Chemical compounds 637: pyridopyrimidinediones as pde4 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

 

The present invention relates to pyridopyrimidines derivatives having pharmaceutical activity, to methods for obtaining such derivatives, to pharmaceutical compositions containing such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active derivatives of pyridopyrimidines disclosed in EP-A-0260817, WO 98/02162, WO 93/19068, WO 00/45800 and WO 2007/101213.

Pharmaceutically active 1,4-dihydro-1,8-naphthirydines disclosed in WO 2007/050576, WO 2004/105698, US 2004/0102472, WO 2004/048374, WO 2004/047836, WO 02/094823 and WO 99/07704.

Phosphodiesterase (PDE) act by transformation of camp or cGMP in AMP and GMP, or inactive nucleotide form, unable to activate the underlying signaling pathways. Inhibition of PDE leads to the accumulation of camp or cGMP and subsequent activation of the below ways. PDE include a large family of second messengers from 11 families and more than 50 isoforms. In addition, for each isoform have been described splice variants. PDE can be camp-specific PDE4, 7, 8, 10), cGMP-specific PDE5, 6, 9) or to have dual specificity (PDE1, 2,3,11).

the camp is formed from the AMP on the inner surface of the plasma membrane due to the action of GPCR-regulated adenylate cyclase (adenylyl cyclase, adjustable G-protein-coupled receptors). Once formed a camp, the only way the term is AI signal ends the action of phosphodiesterase. disperses the camp to 5'AMR. Elevated concentrations of camp are converted into cellular responses mainly due to the activation of camp-dependent protein kinase (PKA). The specific activity of PKA is partially regulated by the subcellular localization of PKA, which limits the phosphorylation of PKA to the substrates in the near surroundings. Subsequent events caused by activation of PKA, poorly understood and involve numerous components in the initiation of signaling cascades. It was shown that PDE4 plays an important role in the regulation of cellular desensitization, adaptation, interaction between the signaling cascades (signal cross-talk), the compartmentalization of camp and feedback loops, and are important regulators of homeostasis camp.

Physiological role associated with elevated levels of camp includes: 1) a wide suppression of the activity of many immune cells; 2) the induction of relaxation of smooth muscles of the respiratory tract; 3) suppression of mitogenesis smooth muscle; and 4) provides a useful modulating effects on the activity of pulmonary nerves.

It was found that PDE4 is the predominant camp-metalicious isozyme family in immune and inflammatory cells and together with the PDE3 family is the main participant in the metabolism of camp in smooth muscle of the respiratory tract.

In the last two decades, the value is positive attention was paid to the development of selective PDE4 inhibitors for the treatment of inflammatory and immune disorders including asthma, rhinitis, bronchitis, COPD (chronic obstructive pulmonary disease), arthritis and psoriasis. Some compounds (for example, rolipram, teenlist and denbufylline)is known to have impressive effects in animal models of inflammation, especially inflammation of the lungs.

Unfortunately, the clinical use of these inhibitors has been limited associated with PDE4 side effects, including nausea, vomiting and secretion of acid gastric juice. It was recently described the second generation PDE4 inhibitors (e.g cilomilast, roflumilast and AWD 12-281), which has significantly reduced the risk of vomiting side effects in animal models vomiting, thus providing the potential for increased therapeutic index.

The present invention discloses new pyridopyrimidines derivatives, which are inhibitors of human PDE4, and are therefore useful in therapy.

In the present invention proposed a compound of formula (I):

where

And represents the CA1;

E represents CE1;

W represents (CH2)n;

Y represents Soboh is (CH 2)p;

n and p are independently 0 or 1;

R1represents phenyl substituted by phenyl {which is possibly substituted with halogen, hydroxy, CH(O)CO2H, C1-4the alkyl, C1-4alkyl-N(C1-4alkyl)2)1-4alkyl(NH2)1-4alkyl(NN(C1-4alkyl)),1-4hydroxyalkyl, CF3With1-4alkylthio,1-4alkyl(heterocyclyl) or (C1-4N(O)O(C1-4alkyl)} or heterocyclyl; and heterocyclyl possibly substituted C1-6by alkyl;

R2represents NHC(O)R3; and R3represents a C1-4alkyl {substituted NR7R8or heterocyclyl}3-7cycloalkyl (possibly substituted by a group NR43R44or heteroaryl; where R7, R8, R43and R44are as defined below; heteroaryl, possibly substituted with halogen, C1-4the alkyl, CF3With1-4alkoxy, F3, heterocyclyl or amino group(C1-4alkyl);

R7and R8independently represent a1-6alkyl;

And1E1and G1independently represent hydrogen or halogen;

unless otherwise stated, heterocyclyl possibly substituted C1-6by alkyl;

R25represent1-6alkyl;

R50represents hydrogen or C1-6alkyl (possibly the about, substituted by a group NR51R52);

R30, R36, R40, R42or R44independently represent hydrogen, C1-6alkyl (possibly substituted by hydroxy, C1-6alkoxy, C1-6alkylthio,3-7cycloalkyl (which is possibly substituted by hydroxy) or NR45R46)3-7cycloalkyl (possibly substituted by hydroxy group(C1-6alkyl)) or heterocyclyl (possibly replaced With1-6by alkyl);

R29, R35, R39, R41, R43, R45, R46and R51independently represent hydrogen or C1-6alkyl;

or its pharmaceutically acceptable salt;

where heterocyclyl represents a non-aromatic 5 - or 6-membered ring containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen; and

where aryl represents phenyl or naphthyl; and

where heteroaryl represents an aromatic 5 - or 6-membered ring, possibly condensed with other ring (which may be carbocyclic and aromatic or non-aromatic, containing one or two heteroatoms selected from the group consisting of nitrogen.

Some compounds of the present invention may exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). Us is Aasee the invention includes all such isomers and mixtures thereof in all proportions. Enantiomerically pure forms are especially desirable. Being in a solid crystalline form of the compound of formula (I) may be in the form of cocrystal with another chemical substance, and the invention covers all such Secretary.

Pharmaceutically acceptable salt of the compounds of formula (I) include salts derived from pharmaceutically acceptable non-toxic base such as an inorganic or organic base. Salt derived from inorganic bases, represents, for example, an aluminium salt, calcium, potassium, magnesium, sodium or zinc. Salt derived from an organic base, represents, for example, salt of a primary, secondary or tertiary amine, such as arginine, betaine, benzathine, caffeine, choline, chloroprocaine, cicloprofen, N',N'-dibenziletilendiaminom, diethanolamine, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, tertiary butylamine, theobromine, the triethylamine, trimethylamine, Tripropylamine, tromethamine or ethanolamine.

Pharmaceutically acceptable salt of the compounds of formula (I) also includes Quaternary ammonium salt, for example, where the amine group to connect the research Institute of the formula (I) reacts with C 1-10alkylhalogenide (for example, chloride, bromide or iodide) with formation of Quaternary ammonium salt.

Pharmaceutically acceptable salts also include salts of pharmaceutically acceptable organic acids such as carboxylic or sulfonic acid, such as acetate, adipate, alginate, ascorbate, aspartate, bansilalpet (besylate), benzoate, butyrate, comfort, camphorsulfonate (such as salt [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid), camsylate, citrate, para-chlorobenzenesulfonate, cyclopentyl, 2,5-dichlorethyl, digluconate, Etisalat (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), Eilat, aconsultant, fumarate, formate, 2-furoate, 3-furoate, gluconate, glucoheptonate, glutamate, glutarate, glycyrrhizinate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonic, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, 2-naphthalenesulfonate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), nicotinate, oleate, orotate, oxalate, Pantothenate, pamoate, pambou acid, pectinate, 3-phenylpropionate, pivalate, propionate, pivalate, pyruvate, saccharinate, salicylate, stearate, succinate, tartrate, para-toluensulfonate, TRANS-cinnamic acid, triptorelin, xinafoate, xenoport, xilt (para-xylene-2-sulfonic KIS the PTA), undecanoate, 2-mesitylenesulfonic, 2-naphthalenesulfonate, D-mandelate, L-mandelate, 2,5-dichlorobenzenesulfonate, cinnamate or benzoate; or a salt of an inorganic acid, such as salt, the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, phosphate, nitrate, hemisulfate, thiocyanate, persulfate, phosphate, or sulfonate. In another aspect of the invention, the stoichiometry of the salt is, for example, hemical, or mono - or dial, or trial.

Pharmaceutically acceptable salt of the compounds of formula (I) can be obtained in situ during the final isolation and purification of the compounds or separately by reacting the compounds with a suitable organic or inorganic acid and excretion of salt formed in this way.

In one aspect of the invention salt accession acids are, for example, hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, malonate, succinate, tartrate, citrate, methanesulfonate or para-toluensulfonate, camphorsulfonate (such as salt [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid). Alternative salt accession acid is trifenatate salt.

Alternatively, a suitable salt may be a Quaternary ammonium salt formed by the interaction of the primary, the secondary is Noah or tertiary amine group in the compound of formula (I), for example, C1-6alkylhalogenide (such as methyliodide or bromide).

Compounds according to the invention can exist in the form of a solvate such as a hydrate), and the present invention covers all such solvate.

The halogen includes fluorine, chlorine, bromine and iodine. Halogen is, for example, fluorine or chlorine.

The alkyl group is unbranched or branched and are, for example, methyl, ethyl, n-propyl, isopropyl or tert-butyl. Halogenoalkane represents, for example, C2F5, CF3or CHF2. Alkoxy is, for example, methoxy or ethoxy; and halogenoalkane represents, for example, F3or OCHF2.

Cycloalkyl represents a mono - or bicyclic ring system which is saturated or unsaturated, but not aromatic. It represents, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[3.1.1]heptenyl. With3-7Cycloalkyl(C1-4alkyl) is, for example, cyclopentyl2. Cycloalkane represents, for example, cyclopropane, cyclopentyloxy or cyclohexyloxy. Cycloalkylation represents, for example, (cyclopropyl)methoxy, or 2-(cyclopropyl)ethoxy.

Heterocyclyl represents a non-aromatic 5 - or 6-membered also, maybe condensed with one or more than one non-aromatic ring, and possibly condensed with the benzene ring containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen. Heterocyclyl represents, for example, azetidine, pyrrolidine, piperidinyl, piperazinil, isoindolyl, morpholinyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[2.2.2]octyl, 2-oxa-6-azabicyclo[5.4.0]undeca-7,9,11-trienyl, 7-oxa-10-azabicyclo[4.4.0]DECA-1,3,5-trienyl, 6-thia-1,4-diazabicyclo[3.3.0]OCTA-4,7-dienyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, 1,2,3,4-tetrahydroquinoline, 1,4-diazepine, hinokitiol, 9-oxa-2,8-diazaspiro[4.4]non-7-enyl, 1,2-dihydroquinazolines, 2,4,10-diazabicyclo[4.4.0]DECA-1,3,5,8-tetraene or 2-oxa-5-Aza-bicyclo[4.4.0]DECA-7,9,11-trienyl. Other examples heterocyclyl include azepines, homopiperazine, 1,4-oxazepine or 1-azabicyclo[2.2.2]octyl. Other examples heterocyclyl include homomorpholine, 1,4'-bipiperidine, 4'-morpholine-4-piperidinyl, 4-pyrrolidin-1-ipipeline or homomorpholine.

Hydroxyalkyl represents, for example, CH2OH; C1-6alkoxy(C1-6)alkyl represents, for example, CH3Och2; and (C1-6alkoxy(C1-6)alkoxy is, for example, CH3Och2O. Dialkylaminoalkyl represents, for example, (CH3)2N the 2or (CH3)(CH3CH2)N2. Amino(C1-4alkyl) is, for example, CH2NH2. Amino(C1-4alkoxy) is, for example, OCH2NH2. With1-4Alkylamino(C1-4alkoxy) is, for example, CH3NHCH2O.

Aryl is, for example, phenyl or naphthyl. In one aspect, the aryl is a phenyl. Aryl(C1-4alkyl) is, for example, benzyl.

Heteroaryl represents, for example, an aromatic 5 - or 6-membered ring, possibly condensed with one or more than one ring (which may be carbocyclic, aromatic or non-aromatic, containing one or two heteroatoms selected from the group consisting of nitrogen. Heteroaryl represents, for example, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazoles, benzimidazoles, honokalani, pyrazolopyrimidine (for example 1H-pyrazolo[3,4-b]pyridinyl or pyrazolo[1,5-a]pyridinyl), imidazopyridine (for example, imidazo[1,2-a]pyridinyl or imidazo[1,2-a]-5,6,7,8-tetrahydropyridine), dihydropyrido[2,3-d]pyrimidine (for example 1,4-dihydropyrido[2,3-d]pyrimidinyl), chinoline, ethenolysis, naphthyridines (for example, [1,6]naphthyridine, [1,7]naphthyridine or [1,8]naphthyridine) or 1H-pyrrolo[2,3-b]pyridinyl.

Who is you, substituted, for example, unsubstituted group or a group carrying 1, 2 or 3 substituent.

In one aspect of the present invention proposed a compound of formula (I), where a represents CH.

In another aspect of the present invention proposed a compound of formula (I), where n and p are both equal to 1.

In another aspect of the present invention proposed a compound of formula (I), where a represents CA1; E represents CE1; W and Y both represent CH2; and G1And1and E1independently represent a hydrogen or halogen.

In another aspect of the present invention proposed a compound of formula (I), where E represents CF.

In another aspect, And1E1and G1independently represent a hydrogen or halogen (e.g. fluorine).

In another aspect of the present invention proposed a compound of formula (I), where E represents CE1and E1represents, for example, hydrogen or halogen (such as fluorine).

In another aspect of the present invention proposed a compound of formula (I), where G1represents a hydrogen or halogen (such as fluorine). For example, G1represents hydrogen.

In another aspect of the present invention proposed a compound of formula (I), where a represents CA1; Th is is th CE 1; W and Y both represent CH2; and G1And1and E1independently represent a hydrogen or halogen (such as fluorine) (e.g., G1and1both represent hydrogen, and E1represents a hydrogen or fluorine (for example, E1represents fluorine)).

In another aspect of the present invention proposed a compound of formula (I), where R1represents phenyl, substituted phenyl (substituted by the group With1-4alkyl(heterocyclyl) [such as CH2(heterocyclyl)] and may additionally substituted by a hydroxy group); heterocyclic possibly substituted C1-6the alkyl.

In another aspect heterocyclyl represents, for example, 1,4-oxazepine, 1,4-diazepan, pyrrolidinyl, morpholinyl, piperidinyl or piperazinil, homopiperazine, homomorpholine, 1,4'-bipiperidine.

In another aspect heterocyclyl represents, for example, pyrrolidinyl, morpholinyl, piperidinyl or piperazinil.

In another aspect heterocyclyl represents, for example, pyrrolidinyl, morpholinyl, piperidinyl or piperazinil, homopiperazine, homomorpholine, 1,4'-bipiperidine.

In another aspect heterocyclyl represents, for example, morpholinyl, piperidinyl or piperazinil.

In another aspect heterocyclyl represents, for example,morpholinyl, piperidinyl or piperazinil, homopiperazine, homomorpholine, 1,4'-bipiperidine.

In another aspect heterocyclyl represents, for example, pyrrolidinyl or piperazinil.

In another aspect heterocyclyl represents, for example, pyrrolidinyl or piperazinil, homopiperazine, homomorpholine, 1,4'-bipiperidine.

In another aspect of the present invention proposed a compound of formula (I), where R2represents NHC(O)R3; and R3represents a C1-4alkyl {substituted NR7R8or heterocyclyl}3-7cycloalkyl (possibly substituted by a group NR43R44or heteroaryl; where R7, R8, R43and R44are as defined above (for example, they independently represent hydrogen or C1-6alkyl); heteroaryl, possibly substituted, halogeno,1-4the alkyl, CF3With1-4alkoxy, F3, heterocyclyl (such as pyrrolidinyl) or amino group(C1-4alkyl).

In another aspect of the present invention proposed a compound of formula (I), where R2represents NHC(O)R3where R3is heteroaryl (for example, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]-5,6,7,8-tetrahydropyridine, pyridinyl, honokalani or chinoline), possibly substituted with halogen (such as fluorine) or (C1-4what Kilom.

In another aspect of the present invention proposed a compound of formula (I), having the stereochemistry shown below:

Compounds according to the invention described in the Examples. Each of the compounds of the Examples represents another aspect of the present invention. In another aspect of the present invention proposed each individual compound from Example or its pharmaceutically acceptable salt. In addition, when an individual compound from Example is a salt of the compounds of formula (I), the invention additionally offered every parent compound of formula (I) or another pharmaceutically acceptable salt.

In another aspect of the present invention proposed a compound of formula (I), which represents:

6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (Example 54);

6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (Example 79);

6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (Example 96);

6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]is iridin-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 246); or

N-{CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-methylpyridin-2-carboxamide (Example 308);

or its pharmaceutically acceptable salt.

In one aspect of the present invention proposed a compound of formula (I), which represents:

its pharmaceutically acceptable salt.

In another aspect of the present invention proposed a compound of formula (I), which represents:

its pharmaceutically acceptable salt.

Compounds of the present invention can be obtained, as described below, by adapting methods known in the art or by using or adapting the preparative methods described in the Examples.

In the invention disclosed is a method of obtaining the compounds of formula (I), where R2represents NHC(O)R3, including the removal of the protective group Boc from compounds of formula (II):

where R1, G1, E, A, Y and W are as defined for formula (I), (for example, with acid, such as triperoxonane acid or hydrochloric acid) and the interaction formed so product with the compound of the formula (IIIa, IIIb or IIIc):

where R3is as defined for formula (I)and LG represents a leaving group. Way with the formula (IIIa) (for which LG is a halogen) is carried out at a suitable temperature, typically from 0°C to the boiling point of the solvent, in a suitable solvent such as dichloromethane or N-methylpyrrolidinone. Way with the formula (IIIb)may be undertaking in the presence of a base and/or agent combinations, such as HATU, NEAT, NOT or DIEA. (When using the agent combinations, then LG is a HE, and when not in use agent combinations, then LG is a halogen.) Way rehabilitation amination with formula (C) is carried out at a suitable temperature, typically from 0°C. to boiling point of solvent in a suitable solvent, such as 1,2-dichloroethane, for example, using triacetoxyborohydride sodium and catalytic acetic acid.

The compound of formula (II), where R1, G1, E, A, Y and W are as defined for formula (I), and where R2represents NHC(O)R3can be obtained by condensation of compounds of formula (IV):

where R1, G1, E, a, Y and W are as defined for formula (I), with a suitable carbonyliron agent, t is Kim as carbonyldiimidazole or ethylchloride, in the presence of a suitable base such as sodium hydride. The method is carried out at a suitable temperature, typically from 0°C to the boiling point of the solvent, in a suitable solvent, such as tetrahydrofuran.

The compound of formula (IV), where R1, G1, E, a, Y and W are as defined for formula (I)can be obtained by reacting the compounds of formula (V):

where R1, G1, E and a are as defined for formula I, with an amine of formula (VI)

where Y and W are as defined for formula (I). The method is carried out at a suitable temperature, typically from 0°C to the boiling point of the solvent, in a suitable solvent such as dichloromethane. The method may be undertaking in the presence of a base and reagent combinations, such as HATU, NEAT, NOT or DIEA.

The compound of formula (V), where R1, G1, E and a are as defined for formula (I)can be obtained by reacting the compounds of formula (VII):

where G1, E and a are as defined for formula (I)and Hal represents a halogen atom, with aniline (VIII):

,

where R1is as defined for formula (I). The method is realized when n is Chadasha temperature, usually from 50°C to the boiling point of the solvent, in a suitable solvent, such as dimethylformamide. The method may be undertaking in the presence of a base such as potassium carbonate.

The connection according to the invention can also be obtained using preparative methods shown in the schemes below wherein R' represents a Deputy on the phenyl group, R1:

Preparative examples of the various intermediate compounds described in the literature or can be obtained by routine adaptation of the methods described in the literature.

In the above methods, it may be desirable or necessary to protect acid group or a hydroxy-group, or other potentially reactive groups. Suitable protective groups and the details of how to add and remove such groups can be found in "Protective Groups in Organic Synthesis", 3rdedition (1999) by Greene and Wuts.

In this izobreteniem disclosed methods of making compounds of formula (I).

In the present invention are disclosed intermediate compounds useful in producing compounds according to the invention, for example, the intermediate compound of formula (II):

or of the formula (IV):

or of the formula (V:

or

or

where R1, R2, G1, E, A, Y and W are as defined for formula (I), and R' represents the substituents on the phenyl group, R1.

The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of the activity of the receptor PDE4, and can be used in the treatment of inflammatory diseases, asthma or COPD.

Examples of medical conditions that can be treated with a compound according to the invention, are:

1. Respiratory tract: obstructive diseases of the respiratory tract, including asthma, including bronchial, allergic, hereditary, acquired, induced physical stress, drug-induced (including aspirin and NSAID-induced) and induced dust asthma, as alternating and chronic, and of all degrees of severity, and other cases of hypersensitivity of the respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; easy farmer's and related diseases; hypersensitive pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idea eticheskie interstitial pneumonia, complicating fibrosis anticancer therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vascular and thrombotic disorders of the pulmonary vascular system and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis, including medication and vasomotor rhinitis; chronic and seasonal allergic rhinitis including nervous rhinitis (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;

2. Bones and joints: the skin lesions of rheumatic or gouty origin, associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and pain in the lower back and neck; osteoporosis; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, reactive is th arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection arthropathies and bone disorders such as tuberculosis, including Pott disease and syndrome Ponce; acute and chronic crystal-induced synovitis including urate gout, the disease is the deposition of calcium pyrophosphate, and inflammation of the tendons, synovial bags associated with Apatite calcium; Behcet's disease; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed disease of connective tissue and diffuse disease of connective tissues; inflammatory myopathies including dermatomyositis and polymyositis; rheumatic rheumatica; juvenile arthritis including idiopathic inflammatory lesions of the skin rheumatic or gouty origin, regardless of the joint distribution and associated syndromes, and rheumatic attack and its systemic complications; vasculitis, including giant cell arteritis diagnostics, Takayasu's arteritis, syndrome Cerca-Strauss, polyarteritis polyarteritis, microscopic polyarteritis and vasculitis associated with viral infection, hypersensitivity reactions, cryoglobulinemia and paraproteins; pain in lower back pain; familial Mediterranean fever syndrome Make wells (Muckle-Wells) and family Irish fever is, disease of Kikuchi; drug-induced arthralgia, tendonitis and myopathy;

3. Pain and remodeling of connective tissue in the musculoskeletal disorders due to injury [for example sports injury] or disease: arthritis (e.g. rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint (TMJ)disease, remodelers bones (such as osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma mixed disorder of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis);

4. Skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and hypersensitivity reactions of the delayed type; phyto - and photodermatitis; subarray dermatitis, herpetiformis dermatitis, red flat zoster, sclerosing and acrotiri zoster, gangrenous pyoderma, sarcoid skin, discoid lupus erythematosus, pemphigus, pemphigoid, congenital bullous bullosa, urticaria, angioedema, vasculitis, toxic erythema, subcutaneous eosinophilia, alopecia alopecia, male pattern hair loss, sweet syndrome, syndrome, Weber-Christian, multiform (exudative) e is itemu; cellulite, both infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including local drug rash;

5. Eyes: blepharitis; conjunctivitis, including chronic and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; chorioidea; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmic, including sympathetic ophthalmic; sarcoidosis; infections including viral, fungal, and bacterial;

6. Gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritus of the anus; coeliac disease, irritable bowel syndrome and food allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. Abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. Genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and chronic ulcer of the bladder; acute and chronic is urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectilnuyu dysfunction (men and women);

9. The allograft rejection: acute and chronic after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or after blood transfusion; or chronic disease graft-versus-host;

10. Central nervous system: Alzheimer's disease and other desantiruemye disorders including CJD disease Creutzfeldt-Jakob disease) and nvCJD (new variant disease of Creutzfeldt-Jakob disease; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteric; severe myasthenia gravis; acute and chronic pain (acute, intermittent or constant, regardless of the Central or peripheral origin)including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, pain in joints and bones, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post herpetic, and HIV-associated neuropathy; neurosarcoidosis; complications in the Central and peripheral nervous system malignant, infectious or autoimmune processes;

11. Other autoimmune and allergic disorders, including the possibility goiter Hashimoto, graves ' disease, Addison disease, diabetes mellitus, idiopathic thrombocytopenic purple, eosinophilic fasciitis, Hyper-IgE syndrome, antiphospholipid syndrome;

12. Other disorders with an inflammatory or immunological component, including acquired immunodeficiency syndrome (AIDS), leprosy, syndrome Cesari and paraneoplastic syndromes;

13. Cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischemic damage during reperfusion; endocarditis, valvular and aortic, including infective (for example syphilitic); vasculitis; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. Oncology: treatment of common types of cancer, including tumors and malignant tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain, affecting the bone marrow (including leukemia) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic with ndrome; or

15. Gastrointestinal tract: coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminate colitis, upset, irritable bowel, irritable bowel syndrome, non-inflammatory diarrhea, food allergies which may have effects remote from the gut, for example, migraine, rhinitis or eczema.

In the present invention is disclosed a method of treating PDE4-mediated pathological state in a mammal, such as people suffering from painful conditions specified, or with a specified risk of the disease condition, comprising administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

The invention also discloses the compound of formula (I) or its pharmaceutically acceptable salt for use in therapy.

The invention discloses the use of compounds of formula (I) or its pharmaceutically acceptable salt for the manufacture of a medicinal product for use in therapy (for example modulating the enzymatic activity of PDE4).

In one aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt as defined above, for use as in the of ibitira PDE4.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt as defined above, for the manufacture of a medicinal product for use in treatment of a PDE4-mediated disease condition.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt as defined above, for the treatment of ROE-mediated disease condition.

The invention also discloses the use of compounds of formula (I) or its pharmaceutically acceptable salt for the manufacture of a medicinal product for use in the treatment of:

1. Respiratory tract: obstructive diseases of the respiratory tract, including asthma, including bronchial, allergic, hereditary, acquired, induced physical stress, drug-induced (including aspirin and NSAID-induced) and induced dust asthma, as alternating and chronic, and of all degrees of severity, and other cases of hypersensitivity of the respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitive pneumonitis; lung fibrosis, including the cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-tumor therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vascular and thrombotic disorders of the pulmonary vascular system and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis, including medication and vasomotor rhinitis; chronic and seasonal allergic rhinitis including nervous rhinitis (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;

2. Bones and joints: the skin lesions of rheumatic or gouty origin associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and pain in the lower back and neck; osteoporosis; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathy, including the surrounding ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection arthropathy and bone disorders such as tuberculosis, including disease Mail and syndrome Ponce; acute and chronic crystal-induced synovitis including urate gout, the disease is the deposition of calcium pyrophosphate and inflammation of the tendons, synovial bags associated with Apatite calcium; disease behceta; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositis and polymyositis; rheumatic polymyalgia; juvenile arthritis including idiopathic inflammatory lesions of rheumatic or gouty origin, regardless of the joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitis, including giant cell arteritis diagnostics, Takayasu's arteritis, syndrome Cerca-Strauss, polyarteritis polyarteritis, microscopic polyarteritis and vasculitis associated with viral infection, hypersensitivity reactions, cryoglobulinemia and paraproteins; pain in the lower part with the ins; familial Mediterranean fever syndrome Make wells (Muckle-WelIs) and family Irish fever, diseases of Kikuchi; drug-induced arthralgia, tendonitis and myopathies;

3. Pain and remodeling of connective tissue in the musculoskeletal disorders due to injury [for example sports injury] or disease: arthritis (e.g. rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint (TMJ)disease, ramblerouser bones, such as osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed disorders of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis);

4. Skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed hypersensitivity reactions; phyto - and photodermatitis; sebrango dermatitis, herpetiformis dermatitis, red flat lichen, sclerosing and atropinelike lichen, pyoderma gangrenosum, sarcoid skin, discoid lupus erythematosus, pemphigus, pemphigoid, congenital bullous of bullosa, urticaria, angioedema, vasculitis, toxic eritem, p is dkoenig of eosinophilia, alopecia areata, alopecia male pattern syndrome Retinue, syndrome, Weber-Christian, multiform (exudative) erythema; cellulitis, both infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including local drug rash;

5. Eyes: blepharitis; conjunctivitis, including chronic and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; oftalmica, including sympathetic ophthalmic; sarcoidosis; infections including viral, fungal, and bacterial;

6. Gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritus of the anus, celiac disease, irritable bowel syndrome and food allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. Abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. Genitourinary: nephritis including interstitially and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and chronic ulcer of the bladder; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; candidiasis; Peyronie's disease; erectile dysfunction (both men and women);

9. The allograft rejection: acute and chronic after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or after blood transfusion; or chronic disease graft-versus-host;

10. Central nervous system: Alzheimer's disease and other remontiruemy disorders including CJD disease Creutzfeldt-Jakob disease) and nvCJD (new variant disease of Creutzfeldt-Jakob disease); amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; severe myasthenia gravis; acute and chronic pain (acute, intermittent or constant, regardless of the Central or peripheral origin)including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, pain in joints and bones, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post herpetic, and HIV-associated neuropathy; neurosarcoidosis; Oslo the clusters in the Central and peripheral nervous system malignant, infectious or autoimmune processes;

11. Other autoimmune and allergic disorders, including goiter Hashimoto's, graves ' disease, Addison disease, diabetes mellitus, idiopathic thrombocytopenic purple, eosinophilic fasciitis, Hyper-lgE syndrome, antiphospholipid syndrome;

12. Other disorders with an inflammatory or immunological component, including acquired immunodeficiency syndrome (AIDS), leprosy, syndrome Cesari and paraneoplastic syndromes;

13. Cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischemic lesions during reperfusion; endocarditis, valvulitis and Arteta, including infective (for example syphilitic); vasculitis; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. Oncology: treatment of common cancers, including tumors and malignant tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain, affecting the bone marrow (including leukemia) and lymphoproliferative systems, such as Hodgkin's and the e-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; or

15. Gastrointestinal tract: coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminate colitis, disorders, irritable bowel, irritable bowel syndrome, non-inflammatory diarrhea, food allergies which may have effects remote from the gut, for example, migraine, rhinitis or eczema;

the mammal (e.g. human).

In the invention disclosed compound of formula (I) or its pharmaceutically acceptable salt for use in the treatment of asthma {such as bronchial, allergic, hereditary, acquired, or induced by dust asthma, particularly chronic or inveterate asthma (for example late asthma or hypersensitivity of the respiratory tract)}; or COPD.

In yet another aspect, the compound of formula (I) or its pharmaceutically acceptable salt are useful in the treatment of COPD.

The present invention also discloses the use of compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in the treatment of asthma {such as bronchial, allergic, hereditary, acquired, or inducion the fair dust asthma, particularly chronic or inveterate asthma (for example late asthma or hypersensitivity of the respiratory tract)}; or COPD.

For application of the compounds according to the invention or its pharmaceutically acceptable salts for therapeutic treatment of a mammal, such as man, this ingredient are usually prepared in the form of a preparation in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore, in another aspect, the present invention proposed a pharmaceutical composition having activity as an inhibitor of PDE4 (phosphodiesterase 4), containing the compound of formula (I) or its pharmaceutically acceptable salt (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier.

