H), 2,87 (s, 3H), 6.87 in (d, H)to 7.50 (s, H), 7,66 (t, H), of 7.96 (t, H), 9,04 (d, 2H), 9,27 (s, H).

Example 221

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

A solution of 2-pyridin-2-yl-4-methylpyrimidin-5-carboxylic acid (1,36 mmol), 5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-ylamine (1,36 mmol), DIPEA (158 mg, 4.07 mmol) and HATU (1,63 mmol) in anhydrous DMF (8 ml) was stirred at 90°C for 15 hours. DMF is evaporated under vacuum. The residue is dissolved in EtOAc (40 ml), washed with water (3×15 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is recrystallized from EtOAc to obtain(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(285 mg) as a solid. MS: 63 (M+H); 1H NMR (300 MHz, CD3OD): δ of 2.35 (s, 3H), 2,87 (s, 3H), 6,92 (d, H), 7,51 (s, H), 7,60 (t, H), of 7.97 (t, H), with 8.05 (t, H), 8,65 (d, H), 8,78 (d, H), 9,23 (s, H).

Example 222

(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid (1,34 mmol), 5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-ylamine (1,34 mmol), DIPEA (158 mg, 4.02 mmol) and HATU (1,60 mmol) in anhydrous DMF (8 ml) was stirred at 90°C for 16 h DMF is evaporated under vacuum. The residue is dissolved in EtOAc (40 ml) and washed with water (3×20 ml) and brine (10 ml). The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-60% EtOAc in heptane, to obtain(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(340 mg) as a solid. MS: 380 (M+H);1H NMR (300 MHz, CDCl3): δ of 2.36 (s, 3H), of 2.86 (s, 3H), at 6.84 (d, H), 7,12-7,35 (m, 2H), 7,52 (kV, H), 7,63 (t, H), 8,10-8,43 (m, 2H), 8,98 (ush., N-H).

Example 223

(5-Methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid

Stage 1. Bromine (4.72 in g, 29.5 mmol) are added to a mixture of 2-methoxy-5-aminopyridine (3,66 g, 29.5 mmol) and sodium acetate (4,84 g to 7.32 mmol) in acetic acid (50 ml)and stirred at room temperature for 20 minutes. Acetic acid is evaporated in a vacuum. The residue is dissolved in EtOAc (40 ml) and washed with water (40 ml), saturated aqueous sodium carbonate (20 ml), water (20 ml) and brine (20 ml). The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 0-40% EtOAc in heptane, to obtain2-bromo-3-amino-6-methoxypyridine(4.35 g) as oil. MS: 202 (M+H);1H NMR (300 MHz, CDCl3): δ to 3.89 (s, 3H), 6,60 (d, H), 7,07 (d, H).

Stage 2. TFAA (5,15 g, 24.5 mmol) is added dropwise to a stirred solution of 2-bromo-3-amino-6-methoxypyridine (4.15 g, 20,5 mmol) and pyridine (1,94 g, 24.5 mmol) in DHM (60 ml) at room temperature and stirred at room temperature for 2.5 hours, water is Added (40 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to obtainN-(2-bromo-6-methoxypyridine-3-yl)-2,2,2-trifurcated (of 5.68 g) in the form of a solid substance.1H NMR (300 MHz, CDCl3): δ 3.96 points (C, H), to 6.80 (s, H)8,23 (ush., N-H), 8,42 (d, H).

Stage 3. A mixture of N-(2-bromo-6-methoxypyridine-3-yl)-2,2,2-trifurcated (5,52 g, 18.5 mmol), allylbromide (3.57 g, 27.7 mmol) and sodium carbonate (5.1 g, 11 mmol) in CH3CN (60 ml) is stirred at a temperature of 80°C for 3 hours the Mixture is filtered and the filtrate concentrated in vacuo. The residue is purified column chromatography on silica gel elwira 0-60% DHM in heptane, to getN-allyl-N-(2-bromo-6-methoxypyridine-3-yl)-2,2,2-trifurcated(of 5.55 g) in the form of butter.1H NMR (300 MHz, CDCl3): δ 3,66 (kV, H)4,00 (s, H), 5,95 (kV, H), 5.08 to and 5.30 (q, 2H), 5,75-5,94 (m, H), 6,74 (d, H), 7,38 (d, H).

Stage 4. A solution of N-allyl-N-(2-bromo-6-methoxypyridine-3-yl)-2,2,2-trifurcated (5,54 g, 16.3 mmol), palladium acetate (147 mg, of 0.65 mmol), chloride, Tetra(n-butylamine) (4,99 g of 17.9 mmol) and triethylamine (and 3.72 g, 26.8 mmol) in anhydrous DMF (35 ml) is stirred at a temperature of 100°C in a stream of N2within hours. DMF is evaporated, and the residue is mixed with water (20 ml) and stirred at room temperature overnight. Add EtOAc (50 ml). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira 30-70% EtOAc in heptane, to obtain5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine(2,62 g) as a solid.1H NMR (300 MHz, CDCl3): δ of 2.38 (s, 3H), of 4.05 (s, 3H), 6,62 (s, H), 7,12 (s, H), 7,54 (d, H), 7,94 (ush., N-H).

Stage 5. A solution of 5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine (17.3 mmol) in anhydrous DMF (20 ml) is added dropwise to a stirred solution of NaH (60%, 260 mmol) in anhydrous DMF (35 ml) in a stream of N2at 0°C for 40 min and then stirred at 0°C under nitrogen atmosphere for 30 minutes. HOSA add portions over 45 minutes at 0°C and then move the're asked at 0°C for 2 hours. The reaction mixture was quenched with ice water (500 ml) and extracted with ether (3×40 ml). The combined organic phase washed with water (20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira 5-60% EtOAc in heptane, to obtain5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-ylamine(1.73 g) as a solid. MS: 178 (M+H);1H NMR (300 MHz, CDCl3): δ was 2.34 (s, 3H), Android 4.04 (s, 3H), 4.75 in (ush., 2N-H), 6,63 (d, H),? 7.04 baby mortality (C, H), 7,60 (d, H).

Stage 6. A solution of 2-pyridin-2-yl-4-methylpyrimidin-5-carboxylic acid (1,69 mmol), 5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-ylamine (1,69 mmol), DIPEA (5,01 mmol) and HATU (2.03 mmol) in anhydrous DMF (8 ml) was stirred at 90°C for 16 h DMF is evaporated under vacuum. The residue is dissolved in EtOAc (40 ml) and washed with water (3×10 ml) and brine (10 ml). The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira 0-15% MeOH in DHM, to get(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid(295 mg) as a solid. MS: 375 (M+H);1H NMR (300 MHz, CD3OD): δ 2.40 a (s, 3H), 2,84 (s, 3H), was 4.02 (s, 3H), 6,70 (d, H), 7,13 (s, H), 7,41 (m, H), 7,50 (d, H), a 7.85 (t, H), 8,51 (m, 2H), 8,78 (s, 2H), 10,57 (ush., N-H).

Example 224

(5-Methoxy-3-methylpr the olo[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid

A solution of 2-(3-phenyl)-4-methylpyrimidin-5-carboxylic acid (1.13 mmol), 5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-ylamine (1.13 mmol), DIPEA (3,39 mmol) and HATU (1,36 mmol) in anhydrous DMF (8 ml) was stirred at 90°C for 16 h DMF is evaporated under vacuum. The residue is dissolved in EtOAc (45 ml) and washed with water (3×20 ml) and brine (10 ml). The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is treated DHM to get(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid(265 mg) as a solid. MS: 392 (M+H);1H NMR (300 MHz, CD3OD): δ of 2.33 (s, 3H), and 2.79 (s, 3H), of 3.97 (s, 3H), to 6.67 (d, H), 7,20-of 7.60 (m, 2H), 7,53 (m, H), of 7.64 (d, H), 8,17 (t, H), 8.34 per (t, 2H), 9,05-9,20 (d, H).

Example 225

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid

Stage 1. A solution of 2-cyanopyridine (1,67 g, 16 mmol), 30% H2O2(3.2 ml) and methyltrioxorhenium (0.2 g, 0.8 mmol) in DHM (6.4 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel, elwira 3-10% MeOH in DHM, to get1-oxypyridine-2-carbonitrile(0,69 g) as a solid.1H NMR (300 MHz, CDCl3): δ 7,34 (t, H), 7,49 (t, H), to 7.67 (d, H), 8.3 (l, H).

Stage 2. A solution of 1-oxypyridine-2-carbonitrile (532 mg, 4,43 mmol) and sodium methoxide (0,5M in MeOH, to 0.88 ml) in MeOH (1.8 ml) was stirred at room temperature overnight. To the mixture is added ammonium chloride (261 mg, to 4.87 mmol) and stirred at a temperature of 56°C for one hour, then add 7h. ammonia in MeOH (1.5 ml). The reaction mixture is placed in a sealed tube and stirred at 40°C for one hour and then cooled to 0°C. To the mixture is added sodium methoxide (0,5M in MeOH, 8,86 ml). The mixture is filtered and the filtrate concentrated in vacuo. The residue is recrystallized from ethanol to obtain1-oxypyridine-2-carboxamidine(370 mg) as a solid.1H NMR (300 MHz, CD3OD): δ 7,52-to 7.68 (m, 2H), of 7.96 (DD, H), 8,35 (d, H).

Stage 3. A solution of 1-oxypyridine-2-carboxamidine (366 mg, to 2.67 mmol) and N,N-dimethylaminoethylmethacrylate (495 mg, was 2.76 mmol) in ethanol (3 ml) and DMF (3 ml) was stirred at 90°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on a column of silica gel, elwira of 2.5% MeOH in DHM, to getethyl ester of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid(127 mg) as a solid.1H NMR (300 MHz, CDCl3): δ of 1.47 (t, 3H), 2.95 and (s, 3H), 4,50 (kV, 2H), 7,39 (m, H), (7,70 (kV, H), at 8.36 (kV, H), 9,37 (s, H).

Stage 4. A solution of ethyl ester of 4-methyl-2-(-1-oxypyridine-yl)pyrimidine-5-carboxylic acid (123 mg, 0.48 mmol) and sodium hydroxide (123 mg, of 3.07 mmol) in a mixture of MeOH/THF/H2O (3 ml, 1:1:1) was stirred at 65°C for 5 minutes and then stirred at room temperature overnight (16 hours). Add an aqueous solution of 1H. HCl (3,07 ml). The resulting solution was concentrated to obtain4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid and sodium chloride(313 mg), which is used in the next stage without additional purification.

Stage 5. A solution of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid and sodium chloride (313 mg), 3-methyl-5-Florinda-1-ylamine (78 mg, 0.48 mmol), DIEA (92 mg, 0.71 mmol) and HATU (217 mg, or 0.57 mmol) in anhydrous DMF (2.4 ml) is stirred at a temperature of 150°C for 1 hour. DMF is evaporated. The residue is purified column chromatography on silica gel, elwira of 2.5-10% MeOH in DHM, to get(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid(169 mg) as a solid. MS: 378 (M+H);1H NMR (300 MHz, CD3OD): δ = of 1.52 (s, 3H), 2,84 (s, 3H), 7,02 (t, H), 7,18 (s, H), 7,25 (d, H), 7,35 (kV, H), a 7.62-7,80 (m, 2H), a 7.85 (DD, H), 8,48 (d, H), of 9.21 (s, H). IC50=851,5 nm.