In another aspect of the present invention, a method for obtaining this composition, including mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration, the pharmaceutical composition will contain, for example, from 0.05 to 99 wt.% (percent by weight), such as from 0.05 to 80 wt.%, for example, from 0.10 to 70 wt.%, such as from 0.10 to 50 wt.% the active ingredient, all percentages by weight based on the total composition.

The pharmaceutical compositions according to this invention can be in order to enter in the standard manner for the disease condition, which it is desirable to treat, for example through local (such as in the lung and/or Airways or to the skin), inhalation, oral, rectal or parenterale introduction. For these purposes the compounds of this invention can be prepared in the form of the preparation methods known in the art. A suitable pharmaceutical composition according to this invention is a composition suitable for oral administration in a standard dosage form, e.g. tablet or capsule, which contains from 0.1 mg to 1 g of the active ingredient.

Each patient may receive, for example, a dose of 0.001 mg∙kg-1to 100 mg∙kg-1for example in the range from 0.1 mg∙kg-1to 20 mg∙kg-1entered active ingredient, for example, from 1 to 4 times per day.

The invention also relates to a combination therapy, where the connection according to the invention, or its pharmaceutically acceptable salt or pharmaceutical composition or drug containing the compound according to the invention, is administered concurrently or sequentially or as a combined preparation with other therapeutic(s) agent or agents for the treatment of one or more of these conditions.

In particular, for the treatment of inflammatory diseases such as (but not limited to) rheumatoid art is it, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease, the compounds according to the invention can be combined with the agents listed below.

Nonsteroidal anti-inflammatory agents (hereinafter NSAIDs)including non-selective cyclo-oxygenase inhibitors MOR-1/SOH-2, applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as mefenamovaya acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib, lumiracoxib, parecoxib, etoricoxib); nitric oxide donors, inhibiting cyclooxygenase (CINOD); glucocorticosteroids (entered local, oral, intramuscular, intravenous or intra-articular routes); methotrexate; Leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular tools, such as derivatives of hyaluronic acid; and nutritional supplements such as glucosamine.

The present invention also relates to combinations of compounds according to the invention, or agopermalink acceptable salt, together with a cytokine or agonist or antagonist of cytokine function, (including agents that act on signaling pathways of cytokines, such as modulators SOCS system)including alpha-, beta - and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL)including IL1-17, and antagonists or inhibitors interleukins, such as anakinra; inhibitors of tumor necrosis factor alpha (TNF-α), such as monoclonal antibodies against TNF (for example infliximab; adalimumab, and CDP-870) and TNF antagonists receptors, including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxifylline.

In addition, the invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, a monoclonal antibody directed by b-lymphocytes (such as CD20 (rituximab), MRA-alLI6R and T-lymphocytes, CTLA4-lg, HuMax II-15).

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, a modulator function of the chemokine receptor, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for C-X3-From the collection.

In addition, the present invention relates to combinations of compounds according to the invention, or its formats whitesky acceptable salt, with the inhibitor of the matrix metalloprotease (DFID), i.e. stromelysins, collagenases and gelatinase and aggrecanases; for example, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11 and MMP-9 and MMP-12, including such agents as doxycycline.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and leukotriene biosynthesis inhibitor, an inhibitor of 5-lipoxygenase (5-LO) or antagonist of 5-lipoxygenase-activating protein (FLAP), such as zileuton; ABT-761; Finlayson; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)thiophene-2-alkylsulfonamides; 2,6-di-tert-butylbenzothiazole; methoxyethylamine, such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene connection, such as L-739,010; 2-cyanohydrine connection, such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY×1005.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of phenothiazines-3-silts, such as L-651,392; amidinopropane, such as CGS-25019c; benzoxazepine, such as ontazolast; benzoperoxide such BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP A), and BAY×7195.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, and an inhibitor of phosphodiesterase (PDE), such as methylxanthines, including theophylline and aminophylline; selective inhibitor of PDE isoenzyme comprising a PDE4 inhibitor, an inhibitor of the isoform PDE4D, or a PDE5 inhibitor.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and antagonist of histamine receptor type 1, such as cetirizine, loratadine, desloratadine, Fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine; used orally, topically or parenterally.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt and a proton pump inhibitor (such as omeprazole) or gastroprotective antagonist histamine receptor type 2.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and antagonist of histamine receptor 4 type.

The present invention is also relates to the combination of compounds according to the invention, or its pharmaceutically acceptable salts, and vasoconstrictor sympathomimetic agent agonist alpha-1/alpha-2 adrenergic receptors, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, nafazolina hydrochloride, Oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochloride, tramazoline hydrochloride or Ethylmorphine hydrochloride.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and anticholinergic agents including muscarinic antagonist receptor (M1, M2, and M3), such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, Tiotropium bromide, oxytrope bromide, pirenzepine or telenzepine.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and agonist beta adrenergic receptors (including beta-receptor subtypes 1-4), such as izoprenalin, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin, bitolterol mesilate, indacaterol or pirbuterol, or chiral enantiomer.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and chromone, such as sodium cromoglycate or nedocromil sodium.

This is completed with the invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt with an agent that modulates nuclear hormone receptors such as PPARs.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, together with immunoglobulin (Ig) or Ig drug or an antagonist or antibody modulating Ig function, such as anti-IgE (e.g. omalizumab).

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and other systemic or locally applied anti-inflammatory agent, such as thalidomide or its derivative, a retinoid, dithranol or calcipotriol.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and combinations aminosalicylates and sulfapiridina, such as sulfasalazin, mesalazine, balsalazide and olsalazine; and immunomodulatory agents, such as thiopurine, and corticosteroids, such as budesonide.

Also what about the, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, together with an antibacterial agent such as a derivative of penicillin, tetracycline, macrolide, beta-covenants, fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamivir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors, such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside inhibitor of reverse transcriptase, such as nevirapine or efavirenz.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, and a cardiovascular agent such as a calcium channel blocker, beta-adrenoreceptor blocker, angiotensin-converting enzyme (ACE)receptor antagonist of angiotensin-2; agent for reducing the level of lipid, such as a statin or fibrate; modulator morphology of blood cells, such as pentoxifylline; thrombolytic agent or an anticoagulant, such as an inhibitor of platelet aggregation.

In addition, the present invention is about what is worn to the combination of compounds according to the invention, or its pharmaceutically acceptable salt, and a CNS agent such as an antidepressant (such as sertraline), anti-Parkinsonian drug (such as deprenyl, L-DOPA, ropinirole, pramipexol, inhibitor IAIA (monoamine oxidase-B), such as selgin and rasagiline, inhibitor comP, such as tasmar, inhibitor-2, an inhibitor of the reuptake of dopamine, ND(N-methyl-D-aspartate receptor)antagonist, agonist nicotine, dopamine agonist or inhibitor synthase neuronal nitric oxide), or a drug against Alzheimer's disease, such as donepezil, rivastigmine, taken, inhibitor SOH-2, propentofylline or metrifonate.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salts, and agent for the treatment of acute or chronic pain, such as Central or perifericheskie current analgetic (for example an opioid or its derivative), carbamazepine, phenytoin, valproate sodium, amitriptyline or other antidepressants, paracetamol or non-steroidal anti-inflammatory agent.

In addition, the present invention relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, together with parenterally or topically applied (including inhalation) a local anesthetic agent, such caliginosa and the and its derivative.

The compound of the present invention, or its pharmaceutically acceptable salt, can also be used in combination with antiosteoporosis agent, including hormonal agent such as raloxifene, or biphosphonate, such as alendronate.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically acceptable salt, together with: (1) a tryptase inhibitor; (2) an antagonist of platelet-activating factor (PAF); (3) the inhibitor of the interleukin converting enzyme (ICE); (4) the inhibitor of IMPDH (insertunorderedlist); (5) inhibitors of adhesion molecules, including antagonist VLA-4; (6) a cathepsin; (7) a kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example, or gefitinib of imatinib mesilate), serine/trionychinae (such as an inhibitor of MAP kinase, such as R, JNK, protein kinase a, b or C, or K), or a kinase involved in cell cycle regulation (such as the cyclin-dependent kinase); (8) an inhibitor of glucose-6-phosphate dehydrogenase; (9) antagonist In1or2-kinin receptor; (10) the agent for treating gout, such as colchicine; (11) an inhibitor of xanthine oxidase, e.g., allopurinol; (12) an agent that promotes the excretion of uric acid, for example, probenecid, sulfinpirazonom or benzbromarone; (13) by means of strengthening the m secretion of growth hormone; (14) transforming growth factor (TGFβ); (15) platelet-derived growth factor (PDGF); (16) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (17) granulocyte-macrophage colony-stimulating factor (GM-CSF); (18) capsaicinoid cream; (19) antagonist PC1- or NK3-thickening receptor, such as NKP-608C, SB-233412 (talnetant) or D-4418; (20) elastase inhibitor such as UT-77 or ZD-0892; (21) an inhibitor of TNF-alpha converting enzyme (TACE); (22) inhibitor-induced synthase nitric oxide (iNOS); (23) molecule homologous to the receptor chemoattractant, expressed on TH2 cells (such as a CRTH2 antagonist); (24) inhibitor R; (25) agent modulating the function of Toll-like receptors (TLR), (26) agent modulating the activity of purinergic receptors such as RH; or (27) inhibitor activation of transcription factors such as NFkB, API, or STATS.

The present invention disclosed a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or its pharmaceutically acceptable salt, as described above, and at least one other active ingredient selected from:

agonist β2-adrenergic receptors

- modulator function of the chemokine receptor,

- inhibitor of kinase function,

- inhibitor of proteases is,

- steroid agonist of the glucocorticoid receptor,

- anticholinergic agent and

- non-steroidal agonist of the glucocorticoid receptor.

The pharmaceutical product may represent, for example, the pharmaceutical composition comprising the first and the other active ingredients in the mixture. Alternatively, the pharmaceutical product may contain, for example, the first and the other active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate introduction of the patient who needs it. Pharmaceutical product finds particular application in the treatment of respiratory diseases such as asthma, COPD or rhinitis.

Examples of agonist β2-adrenergic receptors, which can be used in the pharmaceutical product, include metaproterenol, isoproterenol, izoprenalin, albuterol, salbutamol (e.g. as the sulphate), formoterol (e.g. as fumarata), salmeterol (e.g. as xinafoate), terbutaline, ortsiprenalin, bitolterol (e.g. nelfinavir), pirbuterol or indacaterol. Agonist β2-adrenergic receptors may represent a β2-long acting agonists, such as salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarata), bambuterol (e.g. as hydrochloride), carmoterol(TA 2005, chemical identified as 2(1H)-hinolan, 8-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride, [R-(R*,R*)] also identified a number Chemical Abstract Service Registry 137888-11-0 and disclosed in U.S. patent No. 4579854), indacaterol (CAS No. 312753-06-3; QAB-149), formanilide derivatives, for example 3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, as disclosed in WO 2002/76933, benzosulfimide derivatives, for example 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-benzosulfimide, as disclosed in WO 2002/88167, allanalmovies receptor agonists, as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and connections GSK 159797, GSK 159802, GSK 597901, GSK and GSK 642444 678007.

Examples of the modulator functions of the chemokine receptor, which can be used in the pharmaceutical product, include the CCR1 receptor antagonist.

Examples of an inhibitor of kinase function, which can be used in the pharmaceutical product, include a kinase inhibitor R and IKK inhibitor.

Examples of protease inhibitors that may be used in the pharmaceutical product, include an inhibitor of neutrophil elastase or inhibitor MMR.

Examples of steroid agonist of the glucocorticoid receptor, which can be used is to feed into the pharmaceutical product, include budesonide, fluticasone (e.g., in the form of ester propionate), mometazon (for example, in the form of ester furoate, beclomethasone (e.g., in the form of esters of 17-propionate or 17,21-dipropionate), ciclesonide, loteprednol (in the form of, for example, etabonate), etiprednol (in the form of, for example, dilacerata), triamcinolone (e.g. as acetonide), flunisolide, suticase, flumoxed, rofleponide, butixocort (for example, in the form of ester propionate, prednisolone, prednisone, tipredane, esters steroids, for example, 6α,9α-debtor-17α-[(2-fornicator)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-thiocarbonic acid S-formerely ester, 6α,9α-debtor-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-thiocarbonic acid S-(2-oxo-tetrahydro-furan-3S-silt) ester and 6α,9α-debtor-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-thiocarbonic acid S-formerely ester, esters of steroids in accordance with DE 4129535, steroids in accordance with WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943.

Examples of anticholinergic agent that can be used in the pharmaceutical product include, for example, an antagonist of muscarinic receptor (e.g antagonist of M1, M2 or M3, such as the M3 antagonist)such as IPRT the opium (for example, as bromide), Tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, pirenzepine, telenzepine, glycopyrrolate bromide (such as R,R-glycopyrrolate bromide or a mixture of R,S - and S,R-glycopyrronium bromide); mepenzolate (e.g. as bromide), hinoklidina derivative, such as 3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-phenoxypropan)-1-azonia-bicyclo[2.2.2]octane bromide as disclosed in US 2003/0055080, hinoklidina derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK 656398 or GSK 961081.

Examples of the modulator of non-steroidal glucocorticoid receptor agonist, which can be used in the pharmaceutical product, include described in WO 2006/046916.

The connection according to the invention or its pharmaceutically acceptable salt can also be used in combination with existing therapeutic agent for the treatment of cancer, for example, suitable agents include:

(1) antiproliferative/antineoplastic drug or combination of them, used in medical Oncology, such as alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan or nitrosoanatabine); an antimetabolite (for example, antifolate, such as ftorpirimidinu, such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine Arabi is osid, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (for example, anthracycline, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsin, mitomycin-C, dactinomycin or mithramycin); antimitoticescoe agent (for example, Vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a toxoid, such as Taxol or Taxotere); or a topoisomerase inhibitor (e.g., epipodophyllotoxins, such as etoposide, teniposide, amsacrine, topotecan or camptothecin);

(2) cytotoxic agent, such as an antiestrogen (e.g., tamoxifen, toremifene, raloxifene, droloxifene or idoxifene), step-down regulator of estrogen receptor (for example fulvestrant), an antiandrogen (for example, bikalutamid, flutamide, nilutamide or ciproteron acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leiprorelina or buserelin), a progestogen (for example, megestrol acetate), aromatase inhibitor (for example, anastrozole, letrozole, varsol or exemestane) or an inhibitor of 5α-reductase such as finasteride;

(3) an agent that inhibits the invasion of cancer cells (for example, metalloproteinase inhibitor, such marimastat, or the inhibitor of receptor function plasminogen activator urokinase type);

(4) the inhibitor function of the growth factor, for example: antibody to a growth factor (for example the anti-erbb2 antibody trastuzumab, or anti-erbb1 antibody cetuximab [S]), inhibitor farnesyltransferase, a tyrosine kinase inhibitor or inhibitor of serine/trionychinae, inhibitor family of epidermal growth factors (e.g., an inhibitor of protein tyrosine kinase EGFR (receptor epidermal growth factor), such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) or 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (Cl 1033)), an inhibitor of a family of platelet-derived growth factors, or inhibitor of a family of growth factors hepatocyte;

(5) an antiangiogenic agent such as an agent that inhibits the effects of vascular endothelial growth factor (for example, antibody bevacizumab against growth factor vascular endothelial cells, the compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example, linomide, an inhibitor of the function of integrin αvβ3 or angiostatin);

(6) the agent, damaging blood vessels, such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(7) an agent used in antisense therapy, for example, the agent is directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(8) AG is NT used in gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme proletarienne therapy), such as approaches using sitoindosides, timedancing or bacterial enzyme nitroreductase, and approaches to increase the tolerability of the patient chemotherapy or radiotherapy, such as gene therapy multidrug resistance; or

(9) an agent used in the immunotherapy approach, for example, approaches ex vivo and in vivo to increase the immunogenicity of tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to decrease T-cell tolerance, approaches using transfected immune cells such as cytokine-transfetsirovannyh dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using antiidiotypic antibodies.

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

(1) when there is a,1H NMR data are recorded and reported in the form of Delta values for major diagnostic the diagnostic protons, given in parts per million (million-1regarding tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using Purgatorio DMSO-D6 (CD3SOCD3or CDCl3as solvent unless otherwise indicated;

(2) mass spectra (MS) were obtained with electron energy of 70 electron volts in the way chemical ionization (Cl) using a direct influence on the sample. When this ionization is produced by ionization electrospray (ES)or chemical ionization at atmospheric pressure (APCl)or multimode ionization, the combination of ES ionization and APCl. When you specify values for m/z, then usually presents only ions which indicate the parent mass of the ions, and the recorded mass ions are lots of positive or negative ions: [M]+, [M+H]+or [M-H]-;

(3) specified in the headings and the subheadings of the compounds of the examples and methods were named using the naming chemical compounds (index name program from Advanced Chemistry Development Inc, version 8.00, or are named using the names according to IUPAC of Openeye and stereochemical identity added manually (See. www.eyesopen.com/products/applications/oqham.html).

(4) Unless otherwise specified, HPLC with reversed phase were used in what Itanium Symmetry TM, NovaPakTMor XterraTM, Sunfire, column x-bridge with silica gel, reversed phase, all available from Waters Corp.

(5) use the following abbreviations:

DMSO
DMFN,N-Dimethylformamide
DME1,2-Dimethoxyethan
NMP1-N-Methyl-2-pyrrolidinone
NOT1-Hydroxy-7-asobancaria
DIEAN,N-Diisopropylethylamine
HATUO-(7-Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate
THFTetrahydrofuran
DCMDichloromethane
BOCtert-Butoxycarbonyl
HPLCLiquid chromatography high pressure
dayDay
hHour(s)
minMinute(s)
The sulfoxide
EtOAcThe ethyl acetate

(6) Cartridges Chem elut available from Varian Inc (http://www.varianinc.com/) or Kinesis (http://www.kinesis.co.uk/)

(7) Gemini Column available from Phenomenex (http://www.phenomenex.com).

Source materials for the Examples below, or are commercially available or easily obtained by standard methods from known starting compounds (Compounds are named using the names according to IUPAC from Advanced Chemistry Development Inc, version 8.00).

DESCRIPTION of GRAPHIC MATERIALS

Figure 1-75 presents the picture of x-ray diffraction on the powder (XRPD) for many salts of the compounds specified in the examples.

On Fig presents the XRPD pattern of crystalline form a of example 140.

On Fig presents the XRPD pattern of polymorph And example 172.

On Fig presents the XRPD pattern of crystalline form a of example 179.

On Fig presents the XRPD pattern of crystalline form a of example 184.

On Fig presents the XRPD pattern of crystalline form b of example 184.

On Fig presents the XRPD pattern of polymorph And example 194.

Example 1

N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) 2-(b is phenyl-3-ylamino)-5-fornicative acid

2-Chloro-5-fornicating acid (1,83 g, 10,45 mmol) and potassium carbonate (1,74 g, 12.6 mmol) was added in dry DMF (20 ml). Added copper (41 mg), copper bromide (I) (75 mg) and 3-aminobiphenyl (3.0 g, 17.8 mmol)and the reaction mixture was stirred at 150°C for 12 hours. Added 1 M HCl, and the precipitated precipitated product was collected by filtration, washed with 1 M HCl, then with water and dried to obtain specified in the subtitle compound (1.98 g, 62%).

APCl (-ve): 307 (M-N).

Stage (b) tert-butyl[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]carbamate

2-(Biphenyl-3-ylamino)-5-fornicating acid (1.6 g, 5.2 mmol) was dissolved in dry DMF (20 ml), was added DIEA (4 ml, 23 mmol)and then HATU (1.97 g, 5.2 mmol)and the mixture was allowed to mix at room temperature for 10 minutes was Added tert-butyl(CIS-4-aminocyclohexane)carbamate (945 mg, 4,39 mmol)and the mixture was allowed to mix at room temperature over night. The mixture was suppressed by infusion in water, and precipitated precipitated product was collected by filtration, then purified flash chromatography on silica, using ethyl acetate:isohexane (1:2) as eluent to obtain the intermediate compound (2.0 g). This intermediate compound (1.8 g, 3.6 mmol) was dissolved in dry NMP (10 ml), and added carbonylcyanide the ol (1,83 g, 11.3 mmol), and then 60%sodium hydride in mineral oil (450 mg, 11,25 mmol) in portions for 5 min the Mixture was then heated to 70°C for 15 minutes and the Mixture was left to cool to room temperature, then poured carefully into water, and precipitated precipitated solid substance was collected by filtration, then purified using flash chromatography on silica, using ethyl acetate:isohexane (1:3) as eluent, to obtain specified in the subtitle compound (0,98 g, 36%).

1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.29 (m, 1H), 7.56 (m, 9H), 6.50 (s, 1H), 4.77 (t, 1H), 3.56 (s, 1H), 2.58 (t, 2H), 1.91 (d, 2H), 1.42 (m, 13H).

Stage (C) 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

4.0 M hydrogen chloride in dioxane (20 ml) was added to tert-butyl ether [4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidine-3-yl)-cyclohexyl]-carbamino acid (830 mg, 1.56 mmol)and the mixture was allowed to mix at room temperature for 2 hours the Mixture was evaporated to dryness, and the residue triturated with acetonitrile to obtain specified in the subtitle compound (607 mg, 90%).

1H NMR (400 MHz, DMSO-d6) δ 8.59 (t, 1H), 8.30 (dt, 1H), 7.57 (m, 9H), 4.75 (t, 1H), 3.06 (s, 1H), 2.72 (q, 2H), 1.53 (m, 8H).

APCl (multimode) m/z: 431 [M+H].

Stage (d) N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohe the force]-6-torymidae[1,2-a]pyridine-2-carboxamide.

6-Ftalimidina[1,2A]pyridine-2-carboxylic acid (80 mg, 0.43 mmol) was dissolved in dry DMF (5 ml), was added DIEA (0.2 ml, 1.15 mmol)and then HATU (167 mg, 0.43 mmol)and the mixture was stirred for 10 minutes was Added 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (185 mg, 0,43 mmol)and the mixture was stirred at room temperature overnight. The mixture was poured into water, and precipitated precipitated solid substance was collected by filtration, then purified HPLC with reversed phase (25-95%acetonitrile in aqueous ammonia) to obtain the specified title compound (117 mg, 46%).

1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.60 (s, 1H), 8.33 (m, 2H), 7.58 (m, 10H), 4.88 (t, 1H), 4.17 (s, 1H), 2.63 (m, 2H), 1.67 (m, 4H), 2.01 (d, 2H).

APCl (multimode) m/z 593 [M+H].

Example 2

N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-6-(1-methylpyrrolidine-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 6-(1-Methylpyrrolidine-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

A mixture of 5-(1-methyl-pyrrolidin-2-yl)-pyridine-2-ylamine (600 mg, 3 mmol) and ethylbromoacetate (1,17 g, 6.0 mmol) in ethanol (20 ml) was heated at 70°C for 2 hours the Mixture was evaporated to dryness, and the residue triturated with acetonitrile (10 ml). Dirty ether was collected by filtration and then dissolved in a mixture of water/dioxane (1:1) (20 ml). To this solution was added monohydrate of lithium hydroxide (0.3 g, 7,14 mmol)and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness, and the residue was transferred into water (20 ml)and the pH brought up to 4-5 by addition of acetic acid. The solid is then collected by filtration and dried to obtain specified in the subtitle compound (310 mg, 42%).

1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.35 (s, 1H), 7.55 (d, 1H), 7.29 (dd, 1H), 3.12 (m, 2H), 2.50 (m, 3H), 2.27 (q, 1H), 2.17 (m, 1H), 1.75 (m, 3H).

Stage (b) N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-6-(1-methylpyrrolidine-2-yl)imidazo[1,2-a]pyridine-2-carboxamide.

6-(1-Methylpyrrolidine-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (105 mg, 0.43 mmol) was dissolved in dry DMF (5 ml) was added DIEA (0.2 ml, 1.15 mmol)and then HATU (167 mg, 0.43 mmol)and the mixture was stirred for 10 minutes was Added 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (185 mg, 0.43 mmol)and the mixture was stirred at room temperature overnight. The mixture was poured into water, and precipitated precipitated solid substance was collected by filtration, then purified HPLC with reversed phase (25-95%acetonitrile in aqueous ammonia) to obtain the specified title compound (49 mg, 17.3%).

1H NMR (300 MHz, DMSO-d6) δ 8.60 (dd, 1H), 8.49 (s, 1H), 8.32 (m, 2H), 7.54 (m, 13H), 7.54 (m, 1H), 4.89 (m, 1H), 4.18 (s, 1H), 3.13 (dt, 2H), 2.65 (m, 2H), 2.27 (m, 1H), 2.14 (s, 3H), 1.82 (m, 8H).

APCl (multimode) m/z: 658 [M+H].

p> Example 3

N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]cyclohexyl}carbamate

Imidazo[1,2A]pyridine-2-carboxylic acid (5 g, for 30.8 mmol) was dissolved in NMP (200 ml), was added DIEA (11,96 g, 16,43 ml), then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (14,07 g, 37 mmol). The reaction mixture was stirred for 5 minutes Then added tert-butyl ester (4-aminocyclohexane)carbamino acid (6,61 g, 30,8 mmol)and the solution was stirred at room temperature overnight. Was added water, and the product was extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated in vacuum to obtain specified in the subtitle compound (8.5 g, contains little NMP). It was used without additional purification.

APCl (+ve) m/z: 359 [M+H].

Stage (b) N-(CIS-4-aminocyclohexane)imidazo[1,2-a]pyridine-2-carboxamide

To tert-butyl{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]-cyclohexyl}carbamate was added HCl (4 M in 1,4-dioxane) (30 ml)and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated. Everything ATEM was purified, using flash SCX, using methanol as eluent, then Meon/10%aq. NH3as eluent to obtain pure indicated in the subtitle compound (3.2 g, 40%) as a resin.

1H NMR (400 MHz, DMSO-d6) δ 8.59 (dt, 1H), 8.39 (d, 1H), 7.75 (d, 1H), 7.61 (dd, 1H), 7.35 (ddd, 1H), 6.99 (td, 1H), 3.74-3.96 (m, 3H), 2.98 (s, 1H), 1.52-1.87 (m, 8H).

APCl (+ve) m/z: 259 [M+H].

Stage (C) N-[CIS-4-({[2-(biphenyl-3-ylamino)-5-herperidin-3-yl]carbonyl}amino)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide

To 2-(biphenyl-3-ylamino)-5-fornicating acid (0,298 g, 0.97 mmol) was added DMF (2 ml), N-(CIS-4-aminocyclohexane)imidazo[1,2-a]pyridine-2-carboxamide (0,2498 g, 0.97 mmol), DIPEA (0,345 g, 0,441 ml), then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,404 g, 1.06 mmol). The reaction mixture was stirred at room temperature for 3 hours. Was added water, and the product was extracted with ethyl acetate and DCM. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain crude compound. It was then HPLC purified with reversed phase (35-45%acetonitrile in aqueous ammonia). The result has been mentioned in the subtitle compound (0.126 g, 24%).

1H NMR (400 MHz, CDCl3) δ 8.25 (d, 1H), 8.16-8.14 (m, 2H), 7.82 (t, 1H), 7.70-7.68 (m, 1H), 7.63-7.57 (m, 3H), 7.50-7.32 (m, 7H), 7.28-7.24 (m, 2H), 6.87 (t, 1H), 6.13 (d, 1H), 4.20 (d, 2H), 1.78-1.99 (m, 8H).

APCl (multimode) m/z 549 [M+H].

Stage (d) N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide.

To a solution of N-[CIS-4-({[2-(biphenyl-3-ylamino)-5-herperidin-3-yl]carbonyl}amino)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide (0.05 g) and 1,1'-carbonyldiimidazole (0,0517 g) in NMP (2 ml) was added sodium hydride (in mineral oil) (0,01093 g). This mixture was left to mix for 12 hours at room temperature. Was added water, and the product was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain crude compound. It was then HPLC purified with reversed phase (25-75%acetonitrile in aqueous ammonia). The result has been specified in the header connection (0,020 g, 38%).

1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.25-8.22 (m, 1H), 8.11 (d, 2H), 7.79-7.30 (m, 11H), 7.22-7.18 (m, 1H), 6.82 (dd, 1H), 5.10-5.02 (m, 1H), 4.45-4.43 (m, 1H), 2.75-2.87 (m, 2H), 2.14 (d, 2H), 1.72-1.85 (m, 4H).

APCl (multimode) m/z: 575 [M+H].

Example 4

N-{CIS-4-[1-[3-(anilinoacrolein)phenyl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) Methyl-3-[3-(CIS-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate

4.0 M hydrogen chloride in 1,4-dioxane (20 ml, 80 mmol) EXT is ulali to methyl-3-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate (2 g, 3.9 mmol)and the mixture was stirred at room temperature for 1 h, the Reaction mixture was poured slowly to saturated aqueous sodium carbonate, which then was extracted with DCM (×3). The organic extracts were combined, dried (anhydrous sodium sulfate), filtered and evaporated to obtain specified in the subtitle compound (1.8 g, 100%).

1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, 1H), 8.29 (dd, 1H), 8.08-7.98 (m, 2H), 7.71-7.65 (m, 2H), 4.73 (qt, 1H), 3.87 (s, 3H), 3.06 (d, 2H), 2.69 (qd, 2H), 1.67-1.60 (m, 2H), 1.59-1.48 (m, 2H), 1.47-1.39 (m, 2H), 1.39-1.31 (m, 2H).

Stage (b) Methyl-3-[6-fluoro-3-{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]cyclohexyl}-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate

Imidazo[1,2-a]pyridine-2-carboxylic acid (660 mg, 4.07 mmol) suspended in NMP (30 ml), was added DIEA (1.31 g, 1.77 ml, 10,17 mmol)and then HATU (1.55 g, 4.07 mmol)and the mixture was stirred at room temperature for 10 minutes was Added methyl ether 3-[3-(4-amino-cyclohexyl)-6-fluoro-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-d]pyrimidine-1-yl]-benzoic acid (1.4 g, 3,39 mmol) in DMF (10 ml)and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water, and precipitated precipitated solid substance was collected by filtration and dried to obtain specified in the subtitle compound (1.35 g, 72%).

1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, 1H), 8.56 (d, 1H),8.38 (s, 1H), 8.33 (dd, 1H), 8.06-8.03 (m, 1H), 8.03-8.02 (m, 1H), 7.71-7.68 (m, 3H), 7.65 (d, 1H), 7.34 (ddd, 1H), 6.98 (td, 1H), 4.85 (t, 1H), 4.22-4.11 (m, 1H), 3.87 (s, 3H), 2.59 (d, 2H), 2.00 (d, 2H), 1.78-1.60 (m, 4H).

Stage (C) 3-[6-Fluoro-3-{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]cyclohexyl}-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid

Methyl ester of 3-(6-fluoro-3-{4-[(imidazo[1,2-a]pyridine-2-carbonyl)-amino]-cyclohexyl}-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-d]pyrimidine-1-yl)-benzoic acid (1.75 g, 3.14 mmol) was dissolved in 1,4-dioxane (100 ml)and the solution was added lithium hydroxide (150 mg, of 6.29 mmol) in water (20 ml)and the reaction mixture was stirred at room temperature during the night. The mixture was acidified glacial acetic acid and then concentrated in vacuum. The residue was purified HPLC with reversed phase (25-95%acetonitrile in water triperoxonane acid) to produce specified in the subtitle compound (440 mg, 26%).