Example 226

(5-fluoro-3-methylindol-1-yl)amide 2-(3-deformational)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 158, step 4, but substituting 2-thiazol-2-ilpi is kidin-5-carboxylic acid 2-(3-deformational)-2-Yeremey-5-carboxylic acid, get(5-fluoro-3-methylindol-1-yl)amide 2-(3-deformational)pyrimidine-5-carboxylic acid. MS: 397 (M+H);1H NMR (300 MHz, DMSO-d6): δ, and 2.27 (s, 3H),? 7.04 baby mortality (dt, 1H), 7,13 (d, 1H), 7,32 (s, 1H), 7,34-7,44 (m, 2H), 7,73-a 7.85 (m, 2H), 8,66 (d, 1H), 8,69 (s, 1H), 9,45 (s, 2H). IC50=17 nm.

Example 227

(5-fluoro-3-methylindol-1-yl)amide 2-(3-triptoreline)pyrimidine-5-carboxylic acid

In accordance with the methods similar to those described in example 158, step 4, but substituting 2-thiazol-2-Yeremey-5-carboxylic acid 2-(3-triptoreline)-2-Yeremey-5-carboxylic acid get(5-fluoro-3-methylindol-1-yl)amide 2-(3-triptoreline)pyrimidine-5-carboxylic acid. MS: 415 (M+H).1H NMR (300 MHz, DMSO-d6): δ, and 2.27 (s, 3H),? 7.04 baby mortality (dt, 1H), 7,33 (s, 1H), 7,34-7,44 (m, 2H), 7,86 (t, 1H), 8,00-8,02 (m, 1H), 8,75-8,79 (m, 2H), for 9.47 (s, 2H). IC50=262 nm.

Following the procedures similar to those described in the above examples, it is possible to prepare the following compounds:

(4-benzylpiperazine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

piperazine-1-yl amide 2-phenylpyrimidine-5-carboxylic acid,

(4-methanesulfonylaminoethyl-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-(2-methylthiazole-4-yl)pyrimidine-5-carboxylic acid,

[4-(1-methyl-1H-imidazole-2-carbonyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(1-methyl-1H-imidazol-carbonyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

tert-butyl ester 4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acid,

[4-(4-triptoreline)piperidine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,

[4-(4-triptoreline)piperidine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,

morpholine-4-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,

indol-1-alamid 2-phenylpyrimidine-5-carboxylic acid,

(4-methoxypiperidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

(2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,

(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,

methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-3-(2-morpholine-4-retil)-1H-indole-6-carboxylic acid,

[5-fluoro-3-(tetrahydropyran-4-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

N'-[2-(3-fluoro)phenylpyrimidine-5-carbonyl]hydrazide N-methyl-N-(5-fluoro)indole-3-ylsulphonyl,

[5-fluoro-3-(tetrahydropyran-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b-1-alamid 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-Tr is formatieren[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[3,2-c]pyridine-1-is)amide 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[2,3-c]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-methylpyrrole[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

pyrrolo[3,2-c]pyridine-1-alamid 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-isopropylpyrazole[3,2-c]pyridin-1-yl)and the ID of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-chlorothiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-fluoro-3-methylindol-1-yl)amide 2-(4-methylthiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(2-methyl-3-oxo-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-Florinda-1-yl)amide)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

6-(4-chlorothiazole-2-yl)-2-methyl-N-pyrrolo[2,3-c]pyridine-1-iniatiated,

(5-methyl-4-oxo-4,5-dihydropyrrolo[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyrid the n-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-yerimede the-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-2-(4-methylthiazole-2-yl)pyrimidine-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-metile is kidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[3,2-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-2,2-dottorati)pyrrolo[3,2-c]pyrid the n-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[2,3-c]pyridin-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-c]pyridin-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(3-deformational[2,3-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[2,3-b]pyridine-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,

(5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(5-deformational[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[3,2-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[2,3-c]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-cryptomaterial[2,3-b]pyridine-1-yl)amide 2-(3-torfin the l)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2-dottorati)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-b]pyridine-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[3,2-c]pyridin-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

[3-(2,2,2-triptorelin)pyrrolo[2,3-c]pyridin-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,

(3-deformational-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,

(3-deformational-1-yl)amide 2-(4-chlorothiazole-2-yl)-4-methylpyrimidin-5-carboxylic acid, or

(3-deformational-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,

ANALYSIS PROTOCOLS "IN VITRO" TO IDENTIFY INHIBITORS of HEMATOPOIETIC PGD2 SYNTHASE

Compounds of the present invention can be tested for enzymatic activity inhibition of PGD2 synthase in accordance with one of the following methods of analysis.

Method of analysis 1: Analysis of the polarization of fluorescence

As described in PCT publication WO 2004/016223, example II.

Analysis method 2: Method enzyme-linked immunosorbent assay (ELISA)

I. Analytical solutions

a. Preparation of buffer 0,1M K2HPO4/KH2PO4(pH 7,4)

To prepare 0,1M KH2PO4from 1M KH2PO4(Sigma, cat. No. P-8709)

Sentence is o be catching 0,1M K 2HPO4from powder K2HPO4(Fisher, BP363-500)

Mix 0,1M K2HPO4with 0,1M KH2PO4in order to adjust the pH to 7.4.

b) Preparation of 0.5% γ-globulin

Add 0.1 g of γ-globulin (Sigma, cat. No. G-5009) to 20 ml of buffer 0,1M K2HPO4/KH2PO4(pH 7,4) and prepare aliquots in 1-ml tubes and store them at -80°C.

C) Preparation of 100 mm GSH

Add 307 mg GSH (Sigma, cat. No. G-6529) to 10 ml of buffer 0,1M K2HPO4/KH2PO4(pH of 7.4) and stored at -80°C.

d) Preparation of reaction buffer:

198 ml of buffer 0,1M K2HPO4/KH2PO4(pH 7,4)

2 mm GSH - made from 100 mm GSH

0.4 g of glycerin

2 ml of 0.5% γ-globulin

Add 0.4 g of glycerol and 2 ml of 0.5% γ-globulin to 198 ml of buffer 0,1M K2HPO4/ KH2PO4(pH 7,4).