1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), at 8.62 (s, 1H), 8.57 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H), 8.04-8.01 (m, 1H), 7.99-7.97 (m, 1H), 7.74 (d, 1H), 7.65 (q, 2H), 7.59 (t, 1H), 7.19 (t, 1H), 4.86 (t, 1H), 4.18-4.12 (m, 1H), 2.70-2.59 (m, 2H), 2.11-1.99 (m, 2H), 1.78-1.58 (m, 4H).

Stage (d) N-{CIS-4-[1-[3-(anilinoacrolein)phenyl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

3-(6-Fluoro-3-{4-[(imidazo[1,2-a]pyridine-2-carbonyl)-amino]-cyclohexyl}-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-d]pyrimidine-1-yl)-benzoin the Yu acid (220 mg, 0.41 mmol) was dissolved in DMF (3 ml), was added DIEA (157 mg, 212 μl, 1,22 mmol)and then HATU (185 mg, 0.49 mmol)and the reaction mixture was stirred at room temperature for 10 minutes was Added aniline (to 41.6 mg, 41 μl, 0.45 mmol)and the reaction mixture was allowed to mix at room temperature over night. The solvent was removed, and the residue was distributed between ethyl acetate and water. The organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and evaporated, and the residue was purified HPLC with reversed phase (25-95%acetonitrile in aqueous ammonia) to obtain the specified title compound (120 mg, 48%).

1H NMR (400 MHz, DMSO-d6) δ 10,34 (s, 1H), 8.58 (d, 2H), 8.39 (s, 1H), 8.34 (dd, 1H), 8.08 (d, 1H), 7.98 (s, 1H), 7.77 (d, 2H), 7.73-7.61 (m, 4H), 7.39-7.30 (m, 3H), 7.11 (t, 1H), 6.98 (t, 1H), 4.87 (d, 1H), 4.18 (s, 1H), 2.70-2.56 (m, 2H), 2.01 (d, 2H), 1.78-1.59 (m, 4H).

APCl (multimode) m/z: 618 [M+H].

Example 5

N-{CIS-4-[1-(3-{[(2-amino-ethyl)amino]carbonyl}phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

Stage (a) tert-butyl[2-({3-[6-fluoro-3-{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]cyclohexyl}-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoyl}amino)ethyl]carbamate

3-[6-fluoro-3-{CIS--4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)-amino]cyclohexyl}-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-the l]benzoic acid (220 mg, 0.41 mmol) was dissolved in DMF (3 ml), was added DIEA (157 mg, 212 μl, 1,22 mmol)and then HATU (201 mg, of 0.53 mmol)and the reaction mixture was stirred at room temperature for 10 minutes was Added tert-butyl ether (2-amino-ethyl)-carbamino acid (72 mg, 71 μl, 0.45 mmol)and the reaction mixture was allowed to mix at room temperature over night. The solvent was removed, and the residue was distributed between ethyl acetate and water. The organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified HPLC with reversed phase (25-95%acetonitrile in aqueous ammonia) to obtain specified in the subtitle compound (30 mg, 10%).

1H NMR (400 MHz, DMSO-d6) δ 8.60-8.55 (m. 2H), 8.52 (t, 1H), 8.38 (s, 1H), 8.33 (dd, 1H), 7.93 (d, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.67-7.63 (m, 1H), 7.60 (d, 1H), 7.56-7.53 (m, 1H), 7.36-7.30 (m, 1H), 6.98 (td, 1H), 6.90 (t, 1H), 4.86 (s, 1H), 4.17 (s, 1H), 3.29-3.19 (m, 2H), 3.11 (t, 2H), 2.64-2.54 (m, 2H), 2.00 (d, 2H), 1.70 (dd, 4H), 1.35 (s, 9H).

APCl (multimode) m/z: 685 [M+H].

Stage (b) N-{CIS-4-[1-(3-{[(2-amino-ethyl)amino]carbonyl}phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide.

tert-Butyl[2-({3-[6-fluoro-3-{CIS-4-[(imidazo[1,2-a]pyridine-2-ylcarbonyl)amino]cyclohexyl}-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoyl}amino)ethyl]carbamate (150 mg, 0.22 mmol) was dissolved in 1,4-dioxane (2 ml)was added 4.0 M hydrogen chloride in 1,4-dioxane (5 ml, 20 m is ol), and the reaction mixture was stirred at room temperature for 2 hours the Solvent was evaporated, and the residue was purified HPLC with reversed phase (25-95%acetonitrile in aqueous ammonia) to obtain the specified title compound (35 mg, 50%).

1H NMR (400 MHz, DMSO-d6) δ 8.61-8.55 (m, 2H), 8.46 (t, 1H), 8.38 (s, 1H), 8.33 (dd, 1H), 7.95 (d, 1H), 7.85 (t, 1H), 7.70 (d, 1H), 7.67-7.57 (m, 2H), 7.56-7.52 (m, 1H), 7.37-7.31 (m, 1H), 6.98 (ddd, 1H), 4.86 (s, 1H), 4.17 (s, 1H), 3.16-3.03 (m, 2H), 2.67 (t, 2H), 2.60 (d, 2H), 2.00 (d, 2H), 1.70 (dd, 4H).

APCl (multimode) m/z: 585 [M+H].

Example 6

N-{CIS-[6-fluoro-2,4-dioxo-1-[3-(pyridine-3-ylethynyl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

Stage a) 5-fluoro-2-(3-itfinally)pyridine-3-carboxylic acid

2-Chloro-5-fornicating acid (4.68 g, to 26.7 mmol), potassium carbonate (4,43 g, 32.1 mmol), 3-stanlin (8.8 g, 40,2 mmol), copper bromide (I) (192 mg, of 1.34 mmol) and copper (102 mg, 1.6 mmol) was weighed in a round bottom flask, was added N-methylpyrrolidinone (40 ml). After degassing the mixture was heated in nitrogen atmosphere at 150°C for 4 hours. The black reaction mixture was poured into water, and the mixture was stirred over night. The obtained solid was filtered, washed with water and dried on the crucible for filtering to obtain a dark brown solid (it was specified what the subtitle compound), which was used without further purification in the next stage.

APCI-MS m/z: 358 [MN+].

Stage (b) 3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[3-itfinal]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

5-fluoro-2-(3-itfinally)pyridine-3-carboxylic acid (9.3 g, 26 mmol), CIS-4-amino-1-tert-butoxycarbonylamino-cyclohexane (5.6 g, 26,1 mmol), HATU (up 11,86 g, and 31.2 mmol) and NEAT (4,25 g, and 31.2 mmol) was dissolved in N-methylpyrrolidinone (30 ml) at ambient temperature. Was added slowly over 1 minute, N-ethyl-Diisopropylamine (13.3 ml, with 77.7 mmol), at this time was exothermic interaction. After stirring for 15 hours, the mixture was poured into water and was extracted with dichloromethane. The organic phase is washed 3 N. hydrochloric acid, water, saturated aqueous sodium carbonate, water and brine, dried over sodium sulfate and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate was obtained 3-(4-(tert-butoxycarbonylamino)cyclohexyl-1-aminocarbonyl)-5-fluoro-2-(3-itfinally)pyridine (2.15 g, 3.9 mmol) as a red-brown solid, which was dissolved in a mixture of N-methylpyrrolidinone (3 ml) and tetrahydrofuran (2 ml). Added carbonyldiimidazole (1,9 g, 11.7 mmol), then one portion sodium hydride (60%). The reaction is th the mixture was stirred at ambient temperature for 2 hours, was poured into water and was extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate were obtained is indicated in the subtitle compound (1,05 g) as a yellow solid.

1H NMR (DMSO-d6): δ 8.58 (1H, d); 8.28 (1H, dd); 7.79-7.85 (2H, m); 7.43 (1H, ddd); 7.33 (1H, ddd); 6.52 (1H, brs); 4.72 (1H, bt); 3.55 (1H, bs); 2.50-2.64 (2H, brm); 1.84-1.96 (2H, brd); 1.37-1.56 (4H, brm and N, s).

APCI-MS m/z: 555 [MH+].

Stage (C) 3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[3-(pyridine-3-ylethynyl)phenyl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[3-itfinal]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 g, 1,72 mmol) and 3-pyridylacetate (0,235 g, 2.28 mmol) was dissolved in tetrahydrofuran (5 ml). Was added triethylamine (0.95 ml, 6,83 mmol)was then added to a mixture of bis(triphenylphosphine)palladium(II)dichloride (0.12 g, 0,17 mmol) and copper iodide (I) (16 mg, 0,084 mmol). The mixture was stirred at ambient temperature for 1 h, then poured into a mixture of water and dichloromethane. The organic phase was separated and washed with water, dried over potassium carbonate, filtered and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate floor is Ali mentioned in the subtitle compound as a yellow solid (0.75 g, 79%).

1H NMR (DMSO-d6): δ 8.77 (1H, s); 8.58-at 8.62 (2H, m); 8.29 (1H, dd); 7.98 (1H, d); 7.64-7.71 (2H, m); 7.60 (1H, t); 7.44-7.51 (2H, m); 6.52 (1H, brs); 4.75 (1H, bt); 3.56 (1H, bs); 2.52-2.67 (2H, brm); 1.86-1.95 (2H, brd); 1.42-1.56 (4H, brm); 1.39 (9H, s).

APCI-MS m/z: 555 [MH+].

Stage (d) 3-(4-Aminocyclohexane)-6-fluoro-1-[3-(pyridine-3-ylethynyl)phenyl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[3-(pyridine-3-ylethynyl)phenyl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (700 mg, of 1.26 mmol) was dissolved in dioxane (5 ml) was added hydrogen chloride (1.2 ml of 4 n solution in dioxane, 4.8 mmol)and the solution was heated at 50°C for 24 hours. After cooling to ambient temperature was added diethyl ether to initiate crystallization. The solid was rapidly filtered off, washed with diethyl ether and dried in air atmosphere to obtain the desired compound in the form of dihydrochloride salt, which is very hygroscopic and is used immediately in the next stage.

Alternativna obtained salt was distributed between chloroform and saturated aqueous sodium carbonate, and the organic phase is washed with water, dried over potassium carbonate, filtered and concentrated under reduced pressure to obtain the target compound as a beige solid.

1H NMR (DMSO-d6): δ 8.76 (1H, s); 8.57-at 8.62 (2H,m); 8.30 (1H, dd); 7.99 (1H, add); 7.57-7.71 (3H, m); 7.45-7.51 (2H, m); 4.73 (1H, bt); 3.06 (1H, bs); 2.63-2.78 (2H, brm); 1.60-1.69 (2H, brd); 1.48-1.59 (2H, brm); 1.37-1.47 (2H, brm).

APCI-MS m/z: 455 [MH+].

Stage (e) N-{4-[6-fluoro-2,4-dioxo-1-[3-(pyridine-3-ylethynyl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

To a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid (110 mg, of 0.68 mmol), HATU (250 mg, 0.66 mmol) and 3-(4-aminocyclohexane)-6-fluoro-1-[3-(pyridine-ylethynyl)phenyl]-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride (230 mg, 0.44 mmol) in chloroform was added ethyl-Diisopropylamine (range 0.38 ml, 2.2 mmol) over a period of 20 seconds. Stirring is continued at ambient temperature for 15 hours. To the clear solution was added water, and the mixture was concentrated under reduced pressure using a rotary evaporator. The obtained solid was filtered and dissolved in acetonitrile. In the purification preparative HPLC got listed in the connection header in the form of not-quite-white solid (45 mg, 17%).

1H NMR (DMSO-d6): δ 8.75 (1H, s); 8.55-at 8.62 (3H, m); 8.38 (1H, s); 8.34 (1H, dd); 7.98 (1H, add); 7.57-7.74 (4H, m); 7.44-7.52 (2H, m); 7.33 (1H, brdd); 6.98 (1H, brdd); 4.87 (1H, bt); 4.18 (1H, bs); 2.54-2.69 (2H, brm); 2.00 (2H, brd); 1.59-1.79 (4H, m).

APCI-MS m/z: 599 [MH+].

Example 7

N-[CIS-4-(1-cyclopentyl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide

Stage a) 5-fluoro-2-(cyclopentylamine)pyridine-3-carboxylic acid.

2-Chloro-5-fornicating acid (10,45 g, 60 mmol), potassium carbonate (9,9 g, 71,6 mmol), cyclopentylamine (9 ml, 90,9 mmol), copper bromide (I) (430 mg, 3 mmol) and copper (230 mg, 3.6 mmol) was weighed in a round bottom flask, was added N-methylpyrrolidinone (40 ml). After degassing the mixture was heated in nitrogen atmosphere at 150°C for 3 days. The black reaction mixture was poured into water, and the pH was brought to 5, using 3 N. hydrochloric acid. The mixture was stirred overnight, the resulting solid substance was filtered off, washed with water and dried on the crucible for filtering obtaining specified in the subtitle compound as a gray solid (4,58 g)which was used without further purification in the next stage.

APCI-MS m/z: 225 [MH+].

Stage (b) 3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[cyclopentyl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

5-fluoro-2-(cyclopentylamine)pyridine-3-carboxylic acid (3.15 g, 14.1 mmol), CIS-4-amino-1-tert-butoxycarbonylamino-cyclohexane (3,16 g, 14.7 mmol), HATU (to 6.43 g of 16.9 mmol) and NEAT (2.3 g, to 16.9 mmol) was dissolved in N-methylpyrrolidinone (50 ml) at ambient temperature. Was added slowly over 1 minute N-ethyl-Diisopropylamine (7.3 ml, of 42.6 mmol), in this period of time was esotericism the I reaction. After stirring for 3 hours the mixture was poured into water, and the mixture was stirred for a further hour at ambient temperature. The obtained solid was filtered, washed with water and dried on the crucible to filter with 3-(4-(tert-butoxycarbonylamino)cyclohexyl-1-aminocarbonyl)-5-fluoro-2-(cyclopentylamine)pyridine (5,52 g of 13.1 mmol) in olive-green solid, which was taken as such. 3-(4-(tert-Butoxycarbonylamino)cyclohexyl-1-aminocarbonyl)-5-fluoro-2-(cyclopentylamine)pyridine (or 4.31 g of 10.3 mmol) was dissolved in a mixture of N-methylpyrrolidinone (12 ml) and tetrahydrofuran (8 ml). Added carbonyldiimidazole (4,99 g, 30,8 mmol), then one portion sodium hydride (60%, 1.24 g, 31 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then poured into water and the resulting solid was filtered, washed with water, dried on the crucible for filtration, dissolved in dichloromethane and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate, has been specified in the subtitle compound (3,01 g, 65%) as a colourless solid.

1H NMR (300 MHz, DMSO-d6): δ 8.76 (1H, d); 8.20 (1H, dd); 8.03 (2H, bs); 6.56 (1H, bs); 5.79 (1H, p); 4.73 (1H, bt); 3.55 (1H, bs); 2.49-2.67 (2H, bm); 2.05-2.20 (2H, bd); 1.73-2.01 (6H, m); 1.34-1.67 (16H, m).

APCI-MS m/z: 447 [MH+].

Stage (is) 3-(4-Aminocyclohexane)-1-cyclopentyl-6-fluoro-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-[cyclopentyl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2530 mg, 5,67 mmol) was dissolved in dioxane (15 ml) was added hydrogen chloride (5.5 ml of a 4 n solution in dioxane, 22 mmol)and the solution was heated at 55°C for 15 hours. After cooling to ambient temperature was added diethyl ether to initiate crystallization. The solid was rapidly filtered off, washed with diethyl ether and dried in air atmosphere to obtain the desired compound (1.8 g; 83%) in the form of cleaners containing hydrochloride salt and was used immediately in the next stage.

Alternativna obtained salt was distributed between chloroform and saturated aqueous sodium carbonate, and the organic phase is washed with water, dried over potassium carbonate, filtered and concentrated under reduced pressure to obtain specified in the subtitle compound as not quite white solid.

1H NMR (300 MHz, DMSO-d6): δ 8.78 (1H, d); 8.21 (1H, dd); 8.03 (2H, bs); 5.80 (1H, p); 4.74 (1H, bt); 3.33-3.45 (1H, bs); 2.47-2.64 (2H, bm); 2.05-2.22 (2H, bd); 1.51-2.01 (12H, m).

APCI-MS m/z: 347 [MH+].

Stage (d) N-[4-(1-cyclopentyl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide.

To a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid (89 mg, 0.55 mmol), HATU (220 mg, 0.55 mmol), N is at (75 mg, 0.55 mmol) and 3-(4-aminocyclohexane)-1-cyclopentyl-6-fluoro-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (176 mg, 0.46 mmol) in N-methylpyrrolidinone (10 ml) was added ethyl-di-Isopropylamine (0,31 ml of 1.81 mmol) over a period of 20 seconds. Stirring is continued at ambient temperature for 3 hours, and the reaction mixture was poured into water. The obtained solid was filtered, dried on the crucible for filtration, dissolved in chloroform and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate were obtained is indicated in the title compound (55 mg, 24%) as a colourless solid.

1H NMR (300 MHz, DMSO-d6): δ 8.77 (1H, d); 8.60 (1H, ddd); 8.40 (1H, s); 8.25 (1H, dd); 7.78 (1H, d); 7.68 (1H, d); 7.38 (1H, dd); 7.00 (1H, dd); 5.80 (1H, p); 4.84 (1H, bt); 2.89 (1H, bs); 2.50-2.70 (2H, bm); 2.04-2.22 (2H, bd); 1.41-2.04 (12H, m).

APCI-MS m/z: 491 [MH+].

Example 8

Methyl-TRANS-4-[3-{CIS-4-[(cyclopropanecarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]cyclohexanecarboxylate.

Stage (a) Methyl-TRANS-4-aminocyclohexanecarboxylic

To a solution of TRANS-4-aminocyclohexane-carboxylic acid hydrochloride (2 g, 11,13 mmol) in methanol (30 ml) was added sulfuric acid (0.7 ml). The mixture was boiled under reflux over night at 70°C. Rast is oritel was evaporated, was added water, and the mixture was podslushivaet ammonia. The aqueous solution was extracted again sumarno 500 ml of CH2Cl2. The organic extracts were dried MgSO4, was filtered and was evaporated to obtain specified in subheading connection with some impurities (1,045 g, 59%).

APCI-MS m/z 158 [MH+].

Stage (b) 5-fluoro-2-{[TRANS-4-(methoxycarbonyl)cyclohexyl]-amino}nicotinic acid

To a solution of 2-chloro-5-fornicating acid (640 mg, 3.65 mmol) in DMF (9 ml) was added methyl-TRANS-4-aminocyclohexanecarboxylic (860 mg, vs. 5.47 mmol), copper (70 mg, 1.1 mmol), Cu(I)Br (105 mg, 0.73 mmol) and potassium carbonate (605 mg, of 4.38 mmol). The mixture was heated at 150°C within 1.5 h of the solution was Added HCl, and the mixture was extracted with tO. The organic phase was extracted with a solution of potassium carbonate. The aqueous layer was acidified with HCl and was extracted with tO. The organic phase was dried, MgSO3, was filtered and was evaporated to obtain specified in the subtitle compound (732 mg, 63%).

APCI-MS m/z: 297 [MN+].

Stage (C) Methyl-TRANS-4-({3-[({CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)carbonyl]-5-herperidin-2-yl}amino)cyclohexanecarboxylate

5-fluoro-2-{[TRANS-4-(methoxycarbonyl)cyclohexyl]amino}nicotinic acid (732 mg, 2,47 mmol), tert-butyl-CIS-4-aminocyclohexanol (583 mg, of 2.72 mmol), HATU (1125 mg,2,96 mmol), NOT (403 mg, 2,96 mmol) and DIEA (1,27 ml, 7.41 mmol) in NMP was stirred for 1 h was Added tO, and the mixture was washed with a solution Panso3, dried, MgSO3, was filtered and was evaporated. The remaining oil was purified flash chromatography on silica [acetone:heptane (2:3)] to obtain specified in the subtitle compound (796 mg, 65%).

APCI-MS m/z: 493 [MH+].

Stage (d) Methyl-TRANS-4-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]cyclohexanecarboxylate

To a solution of methyl TRANS-4-({3-[({CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)carbonyl]-5-herperidin-2-yl}amino)cyclohexanecarboxylate (400 mg, 0.81 mmol) purged with argon THF, was added carbonyldiimidazole (395 mg, 2,44 mmol) and NaH (50% in oil, 117 mg of 2.44 mmol). The mixture was heated under reflux at 70°C during the night. Was added an aqueous solution of Na2The HCO3and the mixture was extracted with EtOAc. The crude residue was purified flash chromatography on silica [acetone:heptane (1:4)] to obtain specified in the subtitle compound (180 mg, 43%).

APCI-MS m/z: 419 [MH+].

Stage (d) Methyl-TRANS-4-[3-{CIS-4-[(cyclopropanecarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]cyclohexanecarboxylate.

Methyl-TRANS-4-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]cyclohexanecarboxylate (50 mg, 0,096 mmol) was stirred in 4 M HCl in dioxane for 3 h to obtain the free amine. The solvent is evaporated, and the crude substance used directly in the next stage, added cyclopropylboronic acid (8,5 μl, 0,106 mmol), HATU (44 mg, 0,116 mmol), NEAT (16 mg, 0,116 mmol), DIEA (49 μl, 0,289 mmol) and NMP (1 ml). The mixture was stirred for 1 h, and indicated in the title compound was obtained by preparative HPLC (26 mg, 56%).

1H NMR (400 MHz, DMSO-d6) δ 8.77 (1H, s); 8.22 (1H, dd); 7.93 (1H, s); 5.22 (1H, s); 4.73 (1H, t); 3.78 (1H, s); 3.61 (3H, s); 2.68-2.55 (2H, m); 2.38-2.29 (1H, m); 2.10-2.02 (2H, m); 1.93-1.86 (2H, m); 1.84-1.70 (3H, m); 1.58-1.39 (6H, m); 0,69-0,62 (4H, m).

APCI-MS m/z: 487 [MH+].

Example 9

N-{CIS-4-[6-fluoro-1-(4-terbisil)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage a) 5-fluoro-2-((4-terbisil)amino)pyridine-3-carboxylic acid

2-Chloro-5-fornicating acid (EUR 7.57 g, 43.2 mmol), potassium carbonate (7.2 g, to 52.1 mmol), 4-forbindelsen (7,4 g, 59,1 mmol), copper bromide (I) (310 mg, of 2.16 mmol) and copper (165 mg, 2.6 mmol) was weighed in a round bottom flask, was added N-methylpyrrolidinone (30 ml). After degassing the mixture was heated in nitrogen atmosphere at 150°C for 2 hours. The black reaction mixture was poured into water, and the mixture was stirred over night. The obtained solid is emesto was filtered, washed with water and dried on the crucible for filtering to obtain a light green solid (specified in the subtitle compound, which was used without further purification in the next stage.

APCI-MS m/z: 265 [MN+].

Stage (b) 3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-(4-terbisil)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

5-fluoro-2-(4-forbindelsen)pyridine-3-carboxylic acid (3,18 g, 12 mmol), CIS-4-amino-1-tert-butoxycarbonylamino-cyclohexane (2,72 g, 12.7 mmol), HATU (5,02 g, 13,2 mmol) and NEAT (1.8 g, 13.3 mmol) was dissolved in N-methylpyrrolidinone (30 ml) at ambient temperature. Was added slowly over 1 minute N-ethyl-Diisopropylamine (6.2 ml, and 36.2 mmol), in that time there was an exothermic reaction. After stirring for 15 hours, the mixture was poured into water, and the pH was brought to pH 6 using 3 N. hydrochloric acid. The mixture was stirred for 3 hours and the resulting solid was filtered, washed with water and dried on the crucible to filter with 3-(4-(tert-butoxycarbonylamino)cyclohexyl-1-aminocarbonyl)-5-fluoro-2-(4-forbindelsen)pyridine as a brown solid, which was dissolved in a mixture of N-methylpyrrolidinone (30 ml) and tetrahydrofuran (20 ml). Added carbonyldiimidazole (of 5.84 g, 36 mmol), then one portion of the hydride on the rija (60%, 1.44 g, 36 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then poured into water, and the pH was brought to pH=7 using 3 N. hydrochloric acid. The mixture was stirred overnight and the resulting solid was filtered, washed with water and dried on the crucible for filtering. The solid was dissolved in chloroform and adsorbing on silica gel. In the flash-chromatography using a mixture of petroleum ether and ethyl acetate were obtained is indicated in the subtitle compound (3.6 g, 62%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6): δ 8.75 (1H, d); 8.24 (1H, dd); 7.39 (2H, m); 7.11 (2H, t); 6.57 (1H, bs); 5.38 (2H, s); 4.75 (1H, m); 3.55 (1H, bs); 2.52-2.65 (2H, bm); 1.85-1.94 (2H, bm); 1.36-1.56 (13H, m).

APCI-MS m/z: 487 [MH+].

Stage (C) 3-(4-Aminocyclohexane)-6-fluoro-1-(4-terbisil)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(4-tert-Butyloxycarbonyl)-6-fluoro-1-(4-terbisil)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3,52 g, 7.2 mmol) was dissolved in dioxane (10 ml) was added hydrogen chloride (8 ml of a 4 n solution in dioxane, 32 mmol)and the solution was heated at 50°C for 3 hours. After cooling to ambient temperature, was added diethyl ether to initiate crystallization. The obtained Sol decantation and was distributed between chloroform and saturated aqueous sodium carbonate, organicheskoi phase was washed with water, dried over potassium carbonate, filtered and concentrated under reduced pressure to obtain specified in the subtitle compound as a colourless solid (2,45 g, 88%).

1H NMR (300 MHz, DMSO-d6): δ 8.75 (1H, d); 8.25 (1H, dd); 7.34-7.44 (2H, m); 7.07-7.15 (2H, m); 5.38 (2H, s); 4.73 (1H, m); 3.06 (1H, bs); 2.62-2.78 (2H, bm); 1.23-1.70 (6H, bm).

APCI-MS m/z: 387 [MH+].

Stage (d) N-{4-[6-Fluoro-1-(4-terbisil)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

To a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid (91 mg, 0,56 mmol), HATU (mg, 0.55 mmol) and 3-(4-aminocyclohexane)-6-fluoro-1-[4-terbisil]-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (180 mg, 0.46 mmol) in chloroform (5 ml) was added ethyl-di-Isopropylamine (0,32 ml of 1.87 mmol) over a period of 20 seconds. Stirring is continued at ambient temperature for 15 hours. To the clear solution was added water, and the mixture was concentrated under reduced pressure using a rotary evaporator. The obtained solid was filtered, washed with water and dried on the crucible for filtering obtaining specified in the connection header in the form of not-quite-white solid (120 mg, 49%).

1H NMR (300 MHz, DMSO-d6): δ 8.75 (1H, d); 8.59 (1H, ddd); 8.40 (1H, s); 8.29 (1H, dd); 7.75 (1H, d); 7.69 (1H, d); 7.34-7.43 (2H, m); 7.08-7.17 (2H, m); 6.99 (1H, ddd); 5.39 (2H, s); 4.86 (1H, bt); 4.17 (1H, bs); 2.45-2.69 (2H, bm); 1.94-2.04 (2H, bm); 1.54-1.80 (4H, m).

APCI-MS m/z: 531 [MH +].

Example 10

N-{CIS-4-[1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

Stage a) 5-fluoro-2-[(3-itfinal)amino]nicotinic acid

2-Chloro-5-fornicating acid (27 g, 153,8 mmol) was added to dry DMF (500 ml). Added copper (977 mg), copper bromide (I) (2.20 g), potassium carbonate (25,51 g, 184,6 mmol) and 3-itfinally (27.7 ml, 230,7 mmol)and the reaction mixture was stirred at 110°C for 2.5 hours. Added 1 M HCl, and the product was extracted with ethyl acetate. The organic phase is washed with 1 M HCl, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuum to obtain specified in the subtitle compound as a mixture containing 2-chloro-5-fornicating acid (21,64 g). It was used without additional purification.

APCI (multimode) m/z: 357 [M-N].

Stage (b) 6-fluoro-N-{CIS-4-[({5-fluoro-2-[(3-itfinal)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To 5-fluoro-2-[(3-itfinal)amino]nicotinic acid (8,4 g and 23.4 mmol) and N-(CIS-4-aminocyclohexane)-6-torymidae[1,2-a]pyridine-2-carboxamide (7,34 g and 23.4 mmol) was added acetonitrile (85 ml) and triethylamine (19.6 ml, 140,8 mmol). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,-trioxide (to 17.9 ml, of 28.2 mmol) (50 wt%. solution in butyl acetate) were added dropwise within 15 min, and the reaction mixture was stirred at room temperature for 5 minutes, the Solid is then collected by filtration and washed with water. Added acetonitrile, and the suspension was heated, left to cool and the solid was collected by filtration and dried to obtain specified in the subtitle compound (6.9 g).

1H NMR (400 MHz, DMSO-d6) δ 10.70 (1H, s), 8.80 (1H, qd), 8.53 (1H, d), 8.41 (1H, d), 8.37 (1H, s), 8.23-8.19 (1H, m), 7.81 (1H, d), 7.67 (1H, t), 7.53-7.43 (2H, m), 7.32-7.29 (1H, m), 7.08 (1H, t), 4.05-3.96 (1H, m), 3.42 (1H, s), 1.95-1.87 (2H, m), 1.81-1.64 (6H, m).

APCI (multimode) m/z: 617 [M+H].

Stage (b) 6-Fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 6-fluoro-N-{CIS-4-[({5-fluoro-2-[(3-itfinal)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (6,9 g, and 11.2 mmol) in NMP (35 ml) was added 1,1'-carbonyldiimidazole (6,35 g of 39.2 mmol). The solution was stirred at room temperature for 10 minutes was Added sodium hydride (60% wt. in mineral oil) (806 mg, 33.6 mmol)and the mixture was stirred at 40°C. for 1.5 hours the Mixture was poured into ice water and the product was extracted with ethyl acetate. The organic phase is washed with water, dried anhydrous magnesium sulfate, filtered and which has centriole in vacuum. The residue is triturated with diethyl ether to obtain specified in the subtitle compound (4,50 g).

1H NMR (400 MHz, DMSO-d6) δ 8.80 (1H, qd), 8.59 (1H, d), 8.37 (1H, d), 8.32 (1H, dd), 7.86-7.80 (2H, m), 7.77 (1H, dd), 7.68 (1H, d), 7.49-7.41 (2H, m), 7.33 (1H, t), 4.84 (1H, t), 4.18 (1H, s), 2.63-2.53 (2H, m), 2.04-1.96 (2H, m), 1.76-1.60 (4H, m).

APCI (multimode) m/z: 642 [M+H].

Alternatively, the compound from step (C), [6-fluoro-N-{CIS-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide]can be obtained, as shown in the Method below.