Add 0.4 ml of 100 mm GSH to a 19.6 ml of the reaction buffer before analysis (enough for two 96-cell tablets).

e) Preparation of stop solution FeCl2/citric acid (8 mg/ml FeCl2, 0,1M citric acid)

Add 40 mg of freshly prepared FeCl2(IGN, cat. No. 158046) to 5 ml 0,1M citric acid (Sigma, cat. No. C0759).

f) Preparation of reagent MOX:

10% EtOH - Add 1 ml of EtOH to 9 ml of ultrapure H2O

Dissolve 0.1 g of methoxylamine (Cayman, cat. No. 400036/) in 10% EtOH (10 ml).

Add 0,82 g of sodium acetate (Cayman, cat. No. 400037) to a solution of MOX and dissolve.

I. Materials and methods

Dimethyl sulfoxide (DMSO; Sigma; no cat. D2650)

Set for rapid ELISA prostaglandin D2-MOX (Caymen Chemical, no cat. 500151)

Before analysis to cool and 10 ml of acetone in polypropylene tubes and empty 96-cell tablets on ice. All procedures, except for dissolved compounds, are performed on ice.

III. Dilution connection

1. The diluted compounds in DMSO

The volume of source solution DMSO (ál)DMSO (ál)The concentration of the compound (mm)
4 μl of 10 mm6 ál4
3 µl of the 4 mm6 ál1,3333
3 μl of 1.33 mm6 ál0,4444
3 μl of 0.44 mm6 ál0,1481
3 µl 0,148 mm6 ál0,0494
3 µl 0,049 mm6 ál0,0165
3 µl 0,016 mm6 ál0,0055

2. Dilute 2 ál of each of the above concentrations of the compounds of the reaction buffer to 38 ál in 96-cell tablets and mix.

IV. Preparation of solutions of enzyme and substrate

1. Preparation of 0.39 ng/μl of an enzyme solution (0,35 ng/ál in the final stage after adding the connection).

Mix 4 μl 4 mg/ml human h-PGDS with 396 ál of reaction buffer to obtain a concentration of enzyme of 40 µg/ml). Add to 46.8 μl of 40 μg/ml of h-PGDS to 4,753 ml of the reaction buffer to obtain a total volume of 4.8 ml

2. Preparation of substrate solution (PGH2): Add the 0.375 ml of 0.1 mg/ml of PGH2 to 1,625 ml of acetone.

V. Enzymatic reaction:

1. Add 60 μl of a solution of the enzyme to the cell connection and positive control (without connections) in a polypropylene plate with a U-shaped bottom on ice.

2. Add 60 ál of reaction buffer and 6.6 μl of 5% DMSO in the reaction buffer in cells with a negative control in the tablet.

3. Add to 6.6 μl of diluted compound in the reaction buffer to the cell connection and stir.

4. Add to 6.6 μl of 5% DMSO in the reaction buffer to the cell positive control.

5. Incubate the plate on ice for at least 30 minutes

6. Add 20 µl of substrate solution (PGH2) to the compound, cells positive and negative control in 96-cell tablet with U-shaped the bottom on ice.

7. Dry the plate in a cold room about 25-28 minutes

8. Add by pipette 45 ál of enzyme solution (above) in 96-cell tablet with dried PGH2 and stir 3 times. Incubate on ice for 1 minute

9. Add 45 ál of a solution of FeCl2in each cell and stir.

10. Add 90 μl of a solution MOX and stir.

11. Incubate for 30 min at 60°C.

12. Dilute samples 2500X by ELISA buffer.

VI. Analysis of ELISA

To conduct the analysis in accordance with the procedure for the ELISA test, provided Cayman. The overall level of PGD2 (PG/ml) determined in samples using ELISA kit (Caymen Chemical, cat. No. 500151).

To calculate the amount of PGD2, as shown below.

Estimated % of positive control in accordance with the following equation:

% Of positive control= (connection value - negative control)/(positive value-the value of negative control) × 100.

% Of positive control =(the connection value - negative control)× 100
(Positive value - the value of the negative control)

The connection value = level of PGD2 (PCG/ml)obtained from the standard curve in the ELISA analysis for samples with the connection is.

The value of the negative control = level PGD2 (PG/ml)obtained from the standard curve in the ELISA analysis for samples without enzyme.

The value of the positive control = level PGD2 (PG/ml)obtained from the standard curve in the ELISA analysis for samples with enzyme but without a connection.

IC50determine fitting in Excel to get the value of x when y=1/2Ymax using logistic 4-parameter model for curves IC50.

Results

Compounds according to the present invention provide 50%inhibition in the analysis of the polarization of the fluorescence or the analysis of ELISA at concentrations in the range of from about 1 nanomolar to about 30 micromol, in particular from about 1 nanomolar to about 1 micromole and, more specifically, from about 1 nanomolar to about 100 nanomoles. IC50obtained by ELISA analysis for some examples at the end of each of such examples.

The present invention can be implemented in other specific forms without distorting the essence of the invention or its main characteristics.