Stage (d) N-{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

Acetonitrile (2 ml) was added to palladium (II) acetate (3 mg) and 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (10 mg)and the mixture was stirred at room temperature for 10 minutes was Added potassium carbonate (97 mg, 0.70 mmol) in water (1.6 ml), dimethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amine (104 mg, 0.35 mmol) and 6-the fluorine-imidazo[1,2-a]pyridine-2-carboxylic acid 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.23 mmol)and the reaction mixture was heated to boiling under reflux for 2 hours and left to cool over night. The mixture was loaded is on Varian Bind Chemelut cartridge (available from Kinesis), the product was suirable DCM and concentrated in vacuum. The residue was purified HPLC with reversed phase (50-70%acetonitrile in aqueous ammonia) and liofilizirovanny obtaining specified in the title compound (70 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.79 (1H, dd), 8.59 (1H, d), 8.36 (1H, s), 8.33 (1H, dd), 7.79-7.71 (3H, m), 7.68 (1H, d), 7.65-7.57 (3H, m), 7.47-7.41 (1H, m), 7.39-7.35 (3H, m), 4.92-4.82 (1H, m), 4.17 (1H, s), 3.41 (2H, s), 2.69-2.55 (2H, m), 2.15 (6H, s), 2.00 (2H, d), 1.77-1.63 (4H, m).

APCI (multimode) m/z: 650 [M+H].

The compounds listed in Table 3 (see below), were obtained in a similar manner in the form of solid substances from a suitable Bronevoy acid or ester and 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide using the method described above in Example 10, step (d).

Example 29

N-{CIS-4-[1-[3'-(aminomethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide. Hydrochloride

To a solution of tert-butyl({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-3-yl}methyl)carbamate (150 mg, 0.21 mmol) (example 16) in 1,4-dioxane (2 ml) was added 4M hydrogen chloride in 1,4-dioxane (1 ml)and the reaction mixture was stirred at room temperature for 30 minutes P the obtained solid was filtered and washed with ether, was dried in an oven under vacuum obtaining specified in the title compound as a white solid (130 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.90 (1H, d), 8.58 (1H, d), 8.49 (1H, s), 8.36 (1H, s), 8.32 (1H, dd), 7.88 (1H, d), 7.83 (1H, s), 7.81-7.74 (2H, m), 7.72 (1H, t), 7.67 (1H, dt), 7.63 (1H, t), 7.55 (1H, td), 7.52-7.44 (1H, m), 7.41-7.38 (1H, m), 4.85 (1H, t), 4.12 (1H, s), 4.06 (2H, q), 2.67-2.54 (2H, m), 2.02 (2H, d), 1.76-1.58 (4H, m).

APCI (multimode) m/z: 622 [M+H].

Example 30

N-{CIS-4-[1-[4'-(aminomethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide. The hydrochloride.

To a solution of tert-butyl({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)carbamate (50 mg, 0,069 mmol) (example 19) in 1,4-dioxane (1 ml) was added 4M hydrogen chloride in 1,4-dioxane (1 ml)and the reaction mixture was stirred at room temperature for 1 h resulting solid substance was filtered and washed with ether, dried in a drying oven under vacuum obtaining specified in the title compound as a white solid (42 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.92 (1H, s), 8.59 (1H, d), 8.51 (1H, s), 8.42-8.36 (2H, m), 8.33 (1H, dd), 7.91 (1H, d), 7.82-7.72 (4H, m), 7.63 (2H, t), 7.58 (2H, d), 4.87 (1H, t), 4.18-4.02 (5H, m), 2.71-2.58 (2H, m), 2.08-2.00 (2H, m), 1.77-1.61 (4H, m).

APCI (multimode) m/z: 622 [M+H].

Example 31

N-{the IP-4-[1-{2'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl{CIS-4-[1-{2'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

Acetonitrile (3 ml) was added to a mixture of palladium (II) acetate (4 mg) and 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (14 mg)and the mixture was stirred at room temperature for 10 minutes was Added potassium carbonate (143 mg) in water (2 ml), 2-(N,N-dimethylaminomethyl)phenylboronic acid (90 mg) and tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (200 mg)and the reaction mixture was heated to boiling under reflux for 2 h and left to cool over night. The mixture was loaded onto the cartridge, Varian Bond Chemelut (available from Kinesis), the product was suirable DCM and concentrated in vacuum. The residue was purified column flash chromatography, elwira product of 0.1%triethylamine in ethyl acetate, to obtain specified in the subtitle compound as a pale brown solid (73 mg).

1H NMR (300 MHz, DMSO-d6) δ 8.59 (1H, d), 8.28 (1H, dd), 7.61-7.44 (3H, m), 7.39-7.28 (4H, m), 6.48 (1H, s), 4.77 (1H, t), 3.58 (1H, s), 3.33 (2H, s), 2.62-2.55 (2H, m), 2.11 (6H, s), 1.94-1.84 (2H, m), 1.56-1.41 (4H, m), 1.44 (9H, s).

APCI (multimode) m/z: 588 [M+H].

Stage (b) 3-(CIS-4-aminocyclohexane)-1-{2'-[(dimethylamino)methyl]biphenyl-3-yl}-6-torpedo[2,3-α]feast midin-2,4(1H,3H)-dione hydrochloride

To a solution of tert-butyl{CIS-4-[1-{2'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (70 mg) in 1,4-dioxane (0.5 ml) was added 4M hydrogen chloride in 1,4-dioxane (0.5 ml)and the reaction mixture was stirred at room temperature overnight. The solvents were removed under vacuum to obtain specified in the subtitle compound (70 mg).

APCI (multimode) m/z: 525 [M+H].

Stage (C). To a mixture of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (30 mg, 0.15 mmol), base Hunya (64 mg, 0.5 mmol) in dry DMF (5 ml) was added HATU (57 mg, 0.15 mmol). The mixture was left to mix for 10 min at room temperature. To this mixture was added 3-(CIS-4-aminocyclohexane)-1-{2'-[(dimethylamino)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (68 mg, 0.13 mmol)and the reaction mixture was stirred over night. The mixture was poured into water and the solid is collected and purified HPLC (acetonitrile and 0.1%ammonia in water) and liofilizirovanny obtaining specified in the title compound (30 mg).

1H NMR (300 MHz, DMSO-d6) δ 8.80 (1H, dd), 8.60 (1H, d), 8.37 (1H, s), 8.34-8.31 (1H, m), 7.77-7.21 (11H, m), 4.87 (1H, t), 4.16 (1H, s), 3.31 (2H, d), 2.63 (1H, m), 2.00 (9H, m), 1.69 (4H, m).

APCI (multimode) m/z: 651 [M+H].

Example 32

N-{CIS-4-[1-(3-Benzoylphenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]illogical}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 2-[(3-Benzoylphenyl)amino]-5-fornicative acid

2-Chloro-5-fornicating acid (3,65 g, 21 mmol), potassium carbonate (3.6 g, 26 mmol), 3-benzylaniline (5.4 g, 30 mmol), copper bromide (I) (155 mg, 1.2 mmol) and copper (80 mg, 1.3 mmol) was weighed in a round bottom flask, was added N-methylpyrrolidinone (15 ml). After degassing the mixture was heated in nitrogen atmosphere at 150°C for 2 hours the Black reaction mixture was poured into water, and the mixture was stirred over night. The obtained solid was filtered, washed with water and dried in air atmosphere to obtain specified in the subtitle compound as a pale brown solid (1.3 g, 18%)which was used without further purification in the next stage.

APCI (multimode) m/z: 323 [M+H].

Stage (b) N-{CIS-4-[({2-[(3-Benzoylphenyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To 2-[(3-Benzoylphenyl)amino]-5-fornicating acid (1.22 g, 3.4 mmol) and N-(CIS-4-aminocyclohexane)-imidazo[1,2-a]pyridine-2-carboxamide (1.07 g, 3.4 mmol) was added acetonitrile (20 ml) and triethylamine (2 ml, 14 mmol). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (2.5 ml, 4 mmol) (50%wt. solution in butyl acetate) were added dropwise within 15 mi the, and the reaction mixture was stirred at room temperature for 5 minutes, the Solid is then collected by filtration and washed with water. Added acetonitrile, and the suspension was heated, left to cool and the solid was collected by filtration and dried to obtain specified in the subtitle compound (0.9 g, 47%).

APCI (multimode) m/z: 563 [M+H].

Stage (C) N-{CIS-4-[1-(3-Benzoylphenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

To a solution of N-{CIS-4-[({2-[(3-benzoylphenyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,116 g, 0.21 mmol) in N,N-dimethylformamide (5 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,1672 g of 1.03 mmol) and 60%wt./mass. sodium hydride in mineral oil (0,041 g of 1.03 mmol). The reaction mixture was heated to 70°C for 30 min, then cooled to room temperature and was stirred for another 16 hours, the Reaction mixture was suppressed by addition of water (50 ml), which was then extracted with ethyl acetate (6×50 ml). The organic phases were combined, dried anhydrous sodium sulfate and concentrated to obtain the crude product as a pale brown solid. The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid substances is TBA (0,051 g, 42%).

1H NMR (400 MHz, DMSO-d6) δ 8.60-8.55 (2H, m), 8.39 (1H, s), 8.31-8.28 (1H, m), 7.43 (2H, t), 7.37-7.16 (10H, m), 6.98 (1H. m), 6.98 (1H, t), 4.88-4.79 (1H, m), 4.20-4.13 (1H, m), 4.00 (2H, s), 2.68-2.52 (2H, m), 2.04-1.95 (2H, m), 1.76-1.60 (4H, m).

APCI (multimode) m/z: 589 [M+H].

Example 33

N-{CIS-4-[1-(1-benzyl-1H-indazol-5-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 2-[(1-benzyl-1H-indazol-5-yl)amino]-5-fornicative acid

1-Benzyl-1H-indazol-5-ylamine (1,018 g, 4,56 mmol), potassium carbonate (0,378 g, is 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) was added to a stirred solution of 2-chloro-5-fornicating acid (0.4 g, 2.28 mmol) in N,N-dimethylformamide (5 ml). The solution was heated to 120°C for 1 h, then the reaction mixture was cooled and the DMF evaporated. The obtained solid mass was dissolved in 1 M HCl (50 ml) and was extracted three times with ethyl acetate (50 ml)which was then combined and dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product as a red-brown solid. The crude substance was again dissolved in ethyl acetate (50 ml), washed three times with 1 M HCl (50 ml), then once with saturated aqueous sodium bicarbonate (50 ml). The organic layer was again dried and concentrated to obtain ukazannoj is in the subtitle compound as a brown film (99 mg, 12%).

APCI (multimode) m/z: 362 [M+H].

Stage (b) N-{CIS-4-[({2-[(1-Benzyl-1H-indazol-5-yl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To 2-[(1-benzyl-1H-indazol-5-yl)amino]-5-fornicating acid (2,05 g, 3.4 mmol) and N-(CIS-4-aminocyclohexane)imidazo[1,2-a]pyridine-2-carboxamide (1.07 g, 3.4 mmol) was added acetonitrile (20 ml) and triethylamine (2 ml, 14 mmol). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (2.5 ml, 4 mmol) (50 wt%. solution in butyl acetate) were added dropwise within 15 min, and the reaction mixture was stirred at room temperature for 5 min Obtained solid is then collected by filtration and washed with water. Added acetonitrile, and the suspension was heated, left to cool and the solid was collected by filtration and dried to obtain specified in the subtitle compound (199 mg, 10%).

APCI (multimode) m/z: 603 [M+H].

Stage (C) N-{CIS-4-[1-(1-benzyl-1H-indazol-5-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

To a solution of N-{CIS-4-[({2-[(1-benzyl-1H-indazol-5-yl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,122 g, 0.2 mmol) in N,N-dimethylformamide (3 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,1641 g, 1.01 mmol who) and 60%wt./mass. sodium hydride in mineral oil (0,0405 g, 1.01 mmol). The reaction mixture then was heated to 70°C for 30 min in a nitrogen-filled vial for samples, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by the addition of brine (50 ml) and was extracted with ethyl acetate (6×50 ml). The organic phase is washed once with water, then dried anhydrous sodium sulfate and concentrated to obtain the crude product as an orange oil. The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (0,065 g, 51%).

1H NMR (400 MHz, DMSO-d6) 8.70 (m, 1H), 8.58-8.50 (m, 2H), 8.33-8.28 (m, 1H), 8.19 (m, 1H), 7.99 (s, 1H), 7.83-7.77 (m, 2H), 7.69 (d, 1H), 7.52 (t, 1H), 7.37-7.26 (m, 6H), 7.17-7.11 (m, 1H), 5.71 (s, 2H), 4.87 (t, 1H), 4.14 (s, 1H), 2.70-2.57 (m, 2H), 2.04 (m, 2H), 1.77-1.60 (m, 4H).

APCI (multimode) m/z: 629 [M+H].

Example 34

N-{CIS-4-[1-(1,5-Diethylhexyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) 2-[(1,5-Dimethylpentyl)amino]-5-fornicative acid

Was added 2-amino-6-formed (0,589 g, 4,56 mmol), potassium carbonate (0,378 g, is 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) to a stirred solution of 2-chloro-5-fornicating acid (0.4 g, 2.28 mmol) in N,N-dim is teleformula (5 ml). The solution was heated to 120°C for 2 h DMF evaporated water before processing. The obtained solid mass was dissolved in 1 M HCl (50 ml) and was extracted three times with ethyl acetate (50 ml), which were combined and dried anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain specified in the subtitle compound as a pale orange solid (509 mg, 81%).

APCI (multimode) m/z: 269 [M+H].

Stage (b) N-{CIS--4-[({2-[(1,5-Dimethylpentyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

To a solution of 2-[(1,5-dimethylpentyl)amino]-5-fornicating acid (0,153 g, or 0.57 mmol), triethylamine (0,346 g, 3.42 mmol) and 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (4-aminocyclohexane)amide (0,1961 g, mono-HCl adduct, to 0.63 mmol) in acetonitrile (0.5 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,2176 g, 0,436 ml, 50 wt%. solution in butyl acetate, 0.22 mmol). The reaction mixture was stirred for 10 min in the room, then extinguished the addition of water (50 ml)and the aqueous layer washed with ethyl acetate (3×50 ml). The crude substance was obtained as a yellow oil, which was purified column flash chromatography, elwira a mixture of 1:1 ethyl acetate:petroleum ether - 5%methanol/ethyl acetate, to obtain specified in the subtitle compound as yellow the CSO solids (115 mg, 38%).

APCI (multimode) m/z: 528 [M+H].

Stage (C) N-{CIS-4-[1-(1,5-Diethylhexyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

To a solution of N-{CIS-4-[({2-[(1,5-dimethylpentyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (0,106 g, 0.2 mmol) in N,N-dimethylformamide (3 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,1632 g, 1 mmol) and 60%wt./mass. sodium hydride in mineral oil (0,040 g, 1 mmol). The reaction mixture then was heated to 70°C for 30 min in a nitrogen-filled vial for samples, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by the addition of brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layers were then washed another brine (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude orange oil. The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (0,042 g, 38%).

1H NMR (400 MHz, DMSO-d6) 8.96-8.76 (m, 1H), 8.73-8.69 (m, 1H), 8.40-8.36 (1H, m), 8.22-8.15 (1H, m), 7.77-7.68 (2H, m), 7.48-7.41 (1H, m), 5.56-5.40 (1H, m), 4.92-4.80 (1H, m), 4.24-4.16 (1H, m), 2.69-2.58 (2H, m), 2.21-2.11 (1H, m), 2.05-1.97 (2H, m), 1.87-1.68 (2H, m), 1.62-1.54 (2H, m), 1.51-1.40 (5H, m), 1.27-1.07 (4H, m), 0,82-0,72 (6N, m).

APCI (multimode is) m/z: 553 [M+H].

Example 35

N-{CIS-4-[1-(4-benzoylphenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) 2-[(4-Benzoylphenyl)amino]-5-fornicative acid

Added 4-aminodiphenylamine (0,835 g, 4,56 mmol), potassium carbonate (0,378 g, is 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) to a stirred solution of 2-chloro-5-fornicating acid (0.4 g, 2.28 mmol) in N,N-dimethylformamide (5 ml). The solution was heated to 120°C for a period of 2 h, then DMF evaporated, then was treated with water. The obtained solid mass was dissolved in 1 M HCl (50 ml) and was extracted three times with ethyl acetate (50 ml)which was then combined and dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product as a brown solid. The crude substance was again dissolved in ethyl acetate (50 ml), washed three times with 1 M HCl (50 ml), then once with saturated aqueous sodium bicarbonate (50 ml). The organic layer was again dried and concentrated to obtain specified in the subtitle compound as a brown solid (603 mg, 82%).

APCI (multimode) m/z: 323 [M+H].

Stage (b) N-{CIS-4-[({2-[(4-benzoylphenyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]is iridin-2-carboxamide

To a suspension of 2-[(4-benzoylphenyl)amino]-5-fornicating acid (0,184 g, or 0.57 mmol), triethylamine (0,346 g, 3.42 mmol) and 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (4-aminocyclohexane)amide (0,1961 g, mono-HCl adduct, to 0.63 mmol) in acetonitrile (1 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,2176 g, 0,436 ml, 50 wt%. solution in butyl acetate, of 0.68 mmol). The reaction mixture was stirred for 30 min at room temperature, and then the acetonitrile was removed in vacuo, and the residue was distributed between ethyl acetate and water (50 ml each). The aqueous layer was washed with additional ethyl acetate (2×50 ml), then the organic phases were combined and dried with anhydrous sodium sulfate to obtain specified in the subtitle compound as an orange oil (222 mg, 67%).

ARC (multimode) m/z: 581 [M+H].

Stage (C) N-{CIS-4-[1-(4-Benzoylphenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

To a solution of N-{CIS-4-[({2-1(4-benzoylphenyl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (0.21 g, 0.36 mmol) in N,N-dimethylformamide (5 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,2935 g, is 1.81 mmol) and sodium hydride in mineral oil (60% wt./mass., 0,0724 g, is 1.81 mmol). The reaction mixture was then heated the Ali to 70°C for 30 min in a nitrogen-filled vial for samples, then cooled to room temperature and was stirred for another 16 hours, the Reaction mixture was suppressed by adding to the brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain a very small amount of material, and without the desired product. LC analysis showed that the product remained in the aqueous layer in the form of suspension. It was filtered, and the light brown filtrate is abundantly washed with deionized water. This substance was purified HPLC with reversed phase with obtaining specified in the title compounds as a pale yellow solid (57 mg, 27%).

1H NMR (400 MHz, DMSO-d6) 8.86 (1H, m), 8.55 (1H, d), 8.44 (1H, s), 8.29 (1H, m), 7.80-7.74 (2H, m), 7.54 (1H, m), 7.39-7.20 (10H, m), 4.84 (1H, t), 4.18 (1H, s), 4.01 (2H, s), 2.65-2.52 (2H, m), 2.04-1.96 (2H, m), 1.76-1.57 (4H, m).

APCI (multimode) m/z: 607 [M+H].

Example 36

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-(2-phenylethyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage a) 5-fluoro-2-[(2-phenylethyl)amino]nicotinic acid

Was added 2-phenylethylamine (0,551 g, 4,56 mmol), potassium carbonate (0,378 g, is 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) to a stirred solution of 2-chloro-5-fornicate the OIC acid (0.4 g, 2.28 mmol) in N,N-dimethylformamide (5 ml). The solution was heated to 120°C for 1 h, the Reaction mixture was suppressed by addition of 1 M HCl (50 ml)and was extracted three times with ethyl acetate (50 ml)which was then combined and dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product as a yellow solid. The reaction mixture was treated by dissolving in ethyl acetate (50 ml) and washed posledovatelno 1 M HCl (3×50 ml) and a saturated solution of sodium bicarbonate. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain specified in the subtitle compound as a pale yellow oil (236 mg, 40%).

APCI (multimode) m/z: 523 [M+H].

Stage (b) 6-Fluoro-N-{CIS-4-[({5-fluoro-2-[(2-phenylethyl)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To a suspension of 5-fluoro-2-[(2-phenylethyl)amino]nicotinic acid (0,184 g, or 0.57 mmol), triethylamine (0,429 g, 0,591 ml of 3.42 mmol) and 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (4-aminocyclohexane)amide (0,2432 g, mono-Hcl adduct, of 0.62 mmol) in acetonitrile (1 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,270 g, 0.54 ml, 50% mass. solution in butyl acetate, 0,684 mmol). The reaction mixture was stirred for 60 min at room temperature, then acetone the reel was removed in vacuum, and the residue was distributed between ethyl acetate and water (50 ml each). The aqueous layer was washed with additional ethyl acetate (2×50 ml), then the organic phases were combined and dried anhydrous sodium sulfate to obtain specified in the subtitle compound as a yellow oil (253 mg, 69%)which was used in the next stage without additional purification.

Stage (b) 6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-(2-phenylethyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

To a solution of 6-fluoro-N-{CIS-4-[({5-fluoro-2-[(2-phenylethyl)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.25 g, 0.48 mmol) in N,N-dimethylformamide (3 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,163 g, is 2.41 mmol) and sodium hydride in mineral oil (60% wt./mass., 0,040 g, is 2.41 mmol). The reaction mixture then was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by the addition of brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layer is then washed twice with brine (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a yellow oil. This substance was purified HPLC with reversed phase with obtaining specified in the connection header in the form of b is izvetnogo solid (72 mg, 27%).

1H NMR (DMSO-d6) 8.91-8.86 (1H, m), 8.81 (1H, d), 8.46 (1H, s), 8.29-8.24 (1H, m), 7.88-7.79 (2H, m), 7.60-7.53 (1H, m), 7.33-7.19 (5H, m), 4.84 (1H, t), 4.47-4.39 (2H, m), 4.20 (1H, s), 2.94 (2H, t), 2.66-2.54 (2H, m), 2.05-1.98 (2H, m), 1.77-1.51 (4H, m).

APCI (multimode) m/z: 545 [M+H].

Example 37

N-{CIS-4-[1-(1-Benzyl-1H-indazol-5-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) N-{CIS-4-[({2-[(1-Benzyl-1H-indazol-5-yl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

To a suspension of 2-[(1-benzyl-1H-indazol-5-yl)amino]-5-fornicating acid (0.104 g g, 0.29 mmol), triethylamine (0,174 g of 0.24 ml, 1,72 mmol) and 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (4-aminocyclohexane)amide (0,099 g, mono-Hcl adduct, 0.32 mmol) in acetonitrile (1 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,110 g, 0,219 ml, 50 wt%. solution in butyl acetate, 0.34 mmol). The reaction mixture was stirred for 60 min at room temperature, and then the acetonitrile was removed in vacuo, and the residue was distributed between ethyl acetate and water (50 ml each). The aqueous layer was washed with additional ethyl acetate (2×50 ml)then the organic phase was combined and dried anhydrous sodium sulfate to obtain specified in the subtitle compound as korichnevogo (175 mg, 98%).

APCI (multimode) m/z: 621 [M+H].

Stage (b) N-{CIS-4-[1-(1-Benzyl-1H-indazol-5-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

To a solution of N-{CIS-4-[({2-[(1-benzyl-1H-indazol-5-yl)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (rate £ 0.162 g, 0.26 mmol) in N,N-dimethylformamide (3 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,163 g of 1.31 mmol) and sodium hydride in mineral oil (60% mass./mass., 0,040 g of 1.31 mmol). The reaction mixture then was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by the addition of brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layers were then washed two times with brine (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a red oil. This substance was purified HPLC with reversed phase with obtaining specified in the title compound as a brown solid (31 mg, 18%).

1H NMR (400 MHz, DMSO-d6) 8.85-8.82 (1H, m), 8.53-8.50 (1H, m), 8.43 (1H, s), 8.33-8.29 (1H, m), 8.17 (1H, d), 7.83-7.71 (4H, m), 7.53-7.46 (1H, m), 7.37-7.25 (6H, m), 5.71 (2H, s), 4.92-4.82 (1H, m), 4.19-4.12 (1H, m), 2.65-2.54 (2H, m), 2.05-1.97 (2H, m), 1.77-1.60 (4H, m).

APCI (multimode) m/z: 647 [M+H].

Example 38

6-Fluoro-N-{CIS-4-[6-fluoro-1-(1-METI the piperidine-4-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage a) 5-fluoro-2-[(1-methylpiperidin-4-yl)amino]nicotinic acid

Was added 4-amino-N-methylpiperidine (0,2602 g, 2.28 mmol), potassium carbonate (0,378 g, 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) to perelyaeva solution of 2-chloro-5-fornicating acid (0.4 g, 4,56 mmol) in 1-methyl-2-pyrrolidinone (5 ml). The solution was heated to 120°C for 3 h, then left to cool and mixed for 48 h, then sprayed directly onto the SCX column. The column was washed with 200 ml of methanol, then was suirable 100 ml of 3.5 n ammonia/methanol to obtain a crude product as a yellow oil. This substance was dissolved in methanol (25 ml), loaded on D-OH resin (4 ml), washed with methanol and then was suirable using 10%acetic acid in methanol (50 ml). The acid layer was concentrated to obtain specified in the subtitle compound as a colourless solid (100 mg, 17%).

ARC (multimode) m/z: 254 [M+H].

Stage (b) tert-butyl{CIS-4-[({5-fluoro-2-[(1-methylpiperidin-4-yl)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}carbamate

To a suspension of 5-fluoro-2-[(1-methylpiperidin-4-yl)amino]nicotinic acid (0.1 g, 0.40 mmol), triethylamine (0,120 g, 0,165 ml, 1,19 mmol) and tert-butyl methyl ether (4-aminocyclohexane)carbamino acid (is 0.102 who, 0.47 mmol) in acetonitrile (0.5 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,151 g, 0,3019 ml, 50%solution in butyl acetate, 0.47 mmol). The reaction mixture was stirred for 60 min at room temperature, then added three equivalents of triethylamine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was suppressed by addition of water (50 ml) and was extracted with ethyl acetate (3×50 ml), then dried and concentrated in vacuum. The residue was purified column flash chromatography, elwira 5%methanol in DCM to obtain specified in the title compound as a yellow oil (53 mg, 30%).

APCI (multimode) m/z: 450 [M+H].

Stage (C) tert-Butyl{CIS-4-[6-fluoro-1-(1-methylpiperidin-4-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-α]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

To a solution of tert-butyl{CIS-4-[({5-fluoro-2-[(1-methylpiperidin-4-yl)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}carbamate (0,058 g, 0.13 mmol) in N,N-dimethylformamide (1 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,105 g of 0.65 mmol) and sodium hydride in mineral oil (60% wt./mass., it was 0.026 g of 0.65 mmol). The reaction mixture then was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was extinguished add is the group of the brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layers were then washed two times with brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a yellow oil. The residue was purified column flash chromatography, elwira 5%methanol in DCM to obtain specified in the subtitle compound as a yellow oil (45 mg, 77%).

APCI (multimode) m/z: 476 [M+H].

Stage (b) 6-Fluoro-N-{CIS-4-[6-fluoro-1-(1-methylpiperidin-4-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

tert-Butyl{CIS-4-[6-fluoro-1-(1-methylpiperidin-4-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0,045 g, 0.09 mmol) suspended in 4 M HCl/dioxane (0.5 ml, 2 mmol) during 30 min, then the solution was concentrated in vacuo, was dissolved in N,N-dimethylformamide (0.5 ml) and added dropwise to a pre-mixed (within 10 min) of a mixture of 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,017 g 0,095 mmol), N,N-diisopropylethylamine (0,034 g, 0.38 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (0.036 g, 0,095 mmol) in dry N,N-dimethylformamide (1 ml). The solution was left to mix overnight, then treated between ethyl acetate and water (3×50 ml, 50 ml). The organic layers were dried (magnesium sulfate) and concentrated in vacuo, and the residue was purified HPLC with bresennol phase with obtaining specified in the title compound as a colourless solid (6 mg, 12%).

1H NMR (400 MHz, DMSO-d6) 8.86-8.74 (2H, m), 8.39 (1H, s), 8.25 (1H, m), 8.28-8.21 (1H, m), 7.88-7.80 (1H, m), 7.75 (1H, d), 7.53-7.45 (1H, m), 5.24-5.13 (1H, m), 4.90-4.78 (1H, m), 2.92-2.70 (4H, m), 2.69-2.53 (2H, m), 2.03-1.93 (4H, m), 1.71 (2H, t), 1.57 (4H, d), 2.20 (3H, s).

APCI (multimode) m/z: 538 [M+H].

Example 39

N-{CIS-4-[1-[3-(Dimethylamino)propyl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

Stage (a) 2-{[3-(Dimethylamino)propyl]amino}-5-fornicative acid

Added 3-dimethylaminopropylamine (0,233 g, 2.28 mmol), potassium carbonate (0,378 g, is 2.74 mmol), copper (0.015 g, 0.23 mmol) and copper bromide (I) (0,033 g, 0.23 mmol) to a stirred solution of 2-chloro-5-fornicating acid (0.4 g, 4,56 mmol) in N,N-dimethylformamide (5 ml). The solution was heated to 120°C for 2 h, then was cooled and distributed between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried, concentrated, dissolved in methanol (50 ml) and was applied to a 20 g SCX column, washed with additional methanol (100 ml) and was suirable 3,5 N. ammonia in methanol to give, after concentration, specified in the subtitle compound as a brown oil (423 mg, 77%).

APCI (multimode) m/z: 240 [M+H].

Stage (b) tert-Butyl(CIS-4-{[(2-{[3-(dimethylamino)propyl]amino}-5-herperidin-3-yl)carbonyl]amino}cyclohexyl)carbamate

To a suspension of 2-{[3-(dimethylamino)propyl]amino}-5-fornicating acid (0,423 g of 1.75 mmol), triethylamine (1,47 ml, 10,52 mmol) and tert-butyl methyl ether (4-aminocyclohexane)carbamino acid (0,451 g, 2.51 mmol) in acetonitrile (2 ml) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,669 g of 1.34 ml, 50% masseratti in butyl acetate, 2.51 mmol). The reaction mixture was stirred for 60 min at room temperature, then added another equivalent of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (0,669 g of 1.34 ml, 50%of the mass. solution in butyl acetate, 2.51 mmol)and the mixture was stirred over night. The reaction mixture is then distributed between ethyl acetate (3×50 ml) and water (50 ml) to give the crude product as a red oil. The residue was purified column flash chromatography, elwira 5-10%methanol in DCM to obtain specified in the subtitle compound as an orange oil (320 mg, 41%).

APCI (multimode) m/z: 438 [M+H].

Stage (C) tert-Butyl{CIS-4-[1-[3-(dimethylamino)propyl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

To a solution of tert-butyl(CIS-4-{[(2-{[3-(dimethylamino)propyl]amino}-5-herperidin-3-yl)carbonyl]amino}cyclohexyl)carbamate (0,229 g, 0,523 mmol) in N.N-dimethylformamide (3 ml) at room temperature was added 1,1'-carbonadium the azole (0,401 g, 2,62 mmol) and sodium hydride in mineral oil (60% wt./mass., 0,099 g, 2,62 mmol). The reaction mixture then was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by adding to the brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layers were then washed two times with brine (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a yellow oil. The residue was purified column flash chromatography, elwira 5%methanol/DCM to obtain specified in the subtitle compound as a yellow oil (156 mg, 64%).

APCI (multimode) m/z: 464 [M+H].

Stage (d) N-{CIS-4-[1-[3-(Dimethylamino)propyl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

tert-Butyl ester {4-[1-(3-dimethylaminopropyl)-6-fluoro-2,4-dioxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidine-3-yl]cyclohexyl}carbamino acid (0,082 g, 0,177 mmol) suspended in 4 M HCl/dioxane (1 ml, 2 mmol) for 30 min, then concentrated in vacuo, was dissolved in N,N-dimethylformamide (1 ml) and added dropwise to a pre-mixed (within 10 minutes) a mixture of 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,032 g, 0,177 mmol), N,N-diisopropylethylamine (0,069 g, 0.71 mmol) and O-(7-asobancaria the ol-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (0,067 g, 0.71 mmol) in dry N,N-dimethylformamide (1 ml). The resulting solution was left to mix overnight, then treated with ethyl acetate (3×50 ml) and water (50 ml). The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (20 mg, 22%).