1. The compound of formula (I):

where R1represents phenyl or 5 - or 6-membered heteroaryl containing one to three heteroatoms selected from N, O and S, each of which optionally has one or more with EBUSY independent substituents: halogen, (C1-C6)-alkyl or (C1-C4-halogenated;
R2represents hydrogen or (C1-C4)-alkyl, which is optionally substituted by one or more Halogens;
R3represents hydrogen, (C1-C6)-alkyl or phenyl;
R4represents a C6-cycloalkyl, phenyl, 6-membered heterocyclyl containing one N heteroatom, a 6-membered heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2or-C(=O)-R5where phenyl, 6-membered heteroaryl or 6-membered heterocyclyl group optionally has one or more independent substituents R6or
R3and R4together with the nitrogen atom to which they are bound, form a 5 - or 6-membered heterocyclyl containing one or two heteroatoms selected from N, O and S, 6-membered heterocyclyl containing two or three N heteroatoms, a 5-membered monocyclic or 9-membered bicyclic heteroaryl containing one to three N heteroatoms, vinylheterocyclic where heterocyclyl is a 5 - or 6-membered and contains one or two heteroatoms, selected from N and O, each of which optionally has one or more independent substituents R6;
R5represents phenyl or 6-membered heteroaryl containing an N heteroatom, each of which is optional the part has one or more independent substituents R 6;
L1is a bond or-C(=O)-;
R6represents oxo, cyano, nitro, halogen, hydroxy, carboxy, Y1Y2N, Y1Y2N-C(=O), Y1Y2N-SO2-, (C1-C6)-acyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6-alkoxycarbonyl or (C1-C6)-alkylsulfonyl, each of which optionally has one or more of the following independent deputies:
(C1-C6)-acyloxy, halogen, (C1-C6)-alkoxy, hydroxy, carboxy, (C1-C6-alkoxycarbonyl,
phenyl, phenyloxy, 5 - or 6-membered heteroaryl containing from one to
four N heteroatoms, a 6-membered, heteroaromatic containing N, O as
heteroatoms, a 6-membered heterocyclyl containing N, as heteroatoms,
or
5-membered heteroaryl containing four N as the heteroatoms, a 5-membered heterocyclyl, containing O as the heteroatom, a 6-membered heterocyclyl containing N as heteroatom, (C3-C6-cycloalkyl,
where heterocyclyl, heterocyclyl or cycloalkyl group R6optionally independently substituted by one or more oxo;
Y1and Y2each independently is:
hydrogen, (C1-C6-alkylsulfonyl, benzoyl or
(C1-C )-alkyl, which is optionally substituted 6-membered heterocyclyl containing one or two heteroatoms, selected from N and O, or
Y1and Y2together with the nitrogen atom to which they are attached, form a 6-membered heterocyclyl, containing O as heteroatom;
or its N-oxide, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents phenyl, pyridyl, pyrimidinyl, thiazolyl or oxadiazolyl, each of which optionally has one or more of the following independent substituents: halogen or (C1-C6)-alkyl,
or its N-oxide, or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where R1represents phenyl, pyridyl or pyrimidinyl, each of which optionally has an independent substituent in the ortho - or meta-position with halogen or (C1-C6)-alkyl,
or its N-oxide, or its pharmaceutically acceptable salt.

4. The compound according to claim 1, where R1represents phenyl, which optionally has an independent substituent in the ortho - or meta-position halogen,
or its N-oxide, or its pharmaceutically acceptable salt.

5. The compound according to claim 1, where R1represents pyridyl, or its N-oxide, or its pharmaceutically acceptable salt.

6. The compound according to claim 1, where R2is own the th hydrogen, methyl or trifluoromethyl,
or its N-oxide, or its pharmaceutically acceptable salt.

7. The compound according to claim 1, where R2represents hydrogen
or its N-oxide, or its pharmaceutically acceptable salt.

8. The compound according to claim 1, where R2represents methyl,
or its N-oxide, or its pharmaceutically acceptable salt.

9. The compound according to claim 1, where L1is a relationship
or its N-oxide, or its pharmaceutically acceptable salt.

10. The compound according to claim 1, where
R3and R4together with the nitrogen atom to which they are bound, form [1,2,4]triazolyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl or pyrrolo[2,3-C] pyridyl, each of which optionally has one or more independent substituents R6;
R6is a (C1-C6)-alkoxy, carboxy, (C3-C6-cycloalkyl, halogen, cyano, (C1-C6)-alkylsulfonyl, Y1Y2N-SO2-,
(C1-C6)-alkyl, which optionally has one or more of the following independent substituents: hydroxy, (C1-C6-alkoxycarbonyl, (C1-C6)-alkoxy, carboxy, phenyl, halogen, 6-membered heterocyclyl containing N, as heteroatoms,
(C1-C6)-acyl, optionally independently substituted by one or more halogen,
(C -C6-alkoxycarbonyl, optionally independently substituted by one or more fenelli,
5-membered heterocyclyl, containing O as the heteroatom, optionally substituted by one or more oxo; and
Y1and Y2, each independently, is hydrogen or (C1-C6)-alkyl, optionally substituted by morpholinyl, or
Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;
or its N-oxide, or its pharmaceutically acceptable salt.

11. The compound according to claim 1, where
R3and R4together with the nitrogen atom to which they are bound, form imidazolidinyl, piperazinil, morpholinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyrimidines, piperidinyl, oxazolidinyl, 2,3-dihydroindole, octahydrocyclopenta[with]pyrrolyl or 3,4-dihydrobenzo[1,4]oxazin, each of which optionally has one or more independent substituents R6;
R6represents oxo, (C1-C6)-alkoxy, carboxy, (C3-C6-cycloalkyl, halogen, cyano, (C1-C6)-alkylsulfonyl, Y1Y2N-SO2-,
(C1-C6)-alkyl, which optionally has one or more of the following independent substituents: hydroxy, (C1-C6-alkoxycarbonyl, (C1-C6)-alkoxy, carboxy, phenyl, halogen, 6-membered of heteros CLIL, containing N, as heteroatoms,
(C1-C6)-acyl, optionally substituted by one or more halogen,
(C1-C6-alkoxycarbonyl, optionally independently substituted by one or more fenelli,
5-membered heterocyclyl, containing O as the heteroatom, optionally substituted by one or more oxo; and
Y1and Y2, each independently, is hydrogen or (C1-C6)-alkyl, optionally substituted by morpholinyl, or
Y1and Y2together with the nitrogen atom to which they are bound, form morpholinyl;
or its N-oxide, or its pharmaceutically acceptable salt.