1H NMR (400 MHz, DMSO-d6) 8.83-8.78 (2H, m), 8.39 (1H, s), 8.28-8.22 (1H, m), 7.82-7.70 (2H, m), 7.53-7.46 (1H, m), 4.85 (1H, t), 4.28-4.13 (3H, m), 2.69-2.52 (2H, m), 2.30 (2H, t), 2.12 (6H, s), 2.03-1.96 (2H, m), 1.82-1.66 (4H, m), 1.62-1.53 (2H, m).

APCI (multimode) m/z: 526 [M+H].

Example 40

N-{CIS-4-[1-{3-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) 3-Amino-N-1-azabicyclo[2.2.2]Oct-3-ilasamaja acetic acid salt

(±)-3-Aminoquinuclidine the dihydrochloride (10 g, 0,067 mol) was dissolved in water (20 ml) and cooled to 0°C and slowly added sodium hydroxide (8 g, 0.22 mmol). Then added 1 ml aliquot of the solution of 3-nitrobenzotrifluoride (11 g, 0.07 mol) in dry acetonitrile (20 ml) for 10 minutes and the Mixture was left to mix for 20 min, and then was diluted with water (50 ml) and was extracted with chloroform (3×25 ml). The organic layer was then washed with solution of sodium carbonate (pH of 10.5) and concentrated to obtain the crude substance to the e then triturated in ether (100 ml) to give N-1-azabicyclo[2.2.2]Oct-3-yl-3-nitrobenzamide in the form of a colorless crystalline solid (11.2 g, 74%). It was used in the next stage without additional purification.

3-Amino-N-1-azabicyclo[2.2.2]Oct-3-ilasamaja acetic acid salt (11 g, 0.45 mol) was dissolved in ethanol (150 ml) and was first made at room temperature and a hydrogen pressure of 5 bar (5×105PA). After 8 h to the resulting suspension was added glacial acetic acid, and the mixture again was first made when hydrogen pressure of 3 bar (3×105PA) for 18 hours the Mixture was filtered, and the filtrate was concentrated in vacuum to obtain oil as crude product. It is then rubbed with a mixture of 2:1 isohexane/ether, then with ether and then with one isohexanol for 18 hours Specified in the subtitle compound was isolated as a colourless solid (11.3 g, 99%).

1H NMR (250 MHz, DMSO-d6) 8.09 (1H, d), 7.10-6.94 (3H, m), 6.67 (1H, ddd), 5.39-5.03 (2H, m), 3.93 (1H, d), 3.93 (1H, d), 3.15-3.04 (1H, m), 2.96-2.84 (1H, m), 1.95-1.73 (5H, m), 1.72-1.50 (3H, m), 1.43-1.21 (1H, m).

Stage (b) 2-({3-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}amino)-5-fornicative acid

This compound was obtained from 2-chloro-5-fornicating acid (0.4 g) and 3-amino-N-1-azabicyclo[2.2.2]Oct-3-ilasamaja manner similar to that described in Example 39 stage (a), obtaining specified in the subtitle compound in the form of not-quite-white solid (0.15 g, 17%).

APCI (multimode) m/z: 385 [M+H].

Stage (C) tert-is util-[CIS-4-({[2-({3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}amino)-5-herperidin-3-yl]carbonyl}amino)-cyclohexyl]carbamate

This compound was obtained from 2-({3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}amino)-5-fornicating acid (0.15 g) by the method similar to that described in Example 39 stage (b), obtaining specified in the subtitle compound as a yellow oil (0.167 g, 73%).

APCI (multimode) m/z: 581 [M+H].

Stage (d) tert-Butyl{CIS-4-[1-{3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

This compound was obtained from tert-butyl[CIS-4-({[2-({3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}amino)-5-herperidin-3-yl]carbonyl}amino)cyclohexyl]carbamate (0.167 g) by the method similar to that described in Example 39 stage (C), obtaining specified in the subtitle compound as a yellow oil (0,134 g, 78%).

APCI (multimode) m/z: 607 [M+H].

Stage (e) N-{CIS-4-[1-{3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide.

tert-Butyl{CIS-4-[1-{3-[(1-azabicyclo[2.2.2]Oct-3-ylamino)carbonyl]-phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0,086 g, 0.14 mmol) suspended in 4 M HCl/dioxane (1 ml, 2 mmol) for 30 min, then concentrated in vacuo, was dissolved in N,N-dimethylformamide (1 is l) and added dropwise to a pre-mixed (within 10 min) of a mixture of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0,026 g, 0.14 mmol), N,N-diisopropylethylamine (0,098 ml, or 0.57 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (0,054 g, 0.14 mmol) in dry N,N-dimethylformamide (1 ml). The resulting solution was left to mix overnight, then treated between ethyl acetate (3×50 ml) and water (50 ml). The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (10 mg, 11%).

1H NMR (400 MHz, DMSO-d6) 8.84-8.76 (3H, m), 8.39 (1H, s), 8.25 (1H, dd), 7.83-7.70 (3H, m), 7.55-7.45 (1H, m), 4.85 (1H, t), 4.29-4.13 (4H, m), 2.69-2.52 (2H, m), 2.35-2.27 (4H, m), 2.03-1.96 (4H, m), 1.82-1.65 (7H, m), 1.62-1.53 (3H, m).

APCI (multimode) m/z: 526 [M+H].

Example 41

6-Fluoro-N-{CIS-4-[6-fluoro-1-[3-(2-morpholine-4-ylethoxy)phenyl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage a) 5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]-amino}nicotinic acid

This compound was obtained from 2-chloro-5-fornicating acid (0.4 g) and 3-(2-morpholine-4-ylethoxy)aniline (available from Maybridge) in the manner similar to that described in Example 39 stage (a), obtaining specified in the subtitle compound as a pale yellow solid (0,131 g, 13%).

APCI (multimode) m/z: 362 [M+H].

Stage (b) tert-butyl(CIS-4-{[(5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}pyridine-3-yl)ka is bonyl]amino}cyclohexyl)carbamate

This compound was obtained from 5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}nicotinic acid (0,131 g) by the method similar to that described in Example 39 stage (b), obtaining specified in the subtitle compound as a yellow oil (0,098 mg, 48%).

APCI (multimode) m/z: 458 [-Vos, M+N].

Stage (C) N-(CIS-4-Aminocyclohexane)-5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}nicotinamide

To a solution of tert-butyl(CIS-4-{[(5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}pyridine-3-yl)carbonyl]amino}cyclohexyl)carbamate (0,098 g, 0,176 mmol) in N,N-dimethylformamide (1 ml) at room temperature was added 1,1'-carbonyldiimidazole (0,142 g, 0.88 mmol) and sodium hydride in mineral oil (60% wt./mass., 0.035 g, 0.88 mmol). The reaction mixture then was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours LCMS analysis showed that the main peak meets the Sun unprotected original substance. The reaction mixture was suppressed by the addition of brine (50 ml) and was extracted with ethyl acetate (3×50 ml). The organic layers were then washed two times with brine (50 ml), dried anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain specified in the subtitle compound (0.07 g, 94%) as a yellow oil.

APCI (multimode) m/z: 458 [M+H].

Stage (d) 6-Fluoro-N-(CIS-4-{[(5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}pyridine-3-yl)carbonyl]amino}cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

To a mixture of 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,028 g, 0.15 mmol) and N,N-diisopropylethylamine (0,079 g, 0,107 ml, 0.61 mmol) in dry N,N-dimethylformamide (1 ml) was added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,058 g, 0.15 mmol). The mixture was left to mix for 10 min at room temperature. To this mixture was added N-(CIS-4-aminocyclohexane)-5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}nicotinamide (0.07 g, 0.15 mmol)dissolved in dry N,N-dimethylformamide (1 ml)and the mixture was stirred over night. The reaction mixture was suppressed by addition of water (50 ml), then was extracted using ethyl acetate (3×50 ml). The organic layers were dried and concentrated to obtain specified in the subtitle compound as a yellow oil (0,009 g, 47%).

APCI (multimode) m/z: 584 [M+H].

Stage (d) 6-Fluoro-N-{CIS-4-[6-fluoro-1-[3-(2-morpholine-4-ylethoxy)phenyl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide.

To a solution of 6-fluoro-N-(CIS-4-{[(5-fluoro-2-{[3-(2-morpholine-4-ylethoxy)phenyl]amino}pyridine-3-yl)carbonyl]amino}cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide (0,093 g, 0.15 mmol) in N,N-dimethylformamide (2 ml) with whom atoi temperature was added 1,1'-carbonyldiimidazole (0,123 g, 0.75 mmol) and sodium hydride in mineral oil (60% wt./mass., 0.03 g, 0.75 mmol). The reaction mixture was heated to 70°C for 30 min, then cooled to room temperature and was stirred for a further 48 hours, the Reaction mixture was suppressed by adding to the brine (50 ml), and extracted with ethyl acetate (3×50 ml). The organic layers were then washed two times with brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a yellow oil. The residue was purified HPLC with reversed phase with obtaining specified in the title compound as a white solid (12 mg, 12%).

1H NMR (400 MHz, CD3OD) 8.65-8.13 (4H, m), 7.71-7.23 (4H, m), 7.14-6.78 (4H, m), 5.06-4.75 (3H, m), 4.27-4.08 (4H, m), 2.84-2.69 (4H, m), 2.61-2.49 (4H, m), 2.17-2.06 (2H, m), 1.87-1.64 (4H, m).

APCI (multimode) m/z: 646 [M+H].

Example 42

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(phenylthio)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To a stirred solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0,078 mmol), copper iodide (I) (0.0015 g, 0,008 mmol) and potassium carbonate (of 0.022 g, 0.16 mmol) in an atmosphere of nitrogen was added ethylene glycol (0,010 g, 0,009 ml, 0.16 mmol), isopropanol (0.5 ml) and thiophenol (0,009 g 0,008 ml 0,078 mmol). The reaction is th the mixture was heated up to 80°C for 16 h, then cooled and treated with ethyl acetate and brine (50 ml each). The organic layer was washed 1 N. solution of sodium carbonate, then dried with sodium sulfate and concentrated to obtain the crude product as a yellow oil, which was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (0.036 g, 62%).

1H NMR (400 MHz, DMSO-d6) 8.86-8.83 (1H, m), 8.60 (1H, d), 8.43 (1H, s), 8.32-8.27 (1H, m), 7.80-7.74 (2H, m), 7.55-7.48 (2H, m), 7.43-7.37 (4H, m), 7.36-7.29 (3H, m), 4.90-4.79 (1H, m), 4.20-4.10 (1H, m), 2.66-2.52 (2H, m), 2.05 1.95 (3H, m), 1.76-1.58 (4H, m).

APCI (multimode) m/z: 625 [M+H].

Example 43

tert-Butyl{CIS-4-[6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The palladium (II) acetate (0,0058 g, was 0.026 mmol) and 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (0,021 g, 0,052 mmol) were mixed in acetonitrile (2 ml) for 10 min, then was added water (1 ml) and potassium carbonate (0,107 g, 0.78 mmol). Then to the mixture was added 4-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine (0,078 g, 0.26 mmol), then at the end of tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.15 g, 0.26 mmol)and the reaction mixture was heated up to 80°C within 5 hours the Reaction mixture was cooled and filtered through a Chemelut cartridge and then purified HPLC with reversed phase (column Xterra, 60-40 aqueous ammonia in acetonitrile) to obtain the specified title compound as a colourless solid (44 mg, 2%).

1H NMR (400 MHz, DMSO-d6) 8.59 (1H, d), 8.29 (1H, m), 7.67-7.54 (2H, m), 7.51-7.29 (6H, m), 6.47 (1H, s), 4.81-4.69 (1H, m), 3.58-3.52 (1H, m), 3.45-3.37 (4H, m), 3.35 (2H, s), 2.65-2.51 (2H, m), 2.34-2.20 (4H, m), 1.94-1.85 (2H, m), 1.56-1.34 (13H, m).

APCI (multimode) m/z: 630 [M+H].

Example 44

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.65 g, 1,22 mmol) was dissolved in 0.25 ml of dioxane was then added 4.0 M hydrogen chloride in 1,4-dioxane (5 ml, 10 mmol). The solution was left to mix overnight, then the solvent/Hcl was removed in vacuum to obtain specified in the title compound as an orange solid (550 mg, 96%).

1H NMR (400 MHz, DMSO-d6) 8.57-8.50 (1H, m), 8.27-8.20 (1H, m), 7.78-7.30 (12H, m), 4.86-4.76 (1H, m), 3.78-3.64 (1H, m), 3.56-3.46 (4H, m), 2.66-2.43 (6H, m), 2.00-1.88 (2H, m), 1.86-1.73 (2H, m), 1.70-1.60 (2H, m).

APCI (multimode) m/z: 630 [M+H].

Example 45

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-(4'-methylbiphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) tert-Butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]is eremein-3(2H)-yl]cyclohexyl}carbamate

1,1'-Bis(diphenylphosphino)ferrocene (0,010 g of 0.017 mmol) and chloride (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (0,013 g 0,034 mmol) was dissolved in dimethyl sulfoxide (0.5 ml) and left to mix for 10 min, then was added potassium acetate (is 0.102 g, 1.04 mmol), Tibor-pinacolone ether (0,096 g, 0.38 mmol) and tert-butyl{4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.2 g, 0.35 mmol), then filled with nitrogen. Then was added dimethylsulfoxide (0.5 ml)and the solution was heated up to 80°C overnight, and then the solution was cooled and distributed between water (50 ml) and ethyl acetate (50 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a brown oil, which was purified HPLC with reversed phase (column Xterra, 60-40 aqueous ammonia in acetonitrile) to obtain specified in the subtitle compound as a colourless solid (60 mg, 30%).

APCI (multimode) m/z: 581 [M+H].

Stage (b) tert-Butyl{CIS-4-[6-fluoro-1-(4'-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The palladium (II) acetate (0.002 g, 0.01 mmol) and 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (0,009 g, 0.02 mmol) were mixed together in acetonitrile (0.5 ml) for 10 min. To the floor is built to the solution was added tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.06 g, 0.1 mmol) and potassium carbonate (0,043 g, 0.3 mmol) in water (0.5 ml). Then were added 4-bromthymol (0,021 g, 0.12 mmol)and the reaction mixture was heated up to 80°C for 1 h, then was cooled and distributed between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified HPLC with reversed phase (column Xbridge, 40:30 aqueous ammonia in acetonitrile) to obtain specified in the subtitle compound as a colourless solid (18 mg, 34%).

APCI (multimode) m/z: 545 [M+H].

Stage (C) 3-(CIS-4-aminocyclohexane)-6-fluoro-1-(4'-methylbiphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

tert-Butyl{CIS-4-[6-fluoro-1-(4'-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.015 g, 0,028 mmol) suspended in 4.0 M hydrogen chloride in 1,4-dioxane (0.5 ml, 2 mmol) and left to stand at room temperature for 30 minutes the Solvent was then removed in vacuum to obtain specified in the title compounds as colorless solids (7 mg, 81%).

1H NMR (400 MHz, CD3OD) 8.39 (1H, d), 8.27-8.23 (1H, m), 7.74-7.69 (1H, m), 7.61-7.48 (4H, m), 7.28-7.21 (4H, m), 5.05-4.94 (1H, m), 3.57-3.52 (1H, m), 2.67-2.54 (2H, m), 2.37 (3H, s), 2.09-1.85 (4H, m), 1.82-1.74 (2H, m).

APCI (multimode) m/z: 630 [M+H].

Example 46

N-{CIS-4-[6-Fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-hydroxycyclopent carboxamid.

O-(7-Asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,079 g, 0.21 mmol) was added to a solution of 1-hydroxy-1-cyclopropanecarboxylic acid (0,021 g, 0.21 mmol) and N,N-diisopropylethylamine (0,073 g 0,099 ml, or 0.57 mmol) in N,N-dimethylformamide (1 ml) and left to mix for 10 min, then was added 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.1 g, 0,19 mmol). After 1 h stirring an additional portion of 1-hydroxy-1-cyclopropanecarboxylic acid (10 mg, 0.1 mmol) activated by O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (40 mg, 0.1 mmol)and the reaction mixture was added diisopropylethylamine (50 μl, 0.1 mmol) in DMF (0.2 ml) and left to mix for another hour. The reaction mixture was treated with ethyl acetate (50 ml) and water (50 ml)and the aqueous layer was additionally extracted with ethyl acetate (50 ml). The organic phase was dried anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude substance in the form of a yellow foam. The residue was purified HPLC with reversed phase (ammonia/Xterra 70-50 water) to produce specified in the title compound as a colourless solid (34 mg, 25%).

1H NMR (400 MHz, DMSO-d6) 8.65-8.55 (m, 1H), 8.35-8.29 (m, 1H), 7.67-7.55 (m, 2H), 7.52-7.30 (m, 6H), 6.50-6.35 (m, 1H), 4.89-4.79 (m, 1H), 4.05-3.96 (m, 1H), 3.46-3.38 (m, 4H, 2.62-2.46 (m, 2H), 3.35 (s, 2H), 2.34-2.20 (m, 4H), 1.84-1.74 (m, 2H). 1.69-1.55 (m, 4H), 1.06-0,99 (m, 2H), 0.88 to to 0.80 (m, 2H).

APCI (multimode) m/z: 614 [M+H].

Example 47

3-(CIS-4-Aminocyclohexane)-1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) tert-Butyl{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

Acetonitrile (7.5 ml) was added to a mixture of palladium (II) acetate (0,017 g 0,078 mmol) and 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (0,064 g, 0.16 mmol)and the mixture was stirred at room temperature for 10 min, was added potassium carbonate (0,643 g, 4.65 mmol)dissolved in water (5 ml), then dimethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amine (540 mg, of 1.85 mmol) and then tert-butyl-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1.5 g, 3.1 mmol). The reaction mixture was heated up to 80°C during the night. Then cooled and the solution was passed through a column Chemelut, elwira DCM (100 ml), then 10%mixture of methanol/DCM. Organic solvents were concentrated to obtain specified in the subtitle compound as a pale yellow foam (729 mg, 69%).

1H NMR (400 MHz, DMSO-d6) 8.58 (1H, a), 8.29 (1H, d), 7.79-7.69 (2H, m), 7.65-7.59 (3H, m), 7.40-7.33 (3H, m), 6.55-6.44 (1H, m), 4.81-4.71 (1H, m), 3.59-3.51 (1H, m), 3.43-3.41 (2H, m), 3.29-3.28 (6H, m), 2.65-2.52 (2H, m), 1.94-1.87 (2H, m), 1.55-1.44 (4H, m), 1.40-1.35 (9H, m).

l (multimode) m/z: 588 [M+H].

Stage (b) 3-(CIS-4-Aminocyclohexane)-1-{4'-[(dimethylamino)methyl]-biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.534 g, of 0.91 mmol) was dissolved in a small amount of dioxane, and then was added hydrogen chloride, 4.0 M in 1,4-dioxane (2.1 g, 2 ml, 5.9 mmol). The solution was left to mix at room temperature overnight, then the solvent was removed in vacuum. The residue was stirred in ether (25 ml) for 1 hour, then collected by filtration and washed with additional ether to obtain specified in the title compound as a colourless solid (377 mg, 74%).

1H NMR (40 MHz, DMSO-d6) 11.10 (1H, s), 8.67-8.53 (1H, m), 8.36-8.25 (1H, m), 8.19-7.98 (3H, m), 7.86-7.57 (7H, m), 7.47-7.34 (1H, m), 4.87-4.72 (1H, m), 4.38-4.22 (2H, m), 3.61-3.51 (1H, m), 2.74-2.64 (6H, m), 2.59-2.49 (2H, m), 2.04-1.93 (2H, m), 1.82-1.57 (4H, m).

APCI (multimode) m/z: 488 [M+H].

Example 48

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-(2-morpholine-4-retil)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Acetonitrile (1 ml) was added to a mixture of palladium (II) acetate (0.004 g, to 0.016 mmol) and 2-(dicyclohexylphosphino)-2',6'-dimetho the si-1,1'-biphenyl (0,013 g, 0,031 mmol)and the mixture was stirred at room temperature for 10 minutes was Added potassium carbonate (0,065 g, 0.47 mmol)dissolved in water (0.75 ml), then 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}morpholine (82 mg, 0.23 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.1 g, 0.16 mmol). The reaction mixture was heated to 80°C. overnight, then cooled and passed through a column Chemelut to obtain crude product, which was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (45 mg, 41%).

1H NMR (400 MHz, DMSO-d6) 8.78 (1H, m), 8.59 (1H, d), 8.39-8.30 (2H, m), 7.77-7.56 (6H, m), 7.47-7.30 (4H, m), 4.93-4.82 (1H, m), 4.20-4.06 (2H, m), 3.60-3.54 (4H, m), 2.81-2.73 (2H, m), 2.68-2.48 (4H, m), 2.45-2.39 (4H, m), 2.04-1.96 (2H, m), 1.78-1.61 (4H, m).

APCI (multimode) m/z: 706 [M+H].

Example 49

tert-Butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-carboxylate

A solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,069 g, 0.11 mmol), tert-butyl-1-piperidinecarboxylate (0,031 g, 0,17 mmol) and acetic acid (2 drops) in 1,2-dichloroethane (2 ml) peremeshivaniya room temperature for 30 minutes Added triacetoxyborohydride sodium (0.035 g, 0,17 mmol)and the reaction mixture was stirred for 1 h Then the solution was diluted with DCM (50 ml) and washed with water (50 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product as a colourless oil, which was purified HPLC with reversed phase with obtaining specified in the title compound as a colourless solid (16 mg, 18%).

1H NMR (400 MHz, DMSO-d6) 8.82-8.76 (1H, m), 8.59 (1H, d), 8.38-8.30 (2H, m), 7.79-7.57 (7H, m), 7.47-7.35 (4H, m), 4.92-4.83 (1H, m), 4.20-4.13 (1H, m), 3.53-3.49 (2H, m), 3.33-3.28 (4H, m), 2.69-2.52 (2H, m), 2.36-2.30 (4H, m), 2.06-1.95 (2H, m), 1.78-1.60 (4H, m), 1.41-1.34 (9H, m).

APCI (multimode) m/z: 791 [M+H].

Example 50

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-(2'-methylbiphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) tert-Butyl{CIS-4-[6-fluoro-1-(2'-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

This compound was obtained from 2-bromthymol (0.035 g) and tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate manner similar to that described in Example 45 stage (b) to produce specified in the subtitle compound as a pale yellow solid (0,022 g, 23%).

ARC (mu is Titova) m/z: 444 [M+H-BOC].

Stage (b) 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-(2'-methylbiphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

This compound was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate manner similar to that described in Example 45 stage (C), obtaining specified in the title compound as a colourless solid (0,011 g, 73%).

1H NMR (400 MHz, DMSO-d6) 8.63 (1H, s), 8.33-8.25 (1H, m), 7.76-7.50 (4H, m), 7.46-7.18 (7H, m), 4.84-4.71 (1H, m), 3.42-3.35 (1H, m), 2.63-2.49 (2H, m), 2.28-2.24 (3H, m), 1.95-1.86 (2H, m), 1.84-1.69 (2H, m), 1.68-1.59 (2H, m).

APCI (multimode) m/z: 445 [M+H].

Example 51

N-[CIS-4-(1-Biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-1-(dimethylamino)cyclopropanecarboxamide

A mixture of 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.04 g, 0,078 mmol), formaldehyde (0.025 g, 0,025 ml of 0.333 mmol) in 1,2-dichloroethane (2 ml) was left to mix for 30 min, then was added triacetoxyborohydride sodium (0.036 g, mmol). The mixture was stirred for 16 h at room temperature. Added additional portion of formaldehyde (0.025 g, mmol)was left to mix for 10 minutes, then added another triacetoxyborohydride sodium (0.036 g, 0,17 mmol). The suspension was left to mix for 32 h, then diluted with DCM (0 ml) and washed with water. The organic layer was dried and concentrated in vacuo, and the residue was purified HPLC with reversed phase (Xterra, 60-40 of 0.2%aqueous ammonia in acetonitrile) to obtain specified in the subtitle compound as a colourless solid (9 mg, 21%).

1H NMR (400 MHz, DMSO-d6) 8.61-8.58 (1H, m), 8.34-8.28 (1H, m), 8.11-8.06 (1H, m), 7.80-7.58 (4H, m), 7.52-7.44 (2H, m), 7.42-7.35 (2H, m), 4.89-4.78 (1H, m), 3.98-3.91 (1H, m), 2.65-2.50 (2H, m), 1.82 (2H, d), 1.68-1.55 (4H, m), 0,98-of 0.90 (4H, m).

APCI (multimode) m/z: 542 [M+H].

Example 52

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of hydrogen chloride in dioxane (4.0m, 1,334 ml of 5.34 mmol) was added dropwise to a stirred solution of tert-butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-the carboxylate (256 mg, 0.32 mmol) in 1,4-dioxane (1,432 ml) at 25°C. the resulting solution was stirred at 25°C for 2 h the Solvent was evaporated to dryness to obtain specified in the title compound as a colourless solid (234 mg, 95%).

1H NMR (400 MHz, DMSO-d6) 8.96 (1H, s), 8.59 (2H, d), 8.55 (2H, s), 8.33 (1H, dd), 7.98 (1H, s), 7.84-7.73 (8H, m), 7.66-7.59 (2H, m), 7.44-7.39 (1H, m), 4.88 (2H, s), 4.76-4.48 (11H, m), 4.45-4.40 (4H, m), 4.17-4.11 (1H, m), 3.51-3.42 (8H, m), 2.69-2.58 (2H, m), 2.09-2.01 (2H,m), 1.77-1.61 (6H, m).

APCI (multimode) m/z: 691 [M+H].

Example 53

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-(3-pyridin-2-ylphenyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl{CIS-4-[6-fluoro-2,4-dioxo-1-(3-pyridin-2-ylphenyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

This compound was obtained from 2-bromopyridine (0.037 ml) and tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate manner similar to that described in Example 45 stage (b), obtaining specified in the subtitle compound as a colourless solid (to 0.060 g, 44%).

APCI (multimode) m/z: 532 [M+H].

Stage (b) 3-(CIS-4-aminocyclohexane)-6-fluoro-1-(3-pyridin-2-ylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

This compound was obtained from tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-(3-pyridin-2-ylphenyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.06 g) by the method similar to that described in Example 45 stage (C), obtaining specified in the subtitle compound as a colourless solid (0,046 g, 94%).

APCI (multimode) m/z: 432 [M+H].

Stage (b) 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-(3-pyridin-2-ylphenyl)-1,4-digitop the Rideau[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

Was added 3-(CIS-4-aminocyclohexane)-6-fluoro-1-(3-pyridin-2-ylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (46 mg, 0.11 mmol) to a stirred solution of O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (45 mg, 0.12 mmol), 6-torymidae[1,2-a]pyridine-2-carboxylic acid (25 mg, 0.12 mmol) and N-ethyldiethanolamine (57 μl, 0.32 mmol) in N,N-dimethylformamide (751 ml) at 25°C. the resulting solution was stirred at 25°C for 2 h, the Reaction mixture then was diluted with ethyl acetate (50 ml) and washed with water (150 ml). The aqueous layer was back extracted with ethyl acetate (1×50 ml)and the combined organic layer was dried over sodium sulfate, filtered and evaporated to obtain crude product.

The crude product was purified preparative LCMS to column (Waters X-Terra, using the gradient 60-40% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (24 mg, 59%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 8.84-8.79 (1H, m), 8.68-8.64 (1H, m), 8.59-8.55 (1H, m), 8.40 (1H, s), 8.35-8.30 (1H, m), 8.19-8.13 (1H, m), 8.01-7.97 (1H, m), 7.94-7.89 (1H, m), 7.77-7.71 (2H, m), 7.65 (1H, t), 7.50-7.42 (2H, m), 7.41-7.36 (1H, m), 4.93-a 4.83 (1H, m), 4.20-4.13 (1H, m), 2.68-2.54 (2H, m), 2.05-1.97 (2H,m), 1.77-1.62 (4H, m).

APCI (multimode) m/z: 594 [M+H].

Example 54

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{[(3R)-3-hydroxypyrrolidine-1-yl]methyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihyd is pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (312 mg, 0.50 mmol) and (R)-(+)-3-hydroxypyrrolidine (0,042 ml, 0.50 mmol) was dissolved in 1,2-dichloroethane (5 ml)and the solution left to mix for 10 minutes Then add triacetoxyborohydride sodium (160 mg, 0.75 mmol) for 10 min in air atmosphere. The resulting suspension was stirred at 25°C for 16 hours, the Reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). Organic matter was dried over sodium sulfate, filtered and evaporated to obtain crude product. The crude product was purified preparative LCMS to column (Waters X-Terra, using the gradient 60-40% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (141 mg, 41%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 8.78 (1H, dd), 8.59 (1H, d), 8.38-8.30 (2H, m), 7.79-7.57 (6H, m), 7.47-7.35 (4H, m), 4.92-4.83 (1H, m), 4.66 (1H, d), 4.23-4.13 (2H, m), 3.58 (2H, d), 3.31-3.27 (1H, m), 2.71-2.51 (3H, m), 2.45-2.38 (1H, m), 2.34-2.29 (1H, m), 2.04-1.95 (3H, m), 1.78-1.61 (4H, m), 1.58-1.49 (1H, m).

APCI (multimode) m/z: 692 [M+H].

Example 55

N-{CIS-4-[1-(4'-{[tert-Butyl(methyl)amino]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-is torymidae[1,2-a]pyridine-2-carboxamide

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (300 mg, 0.48 mmol) and N-tert-butylamine (by 0.055 ml, 0.46 mmol) was dissolved in 1,2-dichloroethane (4.6 ml)and the solution was left to mix for 10 minutes Then added over a period of 10 min in an air atmosphere triacetoxyborohydride sodium (145 mg, 0.69 mmol). The resulting suspension was stirred at 25°C for 16 hours Added another equivalent of N-methyl-tert-butylamine (by 0.055 ml, 0.46 mmol) and triethylorthoformate (0,200 ml and 1.83 mmol). The reaction mixture was left to mix for another hour, then added another triacetoxyborohydride sodium (145 mg, 0.69 mmol)and the reaction mixture was stirred for 16 hours the Crude substance was dissolved in methanol (5 ml) and loaded onto a 20 g SCX cartridge. Impurities were washed with methanol (100 ml) and discarded. The product was suirable 3,5 N. methanolic ammonia (100 ml) and evaporated in vacuo to obtain a yellow residue. The crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 60-40% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (47 mg, 15%) as a colourless solid.

1H NMR (400 MHz, DMSO-d ) 8.79 (1H, t), 8.60 (1H, t), 8.40-8.29 (2H, m), 7.82-7.57 (6H, m), 7.50-7.32 (4H, m), 4.97-4.83 (1H, m), 4.22-4.11 (1H, m), 3.57-3.48 (2H, m), 2.69-2.49 (2H, m), 2.07-1.95 (5H, m), 1.79-1.61 (4H, m), 1.12 (9H, s).

APCI (multimode) m/z: 692 [M+H].