12. The compound according to claim 1, where
R3and R4together with the nitrogen atom to which they are bound, form an indolyl which is optionally has one or more independent substituents R6;
R6represents the Y1Y2N-SO2-, (C1-C6-alkoxycarbonyl, carboxy-(C1-C6)-alkyl, cyano, halogen, (C1-C6)-alkylsulfonyl, (C1-C6)-alkoxy or (C1-C6)-acyl, each of which is optionally independently substituted by one or more halogen; and
Y1and Y2, each independently, is hydrogen or -( C1-C6)-alkyl, optionally substituted by morpholinyl, or
Y and Y2together with the nitrogen atom to which they are bound, form morpholinyl;
or its N-oxide, or its pharmaceutically acceptable salt.

13. The compound according to claim 1, where
R5represents phenyl or pyridyl, each of which optionally has one or more independent substituents R6;
R6represents the Y1Y2N-SO2-, hydroxy, (C1-C6)-alkoxy, halogen, (C1-C6)-alkyl or (C1-C6-halogenated; and
Y1and Y2, each independently, is hydrogen or (C1-C6)-alkyl,
or its N-oxide, or its pharmaceutically acceptable salt.

14. The Union, representing
(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,
(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,
(5-fluoro-2-methylindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(5-fluoro-2-mutilin the ol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(5-fluoro-2-methylindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[3-(2,2,2-TRIFLUOROACETYL)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,
(2,3-dimethylindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-chloro-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-bromoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
benzyl ester of 3-oxo-4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-carboxylic acid,
(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(3-dimethylsulphamoyl-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic to the slots,
[5-fluoro-3-sulfamoyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-methylsulfonyl)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[5-fluoro-3-(2-morpholine-4-reticulator)indol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(4-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(4-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(4-Florinda-1-yl)amide 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid,
(4-Florinda-1-yl)amide 2-(pyridin-2-yl)-4-methylpyrimidin-5-carboxylic acid,
[6-(4-forfinal)-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)pyrimidine-5-carboxylic acid,
[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 2-(3-forfinal)-4-metier midin-5-carboxylic acid,
[5-fluoro-3-(2-hydroxy-2-methylpropyl " indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-cyano-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[5-fluoro-3-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[1,2,4]triazole-4-alamid 2-phenylpyrimidine-5-carboxylic acid,
piperidine-1-alamid 2-phenylpyrimidine-5-carboxylic acid,
N'-(2-forfinal)hydrazide 2-phenylpyrimidine-5-carboxylic acid,
N'-ethyl-N'-tolylhydrazine 2-phenylpyrimidine-5-carboxylic acid,
(3-exmortis-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
morpholine-4-alamid 2-(5-methyl-[1,2,4]oxadiazol-3-yl)pyrimidine-5-carboxylic acid,
morpholine-4-alamid 2-benzoylpyridine-5-carboxylic acid,
[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-benzoylpyridine-5-carboxylic acid,
N'-methyl-N'-[5-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid,
N'-methyl-N'-[4-triptorelin-2-yl]hydrazide 2-phenylpyrimidine-5-carboxylic acid,
N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid,
N'-(2-chlorophenyl)hydrazide 2-phenylpyrimidine-5-carboxylic acid,
N'-(2-oxopiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
N'-cyclohexyl-N'-methylhydrazino 2-phenylpyrimidine-5-carboxylic acid,
N'-morpholine-4-alamid 2-phenoxypyridine-5-carboxylic acid, (2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
methyl ester of 3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid,
3-{2,4-dioxo-3-[(2-phenylpyrimidine-5-carbonyl)amino]-1,2,3,4-tetrahydropyrimidin-5-yl}propionic acid,
(4-methylpiperazin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
morpholine-4-alamid 2-phenylpyrimidine-5-carboxylic acid,
[4-(2-hydroxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
((s)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
((R)-2-methoxymethyl)pyrrolidin-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazole-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
pyrrol-1-alamid 2-phenylpyrimidine-5-carboxylic acid,
(5-morpholine-4-ylmethyl-2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(4-cyclopentylpropionyl-1-yl]amide of 2-Fe is Yeremey-5-carboxylic acid,
(2-oxoacridine-3-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl]amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid,
ethyl ester [N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]acetic acid,
2-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]ndimethylacetamide,
4-[3-(4-morpholino)propyl]-1-(2-phenylpyrimidine-5-carbonyl)-3-thiosemicarbazide,
(2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
methyl ester {4-[2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}acetic acid,
(4-cinematelevision-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
2-{4-[(2-phenylpyrimidine-5-carbonyl)amino]piperazine-1-yl}-ethyl ester acetic acid,
(4-acetylpiperidine-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
[4-(2-oxitetraciclina-3-yl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
[4-(2-methoxyethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
[4-(2-morpholine-4-yl-2-oxoethyl)piperazine-1-yl]amide of 2-phenylpyrimidine-5-carboxylic acid,
(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
piperidine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,
piperidine-1-alamid 2-phenylpyrimidine-5-carboxylic acid,
(hexahydrotriazine[C]pyrrol-2-alamid 2-phenylpyrimidine-5-carboxylic acid,
(2,3-dihydroindol-1-yl)amide of 4-methyl-2-phenylpyrimidine-5-carboxylic acid,
pyrrolidin-1-alamid 2-phenylpyrimidine-5-carboxylic acid,
(2,6-dimethylpiperidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(4-cyclopentylpropionyl-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(2-methyl-2,3-dihydroindol-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
N'-methyl-N'-pyridine-2-illitrate 2-phenylpyrimidine-5-carboxylic acid,
(5-Florinda-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(2,3-dihydroindol-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
indol-1-alamid 2-pyridine-2-Yeremey-5-carboxylic acid,
indol-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(2-methyl-2,3-dihydroindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(2-methylindol-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
indol-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(2,3-dihydroindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
indol-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(6 metasolv Jindal-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(5-methanesulfonamido-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