Example 56

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl{CIS-4-[6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

This compound was obtained from 2-(4-bromophenoxy)ethanol (0,112 g) and tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate manner similar to that described in Example 45 stage (b), obtaining specified in the subtitle compound as a colourless solid (0,088 g, 43%).

APCI (multimode) m/z: 491 [M+H-Boc].

Stage (b) 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

This compound was obtained from tert-butyl{CIS-4-[6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0,088 g) by the method similar to that described in Example 45 stage (C), obtaining specified in Pozega the connection information in the form of a colorless solid (0,064 g, 88%).

APCI (multimode) m/z: 491 [M+H].

Stage (b) 6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-(2-hydroxyethoxy)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (46 mg, 0.11 mmol) was added to a stirred solution of O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (45 mg, 0.12 mmol), 6-torymidae[1,2-a]pyridine-2-carboxylic acid (25 mg, 0.12 mmol) and N-ethyldiethanolamine (57 μl, 0.32 mmol) in N,N-dimethylformamide (751 ml) at 25°C. the resulting solution was stirred at 25°C for 2 h, the Reaction mixture then was diluted with ethyl acetate (50 ml) and washed with water (150 ml). The aqueous layer was back extracted with ethyl acetate (1×50 ml) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to obtain crude product. The crude product was purified preparative LCMS to colonc Waters X-Terra, using the gradient 60-40% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (24 mg, 59%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 8.79 (1H, dd), 8.59 (1H, d), 8.36 (1H, s), 8.32 (1H, dd), 7.77-7.66 (4H, m), 7.63-7.54 (3H, m), 7.47-7.41 (1H, m), 7.31 (1H, d), 7.03 (2H, d), 4.93-4.83 (2H, m), 4.20-4.13 (1H, m), 4.0 (2H, t), 3.73 (2H, q), 2.68-2.53 (2H, m), 2.04-1.96 (2H, m), 1.78-1.62 (4H, m).

APCI (multimode) m/z: 653 [M+H].

Example 57

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-({[(1R)-2-hydroxy-1-methylethyl]amino}-methyl) - biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (300 mg, 0.48 mmol) and (R)-(-)-2-amino-1-propanol (0,056 ml, 0.73 mmol) was dissolved in 1,2-dichloroethane (4.8 ml) and the solution was left to mix for 10 minutes Then add triacetoxyborohydride sodium (154 mg, 0.73 mmol) for 10 min in air atmosphere. The resulting suspension was stirred at 25°C for 16 hours, the Reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). Organic matter was dried over sodium sulfate, filtered and evaporated to obtain crude product. The crude product was purified preparative LCMS to column (Waters X-Terra, using the gradient 95-50% water and 0.2%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (57 mg, 17%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 8.81 (2H, dd), 8.74-8.65 (1H, m), 8.59 (1H, d), 8.39-8.33 (2H, m), 7.84-7.60 (8H, m), 7.48-7.41 (2H, m), 4.9-4.83 (1H, m), 4.25-4.14 (2H, m), 3.70-3.64 (1H, m), 3.56-3.50 (1H, m), 3.23-3.16 (1H, m), 2.68-2.56 (2H, m), 2.05-1.97 (2H, m), 1.78-1.63 (4H, m), 1.24 (3H, d).

APCI (multimode) m/z: 680 [M+H].

Example 58

3'-[6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-2-carboxylic acid

Stage (a) 6-Fluoro-N-{CIS-4-[6-fluoro-1-(2'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The palladium (II) acetate (0.035 g, 0.16 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,128 g, 0.31 mmol) were stirred together in acetonitrile (30 ml) for 10 min, then was added a solution of potassium carbonate (1.291 g, 9.34 mmol) in water (15 ml). Then added posledovatelno 2-formylphenylboronic acid (0,467 g, 3.11 mmol) and 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (2 g, 3.11 mmol). The resulting suspension was stirred at 80°C for 16 h, then was separated by filtration and washed with 100 ml of acetonitrile to obtain specified in the connection header (1,36 g, 70%) as a yellowish brown solid.

APCI (multimode) m/z: 621 [M+H].

Stage (b): 3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydrospiro what about[2,3-d]pyrimidine-1(2H)-yl]biphenyl-2-carboxylic acid

The sodium chlorite (70.0 mg, 0.77 mmol)dissolved in water (0.5 ml), was added to the stirred solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(2'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (200 mg, 0.32 mmol) and monobasic phosphate (97 mg, 0,81 mmol) in a mixture of DMSO (2 ml) and water (0.2 ml) over a period of time of 10 minutes in an air atmosphere. The resulting suspension was stirred at 25°C for 3 days. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and saturated brine (50 ml). Organics were dried over magnesium sulfate, filtered and evaporated to obtain crude product. This crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 75-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (81 mg, 40%) as a colourless solid.

Example 59

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{[4-(methylamino)piperidine-1-yl]methyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): tert-butyl[1-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-the]biphenyl-4-yl}methyl)piperidine-4-yl]methylcarbamate

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (300 mg, 0.48 mmol) and tert-butyl methyl(piperidine-4-yl)carbamate (155 mg, 0.73 mmol) was dissolved in 1,2-dichloroethane (4,576 ml) and this solution was stirred for 10 minutes. Then over a period of time of 10 minutes in air atmosphere was added triacetoxyborohydride sodium (145 mg, 0.69 mmol). The resulting suspension was stirred at 25°C for 16 hours Chlorinated solvent was removed in vacuum and the crude substance was dissolved in methanol (5 ml) and applied on a 20g cartridge SCX. Impurities were washed with methanol (100 ml) and discarded. The product was suirable 3,5 N. methanolic ammonia solution (100 ml) and evaporated in vacuo to obtain specified in the subtitle compound as a yellow residue (396 mg, 100%).

APCI (multimode) m/z: 719 [M+H-Boc].

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-{[4-(methylamino)piperidine-1-yl]methyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of hydrogen chloride (4 M/dioxane, 2,418 ml, 9,67 mmol) was added dropwise to a stirred solution of tert-butyl[1-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperidine-4 and who]methylcarbamate (396 mg, 0.48 mmol) in 1,4-dioxane (2 ml) at 25°C. the resulting solution was stirred at 25°C for 4 days. The solvent is evaporated to dryness and then was passed through SCX column, washing with methanol (100 ml) and elwira 3,5 N. ammonia with methanol (50 ml), to obtain the crude product as a yellow oil. This crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-50% water and 0.2% triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (70 mg, 20%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 8.96 (2H, s), 8.83 (1H, dd), 8.59 (1H, d), 8.42 (1H, s), 8.34 (1H, dd), 7.86-7.72 (5H, m), 7.66 (1H, t), 7.60 (2H, d), 7.51-7.42 (2H, m), 4.89 (1H, t), 4.35 (2H, s), 4.17 (1H, s), 3.55-3.48 (2H, m), 3.28-3.17 (1H, m), 3.08-2.97 (2H, m), 2.69-2.54 (4H, m), 2.27-2.17 (2H, m), 2.06-1.98 (2H, m), 1.81-1.62 (4H, m), 3.70-3.62 (4H, m).

APCI (multimode) m/z: 719 [M+H].

Example 60

N-{CIS-4-[6-Fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

Acetic anhydride (to 0.060 ml, 0.64 mmol) was added to a mixture of 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (169 mg, 0.32 mmol) and N-ethyldiethanolamine (0,111 ml, 0.64 mmol) in methanol (3,776 ml) at 25°C for a period of time of 1 minute in nitrogen atmosphere. Received dissolve is stirred at 25°C for 30 minutes. The reaction mixture was evaporated to dryness and pererestorani in ethyl acetate (50 ml), then washed with 1 M hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the title compound (135 mg, 74%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 7.60 (1H, d), 7.44 (1H, dd), 7.00 (1H, d), 6.77 (1H, t), 6.69-6.61 (3H, m), 6.55-6.49 (4H, m), 4.19-4.10 (1H, m), 3.20-3.14 (1H, m), 2.74-2.64 (6H, m), 1.92-1.79 (2H, m), 1.57-1.48 (4H, m), 1.20-1.14 (5H, m), 0,91-0,77 (4H, m).

APCI (multimode) m/z: 572 [M+H].

Example 61

N-{CIS-4-[6-Fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-hydroxybenzamide

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (182 mg, 0.34 mmol) was added in a pre-mixed solution (10 min) salicylic acid (52 mg, 0.38 mmol), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (144 mg, 0.38 mmol) and N,N-diisopropylethylamine (0,180 ml of 1.03 mmol) in DMF (1.7 ml) at 25°C. the resulting solution was stirred at 25°C for 2 h, the Reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (150 ml). The aqueous layer was extracted with ethyl acetate (1×50 ml) and the combined organic layer was dried over sulfate on the matter, was filtered and was evaporated to obtain crude product. This crude product was purified preparative LCMS to column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (27 mg, 12%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) At 8.62-8.55 (2H, m), 8.33 (1H, dd), 7.96 (1H, dd), 7.74-7.34 (7H, m), 6.98-6.86 (3H, m), 4.90-4.80 (1H, m), 4.39-4.28 (2H, m), 4.18-4.10 (1H, m), 3.82-3.59 (4H, m), 3.22-3.05 (4H, m), 2.79-2.57 (2H, m), 2.09-1.94 (2H, m), 1.78-1.56 (4H, m).

APCI (multimode) m/z: 650 [M+H].

Example 62

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-({[2-(methylamino)ethyl]amino}methyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): tert-butyl{2-[({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)amino]ethyl}methylcarbamate

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (200 mg, 0.32 mmol) and BOC-N-methylethylenediamine (0,053 ml, 0.29 mmol) was dissolved in 1,2-dichloroethane (3.5 ml) and the solution was stirred for 10 minutes Then over a period of time of 10 minutes in air utmost the re was added triacetoxyborohydride sodium (102 mg, 0.48 mmol). The resulting suspension was stirred at 25°C for 16 hours, the Reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). Organics were dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound (251 mg, 100%), which is transferred to the next stage of the reaction without additional purification.

APCI (multimode) m/z: 679 [M+H - Boc].

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-[4'-({[2-(methylamino)ethyl]amino}-methyl) - biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Hydrogen chloride (4 M/dioxane) (2,04 ml, 8,14 mmol) was added dropwise to stirred solution of tert-butyl{2-[({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)amino]ethyl}methylcarbamate (251 mg, 0.32 mmol) in 1,4-dioxane (3 ml) at 25°C in air atmosphere. The resulting solution was stirred at 25°C for 16 hours the Crude substance was dissolved in methanol (50 ml), acidified with acetic acid (0.5 ml) and applied to the cartridge 10g SCX. Impurities were washed with methanol (200 ml) and discarded. The product was suirable 1 N. methanolic ammonia solution (100 ml) and evaporated in vacuo to obtain the crude product as a yellow oil. This oil was then purified preparative LCMS to column (Waters X-Terra, is using the gradient 75-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (114 mg, 42%) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) 9.16-9.00 (2H, m), 8.82-8.78 (1H, m), 8.69-8.56 (3H, m), 8.39-8.32 (2H, m), 7.85-7.71 (4H, m), 7.70-7.56 (4H, m), 7.49-7.41 (2H, m), 4.87 (1H, s), 4.27 (2H, s), 4.17 (1H, s), 3.32-3.19 (4H, m), 2.70-2.52 (5H, m), 2.06-1.97 (2H, m), 1.78-1.62 (4H, m).

APCI (multimode) m/z: 679 [M+H].

Example 63

N-[CIS-4-(1-Biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]ndimethylacetamide

To a solution of 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g, 0.46 mmol) in dichloromethane (10 ml) was added DIEA (0.5 ml), then acetylchloride (0.04 ml, 0.46 mmol) and the mixture was stirred over night. The mixture was evaporated to dryness and the residue triturated with water (10 ml) to give a dark yellow solid, which was collected and purified by chromatography on silica, using a mixture of ethyl acetate:dichloromethane (2:8) as eluent, to obtain specified in the title compound as a colourless solid (96 mg, 43%).

1H NMR (400 MHz, DMSO-d6) δ 8.59 (1H, d), 8.30 (1H, dd), 7.68 (6N, m), 7.48 (2H, t), 7.39 (2H, t), 4.77 (1H, t), 3.78 (1H, s), 2.62 (2H, m), 1.86 (5H, m), 1.53 (4H, m)

APCI (multimode) m/z: 473,2 [M+H].

Example 64

1-Biphenyl-3-yl-3-[CIS-4-(dimethylamino)cyclohexyl]-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-pyrimidin-2,4(1H,3H)-dione (0.15 g, 0.34 mmol) in dichloroethane (10 ml) was added 38-40% aqueous solution of formaldehyde (0.1 ml), then triacetoxyborohydride sodium (0,144 mg of 0.68 mmol). This mixture was stirred for 2 h, evaporated to dryness and the residue was purified HPLC with reversed phase (25-95% acetonitrile in aqueous ammonia) to obtain the specified title compound (80 mg, 50%).

1H NMR (400 MHz, DMSO-d6) δ 8.58 (1H, d), 8.29 (1H, dd), 7.77 (1H, m), 7.71 (1H, m), 7.67 (2H, dd), 7.61 (1H, t), 7.48 (2H, m), 7.38 (2H, m), 4.82 (1H, m), 2.69 (2H, dd), 2.15 (6H, s), 2.04 (2H, d), 1.95 (1H, s), 1.39 (4H, m), 8.59 (1H, d), 8.30 (1H, m), 7.68 (6H, m), 7.48 (2H, t), 7.39 (2H, t), 4.77 (1H, t), 3.78 (1H, s), 2.62 (2H, m), 1.86 (5H, m), 1.53 (4H, m).

APCI (multimode) m/z: 459,2 [M+H].

Example 65

1-Amino-N-{CIS-4-[6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopentanecarboxylic, salt triptorelin

1-(BOC-amino)cyclopentanecarbonyl acid (0,082 g, 0.36 mmol), DIEA (0,063 ml, 0.36 mmol) and HATU (0,136 g, 0.36 mmol) in DMF (10 ml) was stirred for 10 minutes at room temperature. To this solution was added 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,190 g, 0.36 mmol) and the mixture was stirred over night. The mixture was poured into water (100 ml) and the crude intermediate compound was collected filter is receiving and dried in vacuum. This solid (0,210 g) was dissolved in 4.0 M hydrogen chloride in dioxane (10 ml) and left to stand for 1 h the Mixture was evaporated to dryness and purified HPLC with reversed phase (5-50% acetonitrile in water triperoxonane acid) to obtain the specified title compound (148 mg, 47%).

1H NMR (400 MHz, DMSO-d6) δ 8.59 (1H, d), 8.33 (1H, dd), 8.11 (3H, s), 7.77-7.38 (9H, m), 4.78 (1H, d), 4.44-2.55 (16H, m), 2.27 (1H, t), 2.02 (2H, d), 1.83 (5H, s), 1.66-1.47 (3H, m).

APCI (multimode) m/z: 641,3 [M+H].

Example 66

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-hydroxy-2'-[(4-methylpiperazin-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt triptorelin

Stage (a): 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

The complex of 1,1'-bis(diphenylphosphino)ferrocenyl-palladium(II)dichloromethane (1.009 g, 1,24 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0,685 g of 1.24 mmol) was stirred in DMSO (40 ml) at room temperature for 10 minutes. In an atmosphere of nitrogen was added 2-bromo-5-hydroxybenzaldehyde (5,00 g, 24,87 mmol), potassium acetate (7,28 g, 74,18 mmol) and LIBOR-pinacolone ether (8,16 g, 32,14 mmol). The reaction mixture was stirred for 16 h at 70°C, cooled and poured into water (300 ml). The resulting mixture was extracted into diethyl ether, washed with brine and dried over sulfa what Ohm sodium obtaining specified in the title compound (6.7 g, 109%) as a purple resin, which was used in the next stage without purification or analysis.

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

To a suspension of palladium acetate (8 mg, 0.04 mmol) in acetonitrile (2 ml) was added 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (to 0.032 g, 0.08 mmol) and the mixture was stirred at room temperature over a period of time of 10 minutes in nitrogen atmosphere. In the resulting solution was added potassium carbonate (0,323 g, 2.34 mmol)dissolved in water (1.6 ml)was then added 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0,290 g at 1.17 mmol) and 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,500 g, 0.78 mmol)and the resulting mixture was heated at 70°C for another 2 h, the Reaction mixture was diluted with ethyl acetate (15 ml) and washed with saturated brine (10 ml). The organic layer was dried over sodium sulfate and purified by chromatography on silica, using a mixture of ethyl acetate:dichloromethane (1:9) as eluent, to obtain specified in the title compound as a yellow-brown solid (195 mg, 40%).

1H NMR (400 MHz, DMSO-d6) δ 10.07 (1H, s), 9.91 (1H, s), 8.79 (1H, dd), 8.60 (1H, d), 8.37 (2H, s), 8.32 (Hz, 2H, dd), 7.75 (2H, dd), 7.54-7.39 (4H, m), 7.29 (1H, d), 7.17 (1H, dd), 4.85 (1H, t), 4.16 (1H, s), 2.71-2.54 (2H, m), 2.04-1.95 (2H, m), 1.75-1.59 (4H, m).

APCI (multimode) m/z: 637,1 [M+H].

Stage (in): 6-fluoro-N-{CIS-4-[6-fluoro-1-{4'-hydroxy-2'-[(4-methylpiperazin-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt triptorelin

1-Methylpiperazine (34,0 mg, 0.34 mmol) and triacetoxyborohydride sodium (77 mg, 0.36 mmol) was added to 6-fluoro-N-{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (180 mg, 0.28 mmol) in dichloroethane (10 ml). The resulting suspension was stirred over night. The mixture was evaporated to dryness and purified HPLC with reversed phase (5-50% acetonitrile in water triperoxonane acid) to obtain the specified title compound (119 mg, 44%).

1H NMR (400 MHz, DMSO-d6) δ 8.87-8.79 (1H, m), 8.60 (1H, d), 8.41 (1H, s), 8.34 (1H, dd), 7.81-7.70 (2H, m), 7.59-7.27 (5H, m), 7.14 (1H, d), 6.89-6.77 (2H, m), 4.85 (1H, s), 4.17 (1H, s), 3.60-3.16 (4H, m), 2.97-2.75 (6H, m), 2.72 (4H, s), 2.68-2.09 (2H, m), 2.09-1.93 (2H, m), 1.80-1.57 (4H, m).

APCI (multimode) m/z: 721,3 [M+H].

Example 67

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-hydroxy-2'-(piperazine-1-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt triptorelin

tert-Butyl-piperaz the n-1-carboxylate (to 63.2 mg, 0.34 mmol) and triacetoxyborohydride sodium (77 mg, 0.36 mmol) was added to 6-fluoro-N-[CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (180 mg, 0.28 mmol) in dichloroethane (10 ml). The resulting suspension was stirred over night. The mixture was evaporated to dryness and the residue was dissolved in dioxane (10 ml), then was added 4.0 M hydrogen chloride in dioxane (10 ml) and the mixture was stirred for 1 h the Mixture was evaporated to dryness and purified HPLC with reversed phase (5-50% acetonitrile in water triperoxonane acid) to obtain the specified title compound (106 mg, 40%).

1H NMR (400 MHz, DMSO-d6) δ 8.83 (1H, dd), 8.60 (1H, d), 8.53 (2H, s), 8.40 (1H, s), 8.34 (2H, dd), 7.80-7.69 (2H, m), 7.59-7.31 (6H, m), 7.16 (1H, d), 6.88 (1H, s), 6.82 (1H, dd), 4.87 (3H, m), 4.17 (2H, s), 3.52 (1H, s), 2.99 (3H, s), 2.69-2.52 (2H, m), 2.02 (2H, d), 1.79-1.57 (4H, m).

APCI (multimode) m/z: 707,3 [M+H].

Example 68

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-hydroxy-2'-{[4-(methylamino)piperidine-1-yl]methyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt triptorelin

4-N-BOC-4-N-Methyl-aminopiperidine (78 mg, 0.36 mmol) and triacetoxyborohydride sodium (77 mg, 0.36 mmol) was added to 6-fluoro-N-{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imide is zo[1,2-a]pyridine-2-carboxamide (180 mg, 0.28 mmol) in dichloroethane (10 ml). The resulting suspension was stirred over night. The mixture was evaporated to dryness and the residue was dissolved in dioxane (10 ml), then was added 4.0 M hydrogen chloride in dioxane (10 ml) and the mixture was stirred for 1 h the Mixture was evaporated to dryness and purified HPLC with reversed phase (5-50% acetonitrile in water triperoxonane acid) to obtain the specified title compound (57 mg, 21%).

1H NMR (400 MHz, DMSO-d6) δ 10.03-9.73 (2H, m), 8.89 (2H, s), 8.82 (1H, dd), 8.61 (1H, d), 8.42-8.32 (2H, m), 7.77 (1H, dd), 7.70 (1H, d), 7.62 (1H, t), 7.51-7.45 (1H, m), 7.41 (2H, dd), 7.29-7.21 (1H, m), 7.13-7.05 (1H, m), 7.00-6.93 (1H, m), 4.85 (3H, s), 4.35-4.11 (6H, m), 3.34 (1H, s), 3.12 (1H, s), 2.69-2.48 (2H, m), 2.02 (4H, d), 1.69 (6H, dd).

APCI (multimode) m/z: 735,3 [M+H].

Example 69

1-Biphenyl-3-yl-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

A suspension of tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (10 g, 17.3 mmol) and HCl (43 ml, 173 mmol) (4 M in dioxane) in diethyl ether (150 ml) was stirred for 20 hours was Added ether (200 ml) and the solid was filtered, washing with ether, to obtain specified in the subtitle compound (9.0 g).

APCI (mul is kodowa) m/z: 431 [M+H].

Stage (b): (6 torymidae[1,2-a]pyridine-2-yl)methanol

6 Torymidae[1,2-a]pyridine-2-carboxylic acid (4 g, 22,21 mmol) suspended in THF (10 ml) and was added to the complex of borane-tetrahydrofuran (111 ml, 111 mmol). This mixture was heated under reflux for 3 h, then was cooled to ambient temperature, was added dropwise methanol (30 ml) and was heated under reflux for 18 hours the Reaction mixture was cooled and concentrated in vacuum. The obtained solid substance was dissolved in methanol and passed through an SCX column, washing with methanol and then elwira product ammonia in methanol (7 M) to obtain, after evaporation, specified in the subtitle compound as a solid (3.5 g, 95%).

APCI (multimode) m/z: 167 [M+H].

Stage (in): 2-(chloromethyl)-6-torymidae[1,2-a]pyridine

(6 Torymidae[1,2-a]pyridine-2-yl)methanol (4,2 g, to 25.3 mmol) was heated at 60°C in thionyl chloride (46,0 ml, 630 mmol) for 2 hours the resulting solution was cooled and concentrated to obtain solid, which was washed with diethyl ether and dried in vacuum to obtain specified in the subtitle compound as a solid (3,45 g, 74%).

1H NMR (300 MHz, DMSO-d6) δ 9.25 (1H, t), 8.54 (1H, s), 8.06 (1H, dd), 7.93 (1H, ddd), 4.99 (2H, s).

GC 184.

Stage (d): 6-fluoro-3-(C is s-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a suspension of 2-(chloromethyl)-6-torymidae[1,2-a]pyridine (0.55 g, 2,98 mmol), 3-(CIS-4-aminocyclohexane)-6-fluoro-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (1.54 g, 2,98 mmol) and substrate Hunya (2,08 ml of 11.9 mmol) in acetonitrile (5 ml) was heated at 80°C for 48 hours the Reaction mixture was cooled, filtered and concentrated in vacuum. Added ethyl acetate and the precipitate was filtered, washing with ethyl acetate, and dried in vacuum to obtain a beige solid. The filtrate was purified flash chromatography on silica, elwira gradient from 100% ethyl acetate to 5% methanol in ethyl acetate. Pure fractions were evaporated to dryness to obtain additional quantities specified in the subtitle compound as a white solid (560 mg, 30%).

ES+(M+N) 629.

Stage (d): 1-biphenyl-3-yl-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The palladium (II) acetate (3.6 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13 mg, 0.03 mmol) were stirred together in acetonitrile (5 ml) for 10 minutes, then the solution was added potassium carbonate (132 mg, 0.95 mmol) in water (2 ml). Then sequentially added 6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.32 mmol) and f is sivoronova acid (39 mg, 0.32 mmol). The resulting solution was stirred at 80°C for 16 h, then was cooled, concentrated and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. This crude product was purified preparative HPLC on a column of Symmetry, using the gradient 95-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (21 mg, 11%).

1H NMR (300 MHz, DMSO-d6) δ 8.94-8.81 (3H, m), 8.61 (1H, d), 8.31 (1H, dd), 8.09 (1H, s), 7.81-7.71 (2H, m), 7.69-7.59 (4H, m), 7.53-7.43 (2H, m), 7.43-7.34 (2H, m), 4.88-4.77 (1H, m), 4.35 (2H, s), 3.42-3.32 (2H, m), 2.18-2.07 (2H, m,), 1.84-1.60 (6H, m).

APCI (multimode) m/z: 579 [M+H].

Example 70

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate

The palladium (II) acetate (3.6 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13 mg, 0.03 mmol) were stirred together in acetonitrile (5 ml) for 10 minutes, then added rasterbate potassium (132 mg, 0.95 mmol) in water (2 ml). Then sequentially added 6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.32 mmol) and 4-formylbenzeneboronic acid (48 mg, 0.32 mmol). The resulting solution was stirred at 80°C for 16 h, then was cooled, concentrated and the crude product was dissolved in dichloromethane (10 ml) and filtered. The filtrate was treated with di-tert-butyl-dicarbonate (0.15 ml, 0.64 mmol) and was stirred for 20 h at ambient temperature. This crude product was purified flash chromatography on silica, elwira gradient from 70 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a brown solid (75 mg, 33%).

APCI (multimode) m/z: 707 [M+H].

Stage (b): 6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate (150 mg, 0.21 mmol) and tert-butyl-1-piperidinecarboxylate (79 mg, 0.42 mmol) was stirred in DCM (15 ml) for 1 h and added triacetoxyborohydride sodium (45 mg, 0.21 mmol). This mixture was stirred for 20 hours we use and methanol and the solution was concentrated in vacuum. The crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness, dissolved in DCM (10 ml) and triperoxonane acid (5 ml) and was stirred for 18 hours the Solution was concentrated in vacuo and the residue triturated with diethyl ether to obtain specified in the title compound as a white solid (70 mg, 49%).

1H NMR (400 MHz, DMSO-d6) δ 8.89 (1H, s), 8.94-8.76 (2H, m), 8.60 (1H, d), 8.31 (1H, dd), 8.09 (1H, s), 7.79 (1H, d), 7.74-7.60 (5H, m), 7.50 (2H, d), 7.42 (2H, d), 4.85-4.76 (1H, m), 4.35 (2H, s), 3.97-3.88 (1H, m), 3.42-3.33 (1H, m), 3.21 (3H, s), 2.97-2.80 (2H, m), 2.17-2.07 (2H, m), 1.82-1.70 (2H, m), 1.69-1.61 (2H, m), 2.68-2.56 (2H, m).

APCI (multimode) m/z: 677 [M+H].

Example 71

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, di-triptorelin

The palladium (II) acetate (3.6 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (13 mg, 0.03 mmol) were stirred together in acetonitrile (5 ml) for 10 min, after which the solution was added potassium carbonate (132 mg, 0.95 mmol) in water (2 ml). Then sequentially added 6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.32 mmol) and 4-(4-morpholinomethyl)-anivorano acid-pinacol (96 mg, 0.32 mmol). The resulting solution was stirred at 80°C for 48 hours the Crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The crude product was purified preparative HPLC on a column of Symmetry Sunfire, using the gradient 95-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (12 mg, 6%).

1H NMR (300 MHz, DMSO-d6) δ 8.96-8.82 (3H, m), 8.61 (1H, d), 8.32 (1H, s), 8.09 (1H, s, dd), 7.85-7.73 (4H, m), 7.69-7.57 (4H, m), 7.47-7.36 (2H, m), 4.86-4.75 (1H, m), 4.38 (4H, s), 4.35 (4H, s), 3.70-3.59 (3H, m), 3.41-3.05 (6H, m), 2.31-2.07 (2H, m), 1.83-1.60 (6H, m).

APCI (multimode) m/z: 677 [M+H].

Example 72

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(methylamino)ethoxy]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): N-{CIS-4-[1-[4'-(2-chloroethoxy)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (1 g, 0.82 mmol), triphenylphosphine (0,43 g of 1.64 mmol and 2-chloroethanol (of 0.11 ml, of 1.64 mmol) in THF (50 ml) dropwise over a period of time of 2 minutes was added aminobutiramida-azodicarboxylate (0.33 g, of 1.64 mmol), which caused a slight exothermic effect. The obtained yellow solution was stirred for 20 h and added an additional portion of triphenylphosphine (0,431 g of 1.64 mmol) and 2-chloroethanol (0,110 ml of 1.64 mmol)was then added aminobutiramida-azodicarboxylate (of 0.332 g of 1.64 mmol) and the solution was stirred for 48 h Cream solid was filtered, washing with ether, and dried in vacuum to obtain specified in the subtitle compound (405 mg, 74%).

APCI (multimode) m/z: 671 [M+H].

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(methylamino)ethoxy]-biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[1-[4'-(2-Chloroethoxy)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (0.2 g, 0.30 mmol), potassium iodide (2.5 mg, 0.01 mmol) and methylamine (1.0 g, 12.9 mmol) in acetonitrile (5 ml) was heated at 70°C for 7 h, the Reaction mixture was cooled, concentrated in vacuo and passed through an SCX column, washing with methanol and elwira ammonia (7 M in the Meon), to obtain solid, which was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile in kachestvenna. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (65 mg, 33%).

1H NMR (300 MHz, DMSO-d6) δ 8.59 (1H, d), 8.36 (1H, s), 8.33 (1H, dd), 7.78-7.71 (2H, m), 7.70-7.61 (3H, m), 7.58 (1H, t), 7.48-7.40 (1H, m), 7.33 (1H, d), 7.07 (2H, d), 4.93-4.82 (1H, m), 4.22-4.13 (1H, m), 4.19 (2H, t), 3.18 (2H, t), 2.55 (3H, s), 2.31-2.23 (2H, m), 2.05-1.95 (2H, m), 1.79-1.60 (4H, m).

APCI (multimode) m/z: 666 [M+H].

Example 73

N-{CIS-4-[1-{4'-[2-(Dimethylamino)ethoxy]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

A solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.2 g, 0.33 mmol), cesium carbonate (0,214 g, 0.66 mmol), potassium iodide (5,46 mg, 0.03 mmol) and 2-diethylaminoethylamine hydrochloride (47 mg, 0,33 mmol) in NMP (4 ml) was heated to 80°C for 24 h, the Reaction mixture was cooled, concentrated and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% aqueous 0.2% ammonia in acetonitrile as eluent, then the gradient 75-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (45 mg, 20%).

1H I Is R (300 MHz, DMSO-d6) δ 9.62 (1H, s), 8.81 (1H, s), 8.59 (1H, d), 8.38 (1H, s), 8.34 (1H, dd), 7.78-7.62 (5H, m), 7.59 (1H, t), 7.46 (1H, dd), 7.34 (1H, d), 7.11 (2H, d), 4.93-4.80 (1H, m), 4.36 (2H, s), 4.17 (1H, s), 3.53 (2H,, s), 2.88 (6H, d), 2.84-2.75 (6H, m), 2.69-2.57 (2H, m), 2.53-2.39 (2H, m), 2.07-1.93 (2H, m), 1.79-1.58 (4H, m).