(5-methanesulfonamido-1-yl)amide 2-pyridin-3-Yeremey-5-carboxylic acid,
(5-methanesulfonamido-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,
pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(5-Florinda-1-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
pyrrolo[3,2-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
pyrrolo[2,3-b]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-Florinda-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-Florinda-1-yl)amide 2-pyridin-2-Yeremey-5-carboxylic acid,
pyrrolo[2,3-b]pyridine-1-alamid 2-pyridine-2-Yeremey-5-carboxylic acid,
pyrrolo[2,3-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
pyrrolo[3,2-b]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
pyrrolo[2,3-C]pyridine-1-alamid 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
pyrrolo[2,3-C]pyridine-1-alamid 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
pyrrolo [3,2-b]pyridine-1-alamid 4-methyl-2-pyridin-3-Yeremey-5-carboxylic acid,
(5-Florinda-1-yl)amide of 4-methyl-2-pyridin-3-Yeremey-5-to benovoy acid,
(5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-methoxyindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(4-cyanoindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[4-(1H-tetrazol-5-yl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
methyl ester 1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid,
1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indole-4-carboxylic acid,
(3-cyanomethyl-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-methoxyindol-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
[3-(1H-tetrazol-5-ylmethyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazinecarboxamide,
2-(2-phenylpyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide,
(2,4-dioxoimidazolidin-1-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid,
N'-(2-phenylpyrimidine-5-carbonyl)hydrazide pyridine-2-carboxylic acid,
4-[N'-(2-phenylpyrimidine-5-carbonyl)hydrazino]benzosulfimide,
N'-(2-phenylpyrimidine--carbonyl)hydrazide 3-hydroxybenzoic acid,
N'-(phenylpyrimidine-5-carbonyl)hydrazide benzo[1,3]dioxo-5-carboxylic acid,
N'-(phenylpyrimidine-5-carbonyl)hydrazide of 3,4-dimethoxybenzoic acid,
N'-methyl-N'-phenylhydrazide 2-phenylpyrimidine-5-carboxylic acid,
(5-methoxy-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-methoxyphenyl)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-methoxyphenyl)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-methoxyphenyl)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(3-hydroxyphenyl)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(2-hydroxyphenyl)pyrimidine-5-carboxylic acid,
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazine-4-yl)amide 2-(4-hydroxyphenyl)pyrimidine-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-thiazol-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide [2,2']bipyridinyl-5-carboxylic acid,
(3-chloro-5-Florinda-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
amide 5-fluoro-1-{[2-(3-forfinal)-4-metylene the one-5-carbonyl]amino}-1H-indole-3-carboxylic acid,
2-{5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indol-3-yl}-2-methylpropionic acid,
2-(5-fluoro-1-{[2-(3-forfinal)-4-methylpyrimidin-5-carbonyl]amino}-1H-indol-3-yl)-2-methylpropionic acid,
[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
[5-fluoro-3-(2-pyridin-3-retil)indol-1-yl]amide of 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-3-formylindole-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
5-fluoro-1-[(4-methyl-2-pyridine-2-Yeremey-5-carbonyl)amino]-1H-indole-3-carboxylic acid
(5-fluoro-3-hydroxymethylene-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
[5-fluoro-3-(3-hydroxy-3-methylbutyl)indol-1-yl]amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(3-ethyl-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(3-ethyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(6-cryptomaterial-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(6-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(6-cryptomaterial-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(6-cryptomaterial-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-cryptomaterial[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(5-methoxy-2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
N',N'-diphenylhydrazine 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(7-fluoro-3-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-methanesulfonyl-3-methylindol-1-yl)amide 2-(3-forfinal)-4-metile is kidin-5-carboxylic acid,
(3-acylpyrrole[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-acylpyrrole[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-acylpyrrole[2,3-C]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-acylpyrrole[2,3-C]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-methyl-5-cryptomaterial-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-methylpyrrole[2,3-C]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(3-methylpyrrole[2,3-C]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-methylpyrrole[3,2-C]pyridin-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-methylpyrrole[3,2-C]pyridin-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-nitroindole-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-aminoindan-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
[5-(dimethanesulfonate)aminoindan-1-yl]amide of 2-(3-forfinal)-4-
methylpyrimidin-5-carboxylic acid,
(5-benzoylamino-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carbon is acid,
[5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)indol-1-yl]amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-pyridin-2-yl-4-cryptomaterial-5-carboxylic acid,
(2-methylindol-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-(3-forfinal)pyrimidine-5-carboxylic acid,
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)amide 2-phenylpyrimidine-5-carboxylic acid,
(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(3-ethyl-5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(5-fererro[2,3-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fererro[2,3-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(2-cyclopropyl-5-Florinda-1-yl)amide of 4-methyl-2-thiazol-2-Yeremey-5-carboxylic acid,
(5-methoxyindol-1-yl)amide 2-pyrimidine-2-yl-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-[2,2']bipyridinyl-5-carboxylic acid,
(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-fluoro-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-metylene the one-5-carboxylic acid,
(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide of 4-methyl-2-pyridine-2-Yeremey-5-carboxylic acid,
(5-methoxy-3-methylpyrrole[3,2-b]pyridine-1-yl)amide 2-(3-forfinal)-4-methylpyrimidin-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide of 4-methyl-2-(1-oxypyridine-2-yl)pyrimidine-5-carboxylic acid,
(5-fluoro-3-methylindol-1-yl)amide 2-(3-deformational)pyrimidine-5-carboxylic acid, or
(5-fluoro-3-methylindol-1-yl)amide 2-(3-triptoreline)pyrimidine-5-carboxylic acid,
or its N-oxide, or its pharmaceutically acceptable salt.