APCI (multimode) m/z: 680 [M+H].

Example 74

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): 1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]ethyl}pyrrolidin

The complex of 1,1'-bis(diphenylphosphino)periodically(II)-D (is 0.135 g, 0,19 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0,103 g 0,19 mmol) in DMSO (5 ml) was stirred at ambient temperature for 15 minutes. Was added potassium acetate (1,09 g, 11.1 mmol), bis(pinacolato)LIBOR (1.22 g, to 4.81 mmol) and 1-(2-(4-bromophenoxy)ethyl)-pyrrolidine (1 g, 3,70 mmol) and this reaction mixture was heated at 80°C for 20 hours, the Reaction mixture was cooled, added water and was extracted with diethyl ether. The ether phase was dried (Na2SO4) and concentrated to obtain specified in the subtitle compound as a brown oil (560 mg, 48%).

1H NMR (300 MHz, CDCl3) δ 7.75 (2H, d), 6.91 (2H, d), 4.19 (2H, t), 3.00 (2H, t), 2.78-2.70 (2H, m), 2.68-2.50 (2H, m), 1.89-1.81 (4H, m), 1.28 (12H, s).

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1-is LaTeXe)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The palladium (II) acetate (3.5 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (13 mg, 0.03 mmol) were stirred together in acetonitrile (15 ml) for 10 minutes, then the solution was added potassium carbonate (0,13 g of 0.93 mmol) in water (10 ml). Then sequentially added 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.2 g, 0.31 mmol) and 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (99 mg, 0.31 mmol). The resulting solution was stirred at 80°C for 16 hours, the Reaction mixture was cooled, concentrated and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent, then the gradient 75-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (21 mg, 9%).

1H NMR (300 MHz, DMSO-d6) δ 9.94-9.70 (1H, m), 8.81 (1H, s), 8.59 (1H, d), 8.39 (1H, s), 8.34 (1H, dd), 7.79-7.62 (5H, m), 7.59 (1H, t), 7.46 (1H, dd), 7.34 (1H, d), 7.11 (2H, d), 4.88 (1H, t), 4.34 (2H, t), 4.20-4.12 (1H, m), 3.68-3.53 (4H, m), 3.21-3.06 (2H, m), 2.74-2.36 (2H, m), 2.08-1.94 (4H, m), 1.92-1.84 (2H, m), 1.80-1.58 (4H, m).

APCI (multimode) m/z: 706 [M+H].

Example 75

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}them is dazo[1,2-a]pyridine-2-carboxamide

This compound was obtained according to Example 74, step (b).

1H NMR (300 MHz, CDCl3) δ 8.38 (1H, d), 8.25 (1H, dd), 8.11 (1H, s), 8.08-8.04 (1H, m), 7.73-7.64 (2H, m), 7.62-7.55 (2H, m), 7.45 (1H, t), 7.36 (1H, dd), 7.17 (1H, ddd), 6.75-6.66 (2H, m), 6.57-6.48 (1H, m), 5.08 (1H, t), 4.49-4.40 (1H, m), 2.88-2.65 (2H, m), 2.16-2.04 (2H, m), 1.93-1.66 (4H, m).

APCI (multimode) m/z: 627 [M+H].

Example 76

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-(3-morpholine-4-ylpropionic)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

This compound was obtained according to Example 74, step (b).

1H NMR (300 MHz, DMSO-d6) δ 8.82-8.74 (1H, m), 8.59 (1H, d), 8.37 (1H, s), 8.32 (1H, dd), 7.78-7.64 (4H, m), 7.64-7.52 (2H, m), 7.44 (1H, t), 7.31 (1H, d), 7.02 (2H, d), 4.94-4.81 (1H, m), 4.21-4.12 (1H, m), 4.05 (2H, t), 3.57 (4H, t), 2.64-2.24 (8H, m), 2.00 (2H, d), 1.88 (2H, t), 1.80-1.59 (4H, m).

APCI (multimode) m/z: 736 [M+H].

Example 77 and Example 78

N-{CIS-4-[1-{2'-[2-(Dimethylamino)ethoxy]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide and

N-{CIS-4-[1-{2'-[2-(dimethylamino)ethoxy]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-N-[2-(dimethylamino)ethyl]-6-torymidae[1,2-a]pyridine-2-carboxamide

A solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-fluoro-2'-hydroxybiphenyl-3-yl)-2,4-dio is co-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.2 g, 0.32 mmol), cesium carbonate (0,208 g, 0.64 mmol), potassium iodide (5,30 mg, 0.03 mmol) and 2-diethylaminoethylamine hydrochloride (46 mg, 0.32 mmol) in NMP (3 ml) was heated to 80°C for 24 h, the Reaction mixture was cooled, concentrated and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the header connections:

N-{CIS-4-[1-{2'-[2-(dimethylamino)ethoxy]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (25 mg, 11%)

1H NMR (300 MHz, DMSO-d6) δ 8.79 (1H, s), 8.61 (1H, d), 8.37 (1H, s), 8.33 (1H, dd), 7.75 (1H, dd), 7.69-7.51 (4H, m), 7.49-7.30 (3H, m), 7.06 (1H, d), 6.91-6.83 (1H, m), 4.95-4.78 (1H, m), 4.16 (1H, s), 4.13-4.08 (2H, m), 3.38-3.22 (2H, m), 2.74-2.58 (2H, m), 2.13 (6H, s), 2.04-1.95 (2H, m), 1.79-1.58 (4H, m).

APCI (multimode) m/z: 698 [M+H]

N-{CIS-4-[1-{2'-[2-(dimethylamino)ethoxy]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-N-[2-(dimethylamino)ethyl]-6-torymidae[1,2-a]pyridine-2-carboxamide (29 mg, 12%)

1H NMR (300 MHz, DMSO-d6) δ 8.84-8.78 (1H, m), 8.60 (1H, d), 8.39 (1H, s), 8.36 (1H, dd), 7.77 (1H, dd), 7.70 (1H, d), 7.60-7.53 (2H, m), 7.52-7.34 (4H, m), 7.15-7.07 (1H, m), 7.01-6.93 (1H, m), 4.91-4.76 (1H, m), 4.60-4.40 (2H, m), 4.23-4.11 (1H, m), 3.81 (2H, s), 3.65-3.42 (4H, m), 3.05 (6H, s), 2.76-2.58 (2H, m), 2.11-1.93 (2H, m), 1.79-1.61 (4H, m).

APCI (multimode) m/z: 769 [M+H].

Example 79

N-{the IP-4-[1-{2'-[3-(Dimethylamino)propoxy]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

This compound was obtained in accordance with Example 77.

1H NMR (300 MHz, DMSO-d6) δ 8.81 (1H, s), 8.61 (1H, s), 8.38 (1H, s), 8.37-8.30 (1H, m), 7.81-7.72 (1H, m), 7.71-7.64 (1H, m), 7.63-7.55 (1H, m), 7.54-7.43 (2H, m), 7.40-7.28 (2H, m), 7.06 (1H, d), 6.95-6.85 (1H, m), 4.92-4.76 (1H, m,), 4.22-4.08 (1H, m), 4.09 (2H, s), 3.06 (2H, s), 2.69 (6H, s), 2.53-2.28 (2H, m), 2.09-1.95 (4H, m), 1.78-1.56 (4H, m).

APCI (multimode) m/z: 712 [M+H].

Example 80

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-fluoro-2'-(2-piperazine-1-ylethoxy)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

This compound was obtained in accordance with Example 77.

1H NMR (300 MHz, DMSO-d6) δ 8.84 (1H, s), 8.79-8.68 (1H, m), 8.61 (1H, d), 8.39 (1H, s), 8.36-8.31 (1H, m), 7.77 (1H, dd), 7.70 (1H, d), 7.64-7.44 (5H, m), 7.41-7.32 (2H, m), 7.09 (1H, d), 6.94-6.86 (1H, m), 4.92-4.78 (1H, m), 4.66-4.22 (3H, m), 4.20 (4H, s), 3.09 (4H, s), 2.98 (1H, s), 2.81 (2H, s), 2.64-2.54 (2H, m), 2.06-1.96 (2H, m), 1.78-1.58 (4H, m).

APCI (multimode) m/z: 739 [M+H].

Example 81

1-Biphenyl-3-yl-6-fluoro-3-{CIS-4-[(2-hydroxyethyl)amino]cyclohexyl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (77 mg, 0.18 mmol) and [[(1,1-dimethylethyl)dimethylsilane]oxy]acetaldehyde (to 34.3 mg, 0.20 mmol) in DCM (3 ml) was added triacetoxyborohydride sodium (41.7 mg, 0.20 mmol) and this reaction mixture was stirred at 80°C for 22 h, the Mixture was suppressed m is canola and diluted HCl (1 ml), was stirred for 2 h and the crude product was purified preparative HPLC column Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (42 mg, 50%) as a white solid.

1H NMR (300 MHz, Dl3) δ 8.41 (1H, d), 8.21 (1H, dd), 7.74 (1H, d), 7.67-7.58 (3H, m), 7.56-7.51 (1H, m), 7.46 (2H, t), 7.41-7.34 (1H, m), 7.30 (1H, d), 5.29-5.22 (1H, m), 5.08-4.93 (1H, m), 3.98-3.89 (2H, m), 3.40 (1H, s), 3.17-3.08 (2H, m), 2.81-2.63 (2H, m), 2.48 (2H, d), 1.91-1.73 (4H, m).

APCI (multimode) m/z: 475 [M+H].

Example 82

{3'-[6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H-yl]biphenyl-4-yl}-N,N,N-trimethylmethanaminium iodide

A solution of N-{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (75 mg, 0.12 mmol) and jodean (of 0.014 ml, 0.23 mmol) was dissolved in acetonitrile (3 ml) and the solution was stirred at 80°C within 24 hours the Reaction mixture was concentrated and was purified preparative HPLC column Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header in the IDA white solid (26 mg, 32%).

1H NMR (300 MHz, CDCl3) δ 8.37 (1H, d), 8.24 (1H, dd), 8.10 (2H, s), 8.08-8.03 (2H, m), 7.75-7.66 (5H, m), 7.58-7.51 (2H, m), 7.39-7.33 (1H, m), 7.19-7.11 (1H, m), 5.11-5.00 (1H, m), 4.97 (2H, s), 4.41 (1H, s), 3.35 (9H, s), 2.86-2.69 (2H, m), 2.13 (2H, d), 1.90-1.52 (4H, m).

APCI (multimode) m/z: 664 [M+H].

Example 83

N-{CIS-4-[1-{2'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-methyl-D-prolinamide

Stage (a): N-{CIS-4-[1-{2'-[(3-itfinal}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-methyl-D-prolinamide

HATU (0,243 g, 0.64 mmol) was added to 1-methyl-pyrrolidin-2-carboxylic acid (82 mg, 0.64 mmol) and the base Hunya (0,41 ml, 2.3 mmol) in NMP (4 ml). This mixture was stirred for 10 minutes and was added 3-(CIS-4-aminocyclohexane)-6-fluoro-1-(3-itfinal)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (0.3 g, of 0.58 mmol). The mixture was stirred at room temperature for 4 h, the Reaction mixture was poured into water and the solid was filtered, washed with water and dried in vacuum to obtain specified in the subtitle compound as a yellow-brown solid (0.2 g, 58%).

APCI (multimode) m/z: 592 [M+H].

Stage (b): N-{CIS-4-[1-{2'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-methyl-D-prolinamide

The palladium (II) acetate (3 mg, 0.015 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (10 mg, 0.03 mmol) were stirred together in acetonitrile (5 ml) for 10 minutes, then the solution was added potassium carbonate (105 mg, from 0.76 mmol) in water (3 ml), then successively added N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-methyl-D-prolinamide (150 mg, 0.25 mmol) and 2-(N N-dimethylaminomethyl)phenylboronic acid (45 mg, 0.25 mmol). The resulting solution was stirred at 80°C for 16 hours, the Reaction mixture was cooled, concentrated and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent, then the gradient 75-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (2 mg, 2%).

1H NMR (300 MHz, DMSO-d6) δ 8.69 (1H, d), 8.59 (1H, s), 8.30 (1H, dd), 7.89 (1H, d), 7.65 (1H, d), 7.58-7.50 (1H, m), 7.50-6.98 (4H, m), 4.86-4.70 (1H, m), 4.28 (2H, s), 4.17-4.05 (1H, m), 3.96-3.83 (1H, m), 3.57 (3H, s), 2.82 (6H, d), 2.65-2.53 (2H, m), 2.37-2.26 (2H, m), 2.14-1.81 (6H, m), 1.72-1.49 (4H, m).

APCI (multimode) m/z: 599 [M+H].

Example 84

N-{CIS-4-[1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

Stage (a): tert-butyl{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]is eremein-3(2H)-yl]cyclohexyl}carbamate

Acetonitrile (10 ml) was added to a mixture of palladium (II) acetate (0.025 g, 0.11 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,092 g, 0.22 mmol) and the mixture was stirred at room temperature for 10 minutes was Added potassium carbonate (0,929 g, 6,72 mmol) in water (3 ml)was then added N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanamine (1,00 g, to 3.36 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1.3 g, 2,24 mmol) and this reaction mixture is boiled under reflux over night at 80°C. the Reaction mixture was applied directly onto the cartridge, Varian Bond Chemelut (available from Kinesis), the product was suirable DCM and concentrated in vacuum. The crude product was purified flash chromatography on silica, elwira gradient from 1 to 5% methanol in dichloromethane with 0.1% 5 N. methanolic solution of ammonia. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a pale yellow solid (1,32 g, 102% - contains a number of solvents).

1H NMR (400 MHz, DMSO-d6) δ 8.58 (1H, d), 8.29 (1H, dd), 7.77 (1H, d), 7.71 (1H, d), 7.64-7.57 (3H, m), 7.41-7.34 (3H, m), 6.54 (1H, s), 4.75 (1H, t), 3.91 (2H, s), 3.59 (1 H, s), 2.65-2.55 (2H, m), 2.17 (6H, s), 1.94-1.86 (2H, m,), 1.54-1.44 (4H, m), 1.38 (9H, s).

APCI (multimode) m/z: 588 [M+H].

Stage (b): 3-(CIS-4-aminocyclohexane)-1-{4'-[(dimethylamine is)methyl]-biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione the dihydrochloride

To a solution of tert-butyl{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1,32 g, 2.25 mmol) in 1,4-dioxane (6 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M) (4 ml, 16,00 mmol) and this reaction mixture was stirred at room temperature for 3 hours the solution was Added hydrogen chloride in 1,4-dioxane (4 M) (2 ml, of 8.00 mmol) and the reaction mixture was stirred at room temperature for another 2 hours was Added a solution of hydrogen chloride in 1,4-dioxane (4 M) (4 ml, 16,00 mmol) and the reaction mixture was stirred at room temperature overnight. Added diethyl ether (25 ml) and the mixture was stirred for 1 h, the Solid was collected by filtration and washed with ether to obtain specified in the subtitle compound as a white solid (1,17 g, 93%).

1H NMR (400 MHz, DMSO-d6) δ 10.96 (1H, s), 8.61 (1H, d), 8.31 (1H, dd), 8.03-7.97 (3H, m), 7.83 (1H, d), 7.79-7.77 (2H, m), 7.75 (1H, s), 7.68 (1H, d), 7.64 (2H, t), 7.43-7.40 (1H, m), 4.83-4.72 (1H, m), 4.31 (2H, d), 3.45-3.37 (1H, m), 2.76 (6H, s), 2.62-2.54 (2H, m), 2.00-1.91 (2H, m), 1.84-1.71 (2H, m), 1.70-1.60 (2H, m).

APCI (multimode) m/z: 488 [M+H].

Stage (in): N-{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

To a solution of 3-(CIS-4-aminocyclohexane)-1-{4'-[(dimethylamino)methyl]-biphenyl-3-and the}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride (0.2 g, 0.36 mmol) in dichloromethane (10 ml) was added N,N-diisopropylethylamine (0.5 ml, of 2.86 mmol)was then added acetylchloride (0,025 ml, 0.36 mmol) and this reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue triturated with water (10 ml) and stirred overnight to obtain solid, which was collected by filtration and was purified flash chromatography on silica, gradient elwira 20%methanol in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in the title compounds as white solids (0,045 g, 24%).

1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, 1H), 8.23 (dd, 1H), 7.73 (d, 1H), 7.70-7.65 (m, 2H), 7.60-7.54 (m, 3H), 7.36-7.28 (m, 3H), 4.78-4.67 (m, 1H), 3.77-3.72 (m, 1H), 3.39 (s, 2H), 2.59-2.52 (m, 2H), 2.12 (s, 6H), 1.86-1.83 (m, 2H), 1.82 (s, 3H), 1.53-1.45 (m, 4H).

APCI (multimode) m/z: 530 [M+H].

Example 85

N-{CIS-4-[1-(3-{[Benzyl(methyl)amino]carbonyl}phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a): 3-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid

To a solution of methyl-3-[3-{CIS-4-[(tert-butoxycarbonyl)amino]-cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate (0.7 g, 1.37 mmol) in 1,4-dioxa the e (10 ml) was added lithium hydroxide (0,046 g, 1.92 mmol) in water (10.5 ml) in General for 3 days. The reaction mixture was extinguished with acetic acid and the solvents evaporated. To the residue was added water and the solid was filtered and dried in a drying Cabinet with obtaining specified in the subtitle compound as a pale yellow solid (0,322 g, 47%).

1H NMR (400 MHz, DMSO-d6) δ 8.56 (1H, a), 8.28 (1H, dd), 8.02 (1H, dt), 7.96 (1H, d), 7.65-7.60 (2H, m), 6.56-6.43 (1H, m), 4.81-4.67 (1H, m), 2.63-2.54 (2H, m), 1.93-1.85 (2H, m), 1.54-1.43 (4H, m), 1.41 (9H, s).

APCI (multimode) m/z: 460 [M+H].

Stage (b): tert-butyl{CIS-4-[1-(3-{[benzyl(methyl)amino]carbonyl}-phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

N,N-Diisopropylethylamine (0,1167 g, 0,1572 ml, 0.90 mmol) and HATU (0,1373 g, 0.14 mmol) was added to a solution of 3-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid (0.15 g, 0.30 mmol) in DMF (3 ml). This mixture was stirred at room temperature for 10 minutes. Was added N-benzylmethylamine (0,0401 g, 0,0427 ml, 0.33 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was distributed between ethyl acetate and water, the organic phase was combined, dried using anhydrous magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column of flash is-chromatography, elwira a mixture of 30% ethyl acetate:70% of isohexane increasing to 50% ethyl acetate:50% of isohexane for obtaining specified in the subtitle compound (0.07 g, 39%).

1H NMR (400 MHz, DMSO-d6) δ 8.59-8.42 (1H, m), 8.27 (1H, dd), 7.62-7.46 (3H, m), 7.38-7.26 (5H, m), 7.20 (1H, d), 6.59 (1H, s), 4.70 (2H, d), 3.55 (1H, s), 2.88 (3H, d), 2.64-2.55 (2H, m), 1.89 (2H, d), 1.54-1.44 (4H, m), 1.39 (9H, s).

APCI (multimode) m/z: 602 [M+H].

Stage (in): 3-[3-(CIS-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]-N-benzyl-N-methylbenzamide hydrochloride

To a solution of tert-butyl{CIS-4-[1-(3-{[benzyl(methyl)amino]carbonyl}-phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.07 g, 0,116 mmol) in 1,4-dioxane (1 ml) was added hydrogen chloride, 4.0 M in 1,4-dioxane (1 ml, 4 mmol)and this reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuum to obtain specified in the subtitle compound in the form of cleaners containing hydrochloride salt in the form of not-quite-white foam (0.06 g, 96%).

APCI (multimode) m/z: 539 [M+H].

Stage (d): N-{CIS-4-[1-(3-{[benzyl(methyl)amino]carbonyl}phenyl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

To a solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0,027 g, 0,123 mmol) in DMF (2 ml) was added N,N-diisopropylethylamine (0,072 g, 0,097 is l, 0,558 mmol) and HATU (0,051 g, 0,134 mmol) and the mixture was stirred at room temperature for 10 minutes. After this was added 3-[3-(4-amino-cyclohexyl)-6-fluoro-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-d]pyrimidine-1-yl]-N-benzyl-N-methyl-benzamide (0.06 g, 0,112 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was partially removed and to the residue was added water. The obtained solid substance was filtered. Was added water (0.5 ml) and the suspension was heated using a jet air dryer and left to cool to room temperature. The solid was filtered, washed with cold water and dried in a drying Cabinet with obtaining specified in the title compounds as white solids (0,050 g, 67%).

1H NMR (400 MHz, DMSO-d6) δ 8.79 (1H, dd), 8.57 (1H, s), 8.38 (1H, s), 8.31 (2H, dd), 7.76-7.65 (3H, m), 7.62-7.40 (7H, m), 7.38-7.28 (5H, m), 7.21-7.15 (2H, m), 4.84 (1H, t), 4.71 (1H, s), 4.22 (HE, s), 2.95 (HE, s), 2.00 (3H, d), 1.81-1.50 (6H, m), 2.65-2.54 (76H, m)

APCI (multimode) m/z: 664 [M+H].

Example 86

3-[3-(CIS-4-Aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid

To a solution of 3-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid (0.07 g, 0.14 mmol) in 1,4-dioxane (0.5 ml) was added hydrogen chloride, 4.0 M in 1,4-dioxane (0.5 ml, 3,mmol), and this reaction mixture was stirred at room temperature overnight. Added an additional portion of hydrogen chloride, 4.0 M in 1,4-dioxane (0.3 ml, 1.92 mmol)and the reaction mixture was stirred for another 4 h at room temperature. The solid was filtered and washed with diethyl ether. The residue was purified HPLC with reversed phase (25-95% acetonitrile in aqueous ammonia) and liofilizirovanny obtaining specified in the title compound as a white solid (0.02 g, 36%).

1H NMR (400 MHz, DMSO-d6) δ 13.20 (1H, s), 8.58 (1H, d), 8.30 (1H, dd), 8.05-8.00 (1H, m), 7.98-7.97 (1H, m), 7.82 (2H, s), 7.67-7.64 (2H, m), 4.79 (1H, t), 3.46 (1H, s), 2.61-2.51 (2H, m), 1.95-1.77 (4H, m), 1.65 (2H, d).

APCI (multimode) m/z: 399 [M+H].

Example 87

N-{CIS-4-[1-{3-[(Benzylamino)carbonyl]phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a): methyl-3-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate

To a solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0,76 g, 4,22 mmol) in DMF (20 ml) was added N,N-diisopropylethylamine (1,636 g, 2,205 ml, 12,66 mmol) and HATU (1,925 g of 5.06 mmol) and this reaction mixture was stirred at room temperature for 10 minutes. To this mixture was added the methyl-3-[3-(CIS-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate (1,74 g, 4,22 mmol) in DMF (10 ml) and the reaction mixture was stirred at room temperature for 2 hours, the Solvents evaporated and the residue was distributed between water and ethyl acetate. The combined organic phase was dried using anhydrous magnesium sulfate, filtered and concentrated in vacuum to obtain specified in the subtitle compound as a pale brown solid (2,43 g, 100%).

1H NMR (400 MHz, DMSO-d6) δ 8.82-8.75 (1H, m), 8.56 (1H, d), 8.37 (1H, s), 8.33 (1H, dd), 8.07-8.01 (2H, m), 7.79-7.67 (1H, m), 7.52 (2H, dd), 7.45 (2H, dd), 4.86 (1H, t), 4.16 (1H, s), 3.88 (3H, s), 1.72-1.62 (4H, m), 1.28-1.24 (4H, m).

APCI (multimode) m/z: 575 [M+H].

Stage (b): 3-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1 (2H)-yl]benzoic acid

To a solution of methyl-3-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoate (2.4 g, 4,18 mmol) in 1,4-dioxane (100 ml) was added a solution of lithium hydroxide (0,0901 g, 3,76 mmol) in water (50 ml) and the reaction mixture was stirred at room temperature for 1 h the Mixture was acidified with acetic acid and then concentrated in vacuum. To the residue was added 4 M HCl in dioxane (300 ml) and the reaction mixture was heated at 70°C for 12 h, left to cool and stand for : the different days. The solvents were removed by evaporation and the residue was purified HPLC with reversed phase (25-95% acetonitrile in aqueous ammonia) to obtain specified in the subtitle compound (0,280 g, 12%).

1H NMR (400 MHz, DMSO-d6) δ 8.87 (1H, dd), 8.57 (1H, d), 8.45 (1H, s), 8.32 (1H, dd), 8.05-8.01 (1H, m), 7.98 (1H, t), 7.83-7.75 (2H, m), 7.65 (2H, td), 7.56-7.50 (1H, m), 4.94-4.77 (1H, m), 4.21-4.10 (1H, m), 2.70-2.55 (2H, m), 2.02 (2H, d), 1.77-1.59 (4H, m).

APCI (multimode) m/z: 559 [M+H].

Stage (in): N-{CIS-4-[1-{3-[(benzylamino)carbonyl]phenyl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

N,N-diisopropylethylamine (0,1729 g, 0,2331 ml, 1,338 mmol) and HATU (0,2035 g, 0,535 mmol) was added to a solution of 3-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]benzoic acid (0.25 g, 0,446 mmol) in DMF (3 ml). This mixture was stirred at room temperature for 10 minutes. Added benzylamine (0,053 g, 0,054 ml, 0,491 mmol) and the reaction mixture was stirred over night at room temperature. The solvent was removed, and the residue was distributed between ethyl acetate and water, the combined organic phase was dried using anhydrous magnesium sulfate, filtered and concentrated in vacuum. The residue was purified HPLC with reversed phase (25-95% acetonitrile in aqueous ammonia) and liofilizirovanny obtaining specified in the header connect the deposits in the form of a white solid (0,174 g, 60%).

1H NMR (400 MHz, DMSO-d6) δ 9.12 (1H, t), 8.79 (1H, dd), 8.56 (1H, d), 8.37 (1H, s), 8.32 (1H, dd), 8.00 (1H, d), 7.90 (1H, d), 7.75 (1H, dd), 7.69-7.61 (2H, m), 7.56 (1H, d), 7.45 (1H, ddd), 7.32 (4H, d), 7.26-7.21 (1H, m), 4.90-4.82 (1H, m), 4.49 (2H, d), 4.19-4.13 (1H, m), 2.65-2.54 (2H, m), 2.00 (2H, d), 1.79-1.60 (4H, m).

APCI (multimode) m/z: 650 [M+H].

Example 88

N-[CIS-4-(1-Biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-4-(dimethylamino)butanamide

To a solution of 4-dimethylamino-butyric acid (0,0337 g, 0,257 mmol) in DMF (2 ml) was added N,N-diisopropylethylamine (0,1107 g, 0,1492 ml, 0,857 mmol) and HATU (0,098 g, 0,257 mmol). This reaction mixture was stirred at room temperature for 10 minutes. Was added 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.1 g, 0,214 mmol) and the reaction mixture was stirred at room temperature overnight. In a separate vessel to a solution of 4-dimethylamino-butyric acid (0,013 g 0,099 mmol) in DMF (1 ml) was added N,N-diisopropylethylamine (by 0.055 g, 0.075 ml, 0,426 mmol) and HATU (0,049 g, 0,129 mmol) and the mixture was stirred at room temperature for 10 minutes. This solution is then added to the initial reaction mixture and the mixture was stirred at room temperature for a further 1 h the Reaction mixture was concentrated in vacuo and the residue was stirred in water. The solid was removed by filtration and purified colonic the Oh flash chromatography, elwira mixture 5% 7 N. methanolic solution of ammonia/95% DCM to obtain specified in the title compounds as white solids (by 0.055 g, 47%).

1H NMR (400 MHz, DMSO-d6) δ 8.59 (1H, d), 8.29 (1H, dd). 7.79-7.76 (1H, m), 7.73 (1H, t), 7.70-7.65 (3H, m), 7.61 (1H, t), 7.48 (2H, t), 7.41-7.36 (2H, m), 4.79 (1H, t), 3.79 (1H, s), 2.67-2.55 (4H, m), 2.45 (6H, s), 2.20 (2H, t), 1.91 (2H, d), 1.73 (2H, quintet), 1.58-1.47 (4H, m).

APCI (multimode) m/z: 544 [M+H].

Example 89

N-{CIS-4-[1-{4'-[(Dimethylamino)methyl]-2'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a): 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The complex of 1,1'-bis(diphenylphosphino)periodically(II)-dichloromethane (0,285 g 0,39 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0,216 g 0,39 mmol) was stirred at room temperature in dimethyl sulfoxide (25 ml) for 10 minutes. Added 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (5 g, for 7.78 mmol), bis(pinacolato)LIBOR (to 2.57 g, 10,12 mmol) and potassium acetate (2,292 g, 23,35 mmol) and the reaction mixture was heated at 80°C during the night. After cooling, was added water and the mixture p is remedial for 3 h and the solid is then filtered. The residue was purified flash chromatography on silica with gradient elution to 100%ethyl acetate to obtain specified in the subtitle compound as a brown resin (4,21 g, 84%).

1H NMR (400 MHz, DMSO-d6) δ 8.79 (ddd, 1H), 8.55 (d, 1H), 8.37 (s, 1H), 8.30 (dd, 1H), 7.78-7.73 (m, 2H), 7.69-7.65 (m, 2H), 7.57-7.49 (m, 2H), 7.44 (ddd, 1H), 4.85 (t, 1H), 4.22 (s, 1H), 2.64-2.55 (m, 2H), 2.03-2.00 (m, 2H), 1.77-1.63 (m, 4H), 1.33 (s, 12H)

APCI (multimode) m/z: 643 [M+H].

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formyl-2'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Acetonitrile (30 ml) was added to a mixture of palladium (II) acetate (0,105 g, 0.47 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,383 g of 0.93 mmol) and the mixture was stirred at room temperature for 10 minutes. To this mixture was sequentially added potassium carbonate (1,936 g, 14,01 mmol) in water (15 ml), 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (3 g, of 4.67 mmol) and 3-hydroxy-4-identilied (1,737 g, 7,00 mmol). The reaction mixture was heated up to 80°C during the night. The reaction mixture was applied directly onto the cartridge, Varian Bond Chemelut (available from Kinesis), the product was suirable DCM and concentrated in vacuum. The residue was purified flash chromatography on d is the oxide of silicon, elwira a mixture of 30% ethyl acetate in 70% dichloromethane to obtain specified in the subtitle compound as a yellow solid (0,282 g, 10%).

1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.03 (s, 1H), 8.57 (d, 1H), 8.32 (dd, 1H), 7.96 (dd, 1H), 7.85 (dd, 2H), 7.63 (d, 1H), 7.54-7.45 (m, 6H), 7.41-7.36 (m, 2H), 4.86 (t, 1H), 4.11-4.06 (m, 1H), 2.63-2.57 (m, 2H), 1.97-1.88 (m, 2H), 1.74-1.59 (m, 4H).

APCI (multimode) m/z: 637 [M+H].