15. Pharmaceutical composition having inhibitory activity against PGDS, comprising an effective amount of a compound according to claims 1 to 14, or its N-oxide, or pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 denotes an ethoxy group; R2 denotes hydrogen; R3 denotes a cyano group; R4 denotes hydrogen; R5 denotes hydrogen, a methoxy group or an ethoxy group; R6 denotes hydrogen or a methoxy group; R7 denotes hydrogen, methyl, ethyl, n-propyl or isopropyl; X1 denotes -NH-; X2 denotes N or CH; X3 denotes N or CH; where X2 and X3 do not denote N at the same time; and pharmaceutically acceptable salts and tautomeric forms thereof. The invention also relates to a medicinal agent for treating and/or preventing a vasopressin-dependent disease, which contains the compound given in claim 1, use of the compound of formula I to prevent and/or treat vasopressin-dependent diseases, as well as a method of treating and/or preventing said diseases.

EFFECT: novel compounds which can be useful in treating vasopressing-dependent diseases are described.

22 cl, 90 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: it has been confirmed that the new azolcarboxamide compound or its pharmaceutically acceptable salt wherein a thiazole ring or an oxazole ring is bound to a benzene ring, a pyridine ring, a pyridazine ring, a thiophen ring, a pyrazole ring or a pyrrol ring through carboxamide or its ring possess high activity of receptor trkA inhibition; it has been found that they may be used as a therapeutic and/or preventive agent which is different in the fact concerning the effectiveness and safety for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain; thereby the present invention has been created.

EFFECT: provided therapeutic and/or preventive agent for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain on the basis of excellent inhibitory action on the receptor trkA.

24 cl, 1195 ex, 215 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-aza-bicyclo[3,1,0]hexane derivatives of formula (I), where A, B, n and R1 are defined in the description, and to use of such compounds or pharmaceutically acceptable salts of such compounds as medicinal agents, particularly as orexin receptor antagonists. The present invention also describes use of compounds of general formula (I) to produce a medicinal agent for preventing or treating insomnia.

EFFECT: improved method.

11 cl, 279 ex, 1 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula I The method is realised via cyclisation of a compound of formula (IV) with an intermediate compound Int4 at room temperature to obtain a compound of formula (III), reducing the nitro group in the compound of formula (III) to obtain a compound of formula (II). Further, by bonding the compound of formula (II) to a compound of formula Int5 in an aprotic solvent, a compound of formula (I) is obtained (structural formulae of compounds (II), (III), (IV), Int4, Int5 are given in the claim).

EFFECT: improved method of producing compounds of formula (I).

25 cl, 3 dwg, 4 ex

Indole derivative // 2454415

FIELD: medicine, pharmaceutics.

SUBSTANCE: object of the present invention is preparing a glucokinase activator effective as a pharmaceutical agent, such as an agent for preventing or treating diabetes, obesity and similar. The present invention presents the glucokinase activator containing a compound presented by formula :

wherein R1 represents hydrogen atom or halogen atom; R2 represents a group presented by formula or wherein each symbol is such as specified in the description, or its pharmaceutically acceptable salt.

EFFECT: developing the agent for preventing or treating diabetes, obesity.

16 cl, 536 ex, 1 tbl, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 and salts thereof, fungicidal compositions based on said compounds, a plant disease control method using compounds of formula , as well as intermediate compounds of formulae and . Values of radicals are given in the description.

EFFECT: high efficiency of the compounds.

14 cl, 20 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it has been confirmed that the new azolcarboxamide compound or its pharmaceutically acceptable salt wherein a thiazole ring or an oxazole ring is bound to a benzene ring, a pyridine ring, a pyridazine ring, a thiophen ring, a pyrazole ring or a pyrrol ring through carboxamide or its ring possess high activity of receptor trkA inhibition; it has been found that they may be used as a therapeutic and/or preventive agent which is different in the fact concerning the effectiveness and safety for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain; thereby the present invention has been created.

EFFECT: provided therapeutic and/or preventive agent for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain on the basis of excellent inhibitory action on the receptor trkA.

24 cl, 1195 ex, 215 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1), where R1 denotes a C1-C4 halogenalkyl group, R2 denotes a halogen atom, R3 denotes a C1-C6alkyl group, C1-C6alkoxy group or a halogen atom, m equals an integer from 0 to 5, n equals an integer from 0 to 4, M denotes an oxygen or sulphur atom, R4 is as defined in the claim. The invention also relates to a insect control method, use of compounds of formula (1) and a composition containing compounds of formula (1) for insect control.

EFFECT: obtaining compounds of formula (1) for insect control.

20 cl, 119 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel xinafoate salt of N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-on)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidine diamine, having the structural formula given below. The invention also relates to a method of producing a salt, use of the latter, a pharmaceutical composition and a treatment method. The method of producing a xinafoate salt involves dissolving N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-on)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidine diamine and 1-1.1 molar equivalents of 1-hydroxy-2-naphthoic acid in a minimum amount of a suitable organic solvent such as acetone, acetonitrile or methyl ethyl ketone, each optionally containing a small amount of water, and subsequent slow cooling of the solution with optional stirring until precipitation of the salt from the solution.

EFFECT: obtained salt has Syk-kinase inhibiting properties and can be used in treating an inflammatory condition such as asthma (I).

12 cl, 6 tbl, 1 ex

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes poly(ADP-riboso)polymerase inhibitors of formula (Ik) its pharmaceutically acceptable salt wherein R101, R104 and R105 represent H; R102 represents R11 wherein R11 is specified from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl with R102 being substituted by one or two (O) substitutes; R103 represents fluorine, besides, a pharmaceutical composition on the basis of said compounds showing poly(ADP-riboso)polymerase (PARP) inhibitory activity, a method of treating cancer and a method of reducing tumour volume in a mammal.

EFFECT: there are produced and described new compounds which show poly(ADP-riboso)polymerase (PARP) inhibitory activity.

9 cl, 491 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to the new compound 5-chlor-N2-[(1S)-1-(5-flouropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine or its pharmaceutically acceptable salt possessing the properties of a tyrosine kinase inhibitor, particularly JAK-kinase. The invention also refers to a based pharmaceutical composition.

EFFECT: compound may be used for treating cancer.

5 cl, 5 dwg, 37 ex

Up!