Stage (in): N-{CIS-4-[1-{4'-[(dimethylamino)methyl]-2'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formyl-2'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.28 g, 0.44 mmol) in 1,2-dichloroethane (10 ml) was added a solution of dimethylamine in tert-butylmethylether ether (2 M) (0,660 ml, of 1.32 mmol) and acetic acid (0,101 ml of 1.76 mmol). The reaction mixture was stirred for 10 min, then was added triacetoxyborohydride sodium (0,140 g, 0.66 mmol). Added an additional portion of the solution of dimethylamine in tert-butylmethylether ether (2 M) (0,660 ml of 1.32 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in methanol (5 ml) and applied to the cartridge 10g SCX. Impurities were washed with methanol (70 ml) and discarded. The product was suirable 1 N. methanolic ammonia solution (100 is l) and evaporated in vacuo. The crude product was purified flash chromatography on silica with gradient elution from 2 to 5% methanol in dichloromethane. The compound was further purified HPLC with reversed phase (gradient 95-50% water with 0.1%triperoxonane acid in acetonitrile) to obtain specified in the title compounds as white solids (0,034 g, 10%).

1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.65 (s, 1H), 8.58 (d, 1H), 8.31 (dd, 1H), 7.91 (dd, 1H), 7.84 (dd, 2H), 7.55-7.46 (m, 5H), 7.39-7.37 (m, 2H), 7.08 (s, 1H), 7.05 (d, 1H), 4.85 (t, 1H), 4.30 (s, 2H), 4.11 (s, 1H), 2.81 (d, 6H), 2.62-2.54 (m, 2H), 2.03-1.90 (m, 2H), 1.73-1.63 (m, 4H).

APCI (multimode) m/z: 666 [M+H].

Example 90

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[3-(isopropylamino)propyl] - biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): 3-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}propyl-methanesulfonate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-[4'-(3-hydroxypropyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.77 mmol) and triethylamine (0,389 g of 3.84 mmol) in dichloromethane (10 ml) was added methanesulfonamide (of 0.066 ml, 0.85 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature is round within 2 h, was poured into water and was extracted with dichloromethane. The organic portion was washed with brine and dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound (0,550 g, 98%) as not quite white solid.

1H NMR (300 MHz, CDCl3) δ 8.38 (d, 1H), 8.23 (dd, 1H), 8.10 (s, 1H), 8.06 (t, 1H), 7.75-7.71 (m, 2H), 7.64 (t, 1H), 7.60-7.53 (m, 4H), 7.32-7.24 (m, 2H), 7.15 (ddd, 1H), 5.06 (s, 1 H), 4.42 (s, 1H), 4.25 (t, 2H), 3.00 (s, 3H), 2.83-2.76 (m, 4H), 2.70-2.60 (m, 2H), 2.16-2.08 (m, 4H), 1.86-1.71 (m, 2H).

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-{4'-[3-(isopropylamino)propyl] - biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of 3-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}propyl-methanesulfonate (0.2 g, 0.27 mmol), Isopropylamine (1 ml, 11,74 mmol) and potassium carbonate (0,379 g, is 2.74 mmol) in acetonitrile (10 ml) was heated at 70°C for 5 hours, the Reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 50-30% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the header connect the FL (9 mg, 5%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 9.18 (2H, s), 8.35 (1H, d), 8.22 (1H, dd), 8.12 (1H, s), 8.05 (1H, t), 7.76-7.55 (4H, m), 7.51-7.45 (3H, m), 7.30-7.25 (1H, m), 7.21-7.13 (3H, m), 5.06 (1H, t), 4.41 (1H, s), 3.28-3.16 (1H, m), 2.93-2.70 (4H, m), 2.68-2.59 (2H, m), 2.17-2.09 (2H, m), 2.06-1.98 (2H, m), 1.87-1.69 (4H, m), 1.27 (6H, d).

APCI (multimode) m/z: 692.3 [M+H].

Example 91

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of 3-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}propyl-methanesulfonate (0.2 g, 0.27 mmol), 3-amino-1-propanol (1 ml, 0.27 mmol) and potassium carbonate (0,379 g that is 2.74 mmol) in acetonitrile (10 ml) was heated at 70°C for 5 hours, the Reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 60-40% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (35 mg, 36%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H), 8.23 (dd, 1H), 8.10 (d, 1H), 8.07-8.04 (m, 1H), 7.76-.71 (m, 2H), 7.66-7.51 (m, 5H), 7.30-7.22 (m, 3H), 7.14 (ddd, 1H), 5.06 (s, 1H), 4.43 (s, 1H), 3.81 (t, 2H), 2.88 (t, 2H), 2.79 (d, 2H), 2.72-2.63 (m, 4H), 2.17-2.08 (m, 2H), 1.88-1.65 (m, 6H).

APCI (multimode) m/z: USD 708.3 [M+H].

Example 92

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(3-piperazine-1-ylpropyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

3-{3'-[6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}propyl-methanesulfonate (0.15 g, 0.21 mmol), potassium carbonate (0.29 grams, 2.10 mmol) and N-BOC-piperazine (0.2 g, 1.07 mmol) were heated together at 70°C for 12 h in acetonitrile (10 ml). The reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The residue was treated with hydrochloric acid (10 ml, 40,00 mmol) in dioxane and stirred for 16 hours the Solvent was evaporated. The crude product was purified preparative HPLC on a Sunfire column using a gradient of 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,050 g, 34%) as a white solid.

1H NMR (400 MHz, DMSO-D6) δ 9.20 (s, 1H), 8.78 (dd, 1H), 8.55 (d, 1H), 8.37 (s, 1H), 8.30 (dd, 1H), 7.75-7.67 (m, 4H), 7.62-7.56 (m, 3H), 7.46-7.40 (m, H), 7.35-7.29 (m, 2H), 4.84 (t, 1H), 4.16 (s, 1H), 3.63-3.31 (m, 8H), 3.11 (t, 2H), 2.67-2.55 (m, 4H), 2.01-1.91 (m, 4H), 1.73-1.60 (m, 4H).

APCI (multimode) m/z: 719 [M+H].

Example 93

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(isopropylamino)ethyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): 6-fluoro-N-{CIS-4-[6-fluoro-1-[4'-(2-hydroxyethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

This compound was obtained in a manner analogous to the method described in Example 74, step (b).

ES+ (M+H) 621.

Stage (b): 2-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl methanesulfonate

This compound was obtained in a manner analogous to the method described in Example 90, step (a).

ES+ (M+H) 715.

Stage (in): 6-fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(isopropylamino)ethyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of 2-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl methanesulfonate (0.15 g, 0.21 mmol) and isopropyl is n (1 ml, 11,74 mmol) and potassium carbonate (0.29 grams, 2.10 mmol) in acetonitrile (10 ml) was heated at 70°C for 5 hours, the Reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 50-30% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,026 g, 18%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 9.47 (s, 2H), 8.36 (d, 1H), 8.23 (dd, 1H), 8.13 (s, 1H), 8.06 (t, 1H), 7.76-7.48 (m, 7H), 7.31-7.24 (m, 2H), 7.18-7.10 (m, 1H), 5.06 (t, 1H), 4.41 (s, 1H), 3.38-3.28 (m, 1H), 3.18-3.03 (m, 4H), 2.84-2.72 (m, 2H), 2.12 (d, 2H), 1.87-1.69 (m, 4H), 1.38 (d, 6H).

APCI (multimode) m/z: 678 [M+H].

Example 94

N-{CIS-4-[1-{4'-[2-(Dimethylamino)ethyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

A solution of 2-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl-methanesulfonate (0.15 g, 0.21 mmol) and dimethylamine (MTBE) M (10 ml, 20,70 mmol) and potassium carbonate (0.29 grams, 2.10 mmol) in acetonitrile (5 ml) was heated at 70°C for 3 hours, the Reaction mixture was cooled, poured into water (5 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a column Xterra, using the gradient 65-45% water 0.1%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,014 g, 10%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H), 8.24 (dd, 1H), 8.11 (s, 1H), 8.07 (t, 1H), 7.72 (d, 2H), 7.67-7.51 (m, 5H), 7.33-7.26 (m, 2H), 7.16 (dd, 1H), 5.06 (t, 1H), 4.44 (s, 1H), 3.29-3.22 (m, 2H), 3.15-3.09 (m, 2H), 2.87 (s, 6H), 2.83-2.76 (m, 2H), 2.13 (d, 2H), 1.88-1.70 (m, 4H).

APCI (multimode) m/z: 664,3 [M+H]

Example 95

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(4-methylpiperazin-1-yl)ethyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide.

A solution of 2-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl-methanesulfonate (0.15 g, 0.21 mmol) and 1-methylpiperazine (1 ml of 9.02 mmol) and potassium carbonate (0.29 grams, 2.10 mmol) in acetonitrile (10 ml) was heated at 70°C for 2 h, the Reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a Sunfire column, use the I gradient 95-60% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,022 g, 15%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H), 8.24 (dd, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.77-7.57 (m, 5H), 7.51 (s, 1H), 7.33-7.17 (m, 3H), 5.11-5.01 (m, 1H), 4.41 (s, 1H), 3.57-2.72 (m, 15H), 2.18-2.10 (m, 2H), 1.87-1.70 (m, 4H).

APCI (multimode) m/z: 719.3 [M+H].

Example 96

N-{CIS-4-[1-(4'-{2-[tert-Butyl(methyl)amino]ethyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

A solution of 2-{3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl-methanesulfonate (0.15 g, 0.21 mmol) and n-methyl-tert-butylamine (1 ml, to 8.34 mmol) and potassium carbonate (0.29 grams, 2.10 mmol) in acetonitrile (10 ml) was heated at 70°C for 5 hours, the Reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The crude product was purified preparative HPLC on a Sunfire column using a gradient of 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,043 g, 29%) as a white solid.

1H NMR (399.824 MHz, Dl3) δ 8.37 (d, 1H), 8.23 (dd, 1H), 8.14 (s, 1H), 8.08 (d, 1H), 7.77-7.69 (m, 2H), 7.64 (t, 1H), 7.58 (d, 2H), 7.50 (t, 1H), 7.31 (d, 2H), 7.25-7.20 (m, 1H), 5.10-5.01 (m, 1H), 4.40 (s, 1H), 3.59-3.52 (m, 1H), 3.34-3.26 (m, 1H), 3.06 (td, 1H), 2.87-2.75 (m, 6H), 2.15-2.12 (m, 2H), 1.85-1.70 (m, 4H), 1.46 (s, 9H)

APCI (multimode) m/z: 706,3 [M+H].

Example 97

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-piperazine-1-retil)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

2-{3'-[6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}ethyl methanesulfonate (0.15 g, 0.21 mmol), potassium carbonate (0.29 grams, 2.10 mmol) and N-BOC-piperazine (0.2 g, 1.07 mmol) were heated together at 70°C for 12 h in acetonitrile (10 ml). The reaction mixture was cooled, poured into water (50 ml) and was extracted with ethyl acetate. The organic portions were combined, dried (magnesium sulfate), filtered and evaporated. The residue was treated with hydrochloric acid (10 ml, 40,00 mmol) in dioxane and stirred for 16 hours the Solvent is evaporated. The crude product was purified preparative HPLC on a Sunfire column using a gradient of 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (0.015 g, 10%) as a white solid.

p> 1H NMR (400 MHz, DMSO-D6) δ 8.82 (dd, 1H), 8.59 (d, 1H), 8.40 (s, 1H), 8.34 (dd, 2H), 7.79-7.59 (m, 8H), 7.49-7.43 (m, 4H), 7.41-7.37 (m, 4H), 4.88 (m, 1H), 4.16 (s, 1H), 4.09-3.83 (m, 2H), 3.44-3.32 (m, 8H), 3.04-2.99 (m, 2H), 2.68-2.56 (m, 4H), 2.02 (d, 2H), 1.77-1.63 (m, 4H).

APCI (multimode) m/z: 705 [M+H].

Example 98

6-Fluoro-N-{CIS-4-[6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): [4-hydroxy-2-(morpholine-4-ylmethyl)phenyl]baronova acid

To a solution of 4-bromo-3-(morpholinomethyl)phenol (0.5 g, of 1.84 mmol) in THF (10 ml) was added tert-utility (to 3.67 ml, 5.51 mmol) and this reaction mixture was stirred at -78°C for 10 minutes, then was heated to 0°C for 15 minutes. The reaction mixture then was cooled to -78°C and added triisopropylsilyl (1,272 ml, 5.51 mmol). The reaction mixture was heated to room temperature and was stirred for 1 h was Added saturated NH4Cl and the reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with ethyl acetate (200 ml). The product was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine (50 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound (0,442 g, 97%). It is used in the if without additional purification.

ES (-) m/z: 236 [M-N].

Stage (b): 6-fluoro-N-{CIS-4-[6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The palladium (II) acetate (6,99 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,026 g, 0.06 mmol) were stirred together in acetonitrile (1.5 ml) for 10 minutes, after which the solution was added potassium carbonate (0,129 g of 0.93 mmol) in water (1.5 ml). Then were added 4-hydroxy-2-(morpholinomethyl)phenylboronic acid (0,074 g, 0.31 mmol) and 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.2 g, 0.31 mmol). The resulting suspension was stirred at 80°C for 16 hours the Crude reaction mixture was passed through a Chemelut cartridge, elwira DCM, and after concentration in vacuo got a brown oil. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (39 mg, 18%) as a white solid.

1H NMR (399.824 MHz, CDCl3) δ 8.39 (d, 1H), 8.24 (dd, 1H), 8.17 (s, 1H), 8.13 (t, 1H), 7.82 (dd, 1H), 7.72-7.71 (m, 1H), 7.65 (t, 2H), 7.48 (d, 1H), 7.37-7.28 (m, 3H), 7.18 (t, 1H), 7.00 (dd, 1H), 5.05-4.98 (m, 1H), 4.38 (s, 1H), 4.29 (s, 2H, 3.79-3.73 (m, 4H), 2.81-2.73 (m, 2H), 2.37 (s, 4H), 2.19-2.16 (m, 2H), 1.85-1.78 (m, 2H), 1.72-1.69 (m, 2H).

APCI (multimode) m/z: 708 [M+H].

Example 99

N-{CIS-4-[1-{2'-1(Dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a): {2-[(dimethylamino)methyl]-4-hydroxyphenyl}baronova acid

To a solution of 4-bromo-3-((dimethylamino)methyl)phenol (2,05 g, 8,91 mmol) in THF (40 ml) was added tert-utility (17,82 ml, 26,73 mmol) and this reaction mixture was stirred at -78°C for 10 minutes, then was heated to 0°C for 15 minutes. The reaction mixture then was cooled to -78° was added triisopropylsilyl (6,17 ml, 26,73 mmol). The reaction mixture was heated to room temperature and was stirred for 1 h was Added saturated NH4Cl and the reaction mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with ethyl acetate (200 ml). The product was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine (200 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound 2-((dimethylamino)methyl)-4-hydroxyflavanone acid (1.40 g, 81%) as a resin. It was used without further clean the key.

ES (-) m/z: 294 [M-N].

Stage (b): N-{CIS-4-[1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

The palladium (II) acetate (11 mg, 0.05 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,038 g, 0.09 mmol) were stirred together in acetonitrile (3 ml) for 10 minutes, after which the solution was added potassium carbonate (0,258 g of 1.87 mmol) in water (3 ml). Then were added 2-((dimethylamino)methyl)-4-hydroxyphenylarsonic acid (of 0.182 g of 0.93 mmol) and 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.3 g, 0.47 mmol). The resulting suspension was stirred at 80°C for 16 hours the Crude reaction mixture was passed through a Chemelut cartridge, elwira DCM, and after concentration in vacuo got a brown oil. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain still contaminated by the impurities of the product as a white solid. This compound was further purified preparative HPLC column Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as e is enta. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (31 mg, 10%) as a white solid.

1H NMR (399.824 MHz, CDCl3) δ 8.37-8.36 (m, 1H), 8.22-8.20 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.77-7.75 (m, 1H), 7.60-7.56 (m, 2H), 7.46 (d, 1H), 7.33 (s, 1H), 7.28-7.26 (m, 1H), 7.18-7.13 (m, 2H), 6.99 (d, 1H), 6.77 (dd, 1H), 5.04 (t, 1H), 4.42 (s, 1H), 3.37 (s, 2H), 2.79 (dd, 2H), 2.12 (s, 8H), 1.83-1.69 (m, 4H).

APCI (multimode) m/z: 666 [M+H].

Example 100

tert-Butyl 4-(2-{[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]amino}-2-oxoethyl)piperazine-1-carboxylate

To a solution of tert-butyl methyl ether 4-carboxymethyl-piperazine-1-carboxylic acid (0.125 g, 0.51 mmol) in DMF (3 ml) was added DIPEA (0,2404 g, 0,331 ml of 1.86 mmol)was then added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,1945 g, 0.51 mmol). This reaction mixture was stirred for 10 minutes. Then added 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g, 0.47 mmol) and the reaction mixture was stirred for 12 hours was Added water and the product was filtered to obtain specified in the connection header (0,176 g, 71%).

1H NMR (399.824 MHz, CDCl3) δ 8.38 (1H, d), 8.17 (1H, dd), 7.84 (1H, d), 7.73 (1H, dt), 7.64-7.60 (3H, m), 7.49 (1H, t), 7.45-7.42 (2H, m), 7.38-7.34 (1H, m), 7.27-7.25 (1H, m), 5.03 (1H, s), 4.28 (1H, d), 3.45 (4H, s), 3.02 (2H, s), 2.64-2.60 (2H, m), 2.49 (4H, s), at 1.91 (2H, d), 1.72-1.65 (4H, m), 1.47 (9H, s).

APCI(multimode) m/z: 657 [M+H].

Example 101

N-[CIS-4-(1-Biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]-2-piperazine-1-ylacetamide

To a solution of tert-butyl 4-(2-{[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]amino}-2-oxoethyl)piperazine-1-carboxylate (0,176 g, 0.27 mmol) in dioxane (2 ml) was added HCl (4 M in 1,4-dioxane) (3 ml, 12 mmol) and the reaction mixture was stirred within 10 hours, the Solvents evaporated. The crude product was purified preparative HPLC on a column Xterra, using the gradient 75-5% aqueous ammonia (0.1%) acetonitrile as eluent, to obtain specified in the connection header (0,071 g, 44%).

APCI (multimode) m/z: 557 [M+H].

Example 102

1-Biphenyl-3-yl-6-fluoro-3-[(3R)-pyrrolidin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H]-Dion

To a solution of 2-(biphenyl-3-ylamino)-5-fornicating acid (0,065 g, 0.21 mmol) in DMF (1.5 ml) was added 1,1'-carbonyldiimidazole (0,051 g, 0.32 mmol) and this reaction mixture was stirred for 10 minutes. Added tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate (0,0432 g, 0.23 mmol) and the reaction mixture was stirred at 35°C for 1 h was Added 1,1'-carbonyldiimidazole (0,1196 g of 0.74 mmol), then sodium hydride (60% in mineral oil) (0.015 g, to 0.63 mmol) and the reaction mixture was stirred for 30 minutes at 50°C. was Added water and the product was filtered. The residue was purified column flash chromatography, elwira a mixture of 10% ethyl acetate/hexane. Added 4M HCl in dioxane (10 ml) and was stirred for 24 h, the Solvents evaporated. The residue was purified column flash chromatography, elwira a mixture of 5% MEOH/DCM (0.2% aq. NH3), obtaining specified in the connection header (0,006 g, 7%) as a solid.

1H NMR (400 MHz at 90°C in DMSO-D6) δ 2.26-2.17 (2H, m), 3.24-3.17 (2H, m), 3.41-3.34 (2H, m), 5.61 (1H, s), 7.37 (2H, t), 7.46 (2H, t), 7.68-7.58 (5H, m), 7.74 (1H, d), 8.26-8.23 (1H, m), 8.54 (1H, s).

APCI (multimode) m/z: 403 [M+H].

Example 103

N-{CIS-4-[6-Fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

Stage (a): N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

N-{CIS-4-[6-Fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide was obtained from 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.85 g, 14,27 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2 g, 14,27 mmol) in a manner analogous to the method described in Example 36, step (b), with the formation specified in the subtitle compound as a white solid (4.6 g)./p>

1H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.31 (dd, 1H), 7.85-7.81 (m, 2H), 7.44 (dt, 1H), 7.33 (t, 1H), 7.21 (d, 1H), 6.42 (d, 1H), 4.82 (t, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 2.58-2.51 (m, 2H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.71-1.55 (m, 4H).

Stage (b): N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

N-{CIS-4-[6-Fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide was obtained from the product from step (a) (4.5 g, 7,47 mmol) and 4-formylphenylboronic acid (1,680 g, 11,21 mmol) in a manner analogous to the method described in Example 47, step (a)with education specified in the subtitle compound as a cream solid (3.75 g).

1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.59 (d, 1H), 8.33 (dd, 1H), 8.01 (dd, 2H), 7.94-7.86 (m, 4H), 7.67 (t, 1H), 7.47 (dtd, 1H), 7.21 (d, 1H), 6.41 (d, 1H), 4.85 (s, 1H), 4.08 (s, 1H), 3.74 (s, 3H), 2.60-2.54 (m, 2H), 2.25 (s, 3H), 1.98-1.93 (m, 2H), 1.72-1.60 (m, 4H).

Stage (in): N-{CIS-4-[6-fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

N-{CIS-4-[6-Fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-intstrumental}-1,5-dimethyl-1H-pyrazole-3-carboxamide was obtained from the product from step (b) (400 mg, 0.69 mmol) in a manner analogous to the method described in Example 49, with the formation of the decree of the frame in the title compound as a white solids (in the form of di-triptoreline salt) (142 mg).

1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.59 (d, 1H), 8.34 (dd, 1H), 7.85-7.77 (m, 4H), 7.67-7.59 (m, 3H), 7.43 (ddd, 1H), 7.20 (d, 1H), 6.42 (s, 1H), 4.85 (t, 1H), 4.39 (s, 2H), 4.08 (s, 1H), 3.98-3.92 (m, 2H), 3.75 (s, 3H), 3.70-3.59 (m, 2H), 3.33-3.23 (m, 2H), 3.19-3.08 (m, 2H), 2.63-2.53 (m, 2H), 2.25 (s, 3H), 1.96 (d, 2H), 1.72-1.59 (m ,4H).

[M+H]+=652 (multimode+).

Example 104

N-{CIS-4-[6-Fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

Stage (a): N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[6-Fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained from 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (6,53 g, mmol 13,60) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (2,87 g, 14,16 mmol) in a manner analogous to the method described in Example 36, step (b), with the formation specified in the subtitle compound as a white solid (2,598 g).

1H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.31 (dd, 1H), 7.84-7.82 (m, 2H), 7.49 (s, 1H), 7.45-7.42 (m, 1H), 7.33 (t, 1H), 7.29 (d, 1H), 4.81 (t, 1H), 4.10-4.07 (m, 1H), 3.96 (t, 2H), 2.75 (t, 2H), 2.57-2.52 (m, 2H), 1.92-1.83 (m, 6H), 1.69-1.59 (m, 4H).

Stage (b): N-{CIS-4-[6-fluoro-1-(4'-formilli enyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[6-Fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained from the product from step (a) (3,70 g of 5.89 mmol) and 4-formylphenylboronic acid (1,324 g, 8,83 mmol) in a manner analogous to the method described in Example 47, step (a), with the formation specified in the subtitle compound as a cream solid (2.28 g).

1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.59 (d, 1H), 8.33 (dd, 1H), 8.01 (d, 2H), 7.91-7.86 (m, 4H), 7.67 (t, 1H), 7.48-7.46 (m, 2H), 7.29 (d, 1H), 4.84 (t, 1H), 4.11-4.07 (m, 1H), 3.95 (t, 2H), 2.72 (t, 2H), 2.60-2.52 (m, 2H), 1.93-1.79 (m, 6H), 1.71-1.61 (m, 4H).

Stage (in): N-{CIS-4-[6-fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[6-Fluoro-1-[4'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide was obtained from the product from step (b) (306 mg, 0.50 mmol) in a manner analogous to the method described in Example 49, with education specified in the connection header in the form of a white solid substance (in the form of di-triptoreline salt) (334 mg).

1H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.31 (dd, 1H), 8.16-8.12 (m, 2H), 7.84-7.77 (m, 4H), 7.65 (t, 1H), 7.60 (d, 2H), 7.42 (d, 1H), 4.84 (t, 1H), 4.39 (s, 2H), 4.11-4.09 (m, 2H), 4.03-4.00 (m, 1H), 3.27-3.14 (m, 8H), 2.92-2.89 (m, 2H), 2.692.60 (m, 2H), 2.07 (d, 2H), 1.97-1.86 (m, 4H), 1.71-1.57 (m, 4H).

[M+H]+=678 (multimode+).

Example 105

1-(Dimethylamino)-N-{CIS-4-[1-(4'-{[[2-(dimethylamino)ethyl](methyl)amino]-methyl} - biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide

Stage (a): 1-(dimethylamino)-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-cyclopropanecarboxamide

1-(Dimethylamino)-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide was obtained from 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (7,83 g, 16.30 mmol) and 1-(dimethylamino)cyclopropanecarboxylic acid (2.00 g, 15,49 mmol) in a manner analogous to the method described in Example 36, step (b), with the formation specified in the subtitle compound as a foam (7.5 g).

1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.19 (dd, 1H), 7.86-7.81 (m, 1H), 7.68-7.65 (m, 1H), 7.31-7.27 (m, 2H), 5.02-4.92 (m. 1H), 4.20-4.14 (m, 1H), 2.73-2.60 (m, 2H), 2.26 (s, 6H), 2.00-1.82 (m, 3H), 1.73-1.58 (m, 3H), 1.18 (dd, 2H), 0,96 (dd, 2H).

Stage (b): 1-(dimethylamino)-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide

1-(Dimethylamino)-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide was obtained from the product from step (a) (2.66 g, 4.5 mmol)which was dissolved in ethanol (7.2 ml) and toluene (12 ml) was added 4-formylbenzeneboronic acid (0,675 g, 4,50 mmol) and 2 M aqueous solution of PA2CO3(6 ml). Added tetrakis(triphenylphosphine)palladium (0) (60 mg) and the mixture was heated at 85°C during the night. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with water and purified on SCX. The fractions containing the product were concentrated and stirred in acetone (30 ml) and 2 M aqueous HCl (1 ml) for 3 days. After concentration and azeotropic distillation has been specified in the subtitle compound as a foam (2.1 g).

1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.60 (d, 1H), 8.32 (dd, 1H), 8.02 (d, 2H), 7.92 (d, 2H), 7.88 (d, 2H), 7.68 (t, 1H), 7.47 (d, 1H), 4.88-4.77 (m, 1H), 3.96-3.53 (m, 7H), 3.88-3.84 (m, 2H), 1.99-1.90 (m, 2H), 1.64-1.49 (m, 4H), 1.40-1.22 (m, 4H). The hidden resonances peaks of water and DMSO.

Stage (in): 1-(dimethylamino)-N-{CIS-4-[1-(4'-{[[2-(dimethylamino)ethyl]-(methyl)amino]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide

1-(Dimethylamino)-N-{CIS-4-[1-(4'-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopropanecarboxamide was obtained from the product from step (b) (300 mg, of 0.53 mmol) in a manner analogous to the method described in Example 49, with the formation of specified in the title compound as a white solid which substances (in the form of di-triptoreline salt) (43 mg).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.41-8.27 (m, 1H), 7.91-7.68 (m, 4H), 7.69-7.59 (m, 1H), 7.59-7.50 (m, 2H), 7.47-7.37 (m, 1H), 4.92-4.72 (m, 1H), 4.25-3.93 (m, 1H), 3.93-3.79 (m, 1H), 2.81 (s, 6H), 2.09 (s, 3H), 1.99-1.85 (m, 2H), 1.67-1.46 (m, 4H), 1.43-1.13 (m, 4H). Other resonances obscured the peaks of DMSO.

[M+H]+=656 (multimode+).

Example 106

N-{CIS-4-[6-Fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a): N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[6-Fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide was obtained from 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,820 g, 1,71 mmol) and 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (0,342 g, 1.94 mmol) in a manner analogous to the method described in Example 36, step (b), with the formation specified in the subtitle compound in the form of a cream solid color (0,823 g).

1H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.32 (dd, 1H), 8.27 (s, 1H), 7.84-7.82 (m, 2H), 7.74 (d, 1H), 7.58 (d, 1H), 7.45-7.43 (m, 1H), 7.35-7.31 (m, 2H), 6.86 (d, 1H), 4.85 (t, 1H), 4.21-4.17 (m, 1H), 2.67-2.55 (m, 5H), 2.01 (d, 2H), 1.76-1.63 (m, 4H).

Stage (b): N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrim the DIN-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[6-Fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide was obtained from the product from step (a) (0,823 g, 1,29 mmol) and 4-formylphenylboronic acid (0,290 g of 1.93 mmol) in a manner analogous to the method described in Example 47, step (a), with the formation specified in the subtitle compound as a cream solid (0,611 g).

1H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.60 (d, 1H), 8.34 (dd, 1H), 8.26 (s, 1H), 8.02-8.00 (m, 2H), 7.94-7.91 (m, 2H), 7.91-7.87 (m, 2H), 7.74 (d, 1H), 7.67 (t, 1H), 7.55 (d, 1H), 7.49-7.47 (m, 1H), 7.33-7.29 (m, 1H), 6.85 (d, 1H), 4.89 (t, 1H), 4.21-4.17 (m, 1H), 2.68-2.58 (m, 5H), 2.02 (d, 2H), 1.77-1.66 (m, 4H).

Stage (in): N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)-biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide

The product from step (b) (300 mg, 0.49 mmol) was subjected to interaction with tert-butyl piperazine-1-carboxylate (181 mg, 0.97 mmol) in a manner analogous to the method described in Example 49, with raw oil. Protection was removed in a manner analogous to the method of Example 52, obtaining specified in the title compounds as white solids (in the form of di-triptoreline salt) (0,253 g).

1H NMR (400 MHz, DMSO) δ 8.81-8.69 (m, 1H), 8.59 (d, 1H), 8.47-8.43 (m, 1H), 8.34 (dd, 1H), 7.95-7.89 (m, 1H), 7.80-7.79 (m, 1H), 7.74-7.71 (m, 3H), 7.65-7.58 (m, 2H), 7.52-7.40 (m, 3H), 6.99 (d, 1H), 4.88 (t, 1H), 4.19-4.15 (m, 1H), 4.0-2.60 (m, 15H), 2.05 (d, 2H), 1.77-1.65 (m, 4H).

[M+H]+=687 (multimode+).

The compounds listed in Table 4 (see to the end of the description), were obtained in a similar way in the form of solid substances from the corresponding aldehyde and the appropriate amine using the method described above in Example 49.

Source materials for the Examples below, either available commercially or can be easily obtained by experts in the field of standard methods from known starting compounds or methods described in the Examples above.

X-ray diffraction on the powder (XRPD) were recorded using a PANalytical CubiX PRO (wavelength of x-rays 1,5418 Å, si source, a voltage of 45 kV, emission 40 mA). The samples were scanned from 2-40° 2Θ with a step of 0.02° and 100-second countdown using detector X celerator detector (active length of 2.54° 2Θ).

Example 134

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt, mono-methanesulfonate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,341 g, 0.49 mmol) in tO (10 ml), heated to 50°C., was added methanesulfonyl acid (0,02 ml, 0.49 mmol). This mixture was allowed to cool to room temperature overnight. Solid, which was precipitate was isolated by filtration to obtain a white solid. It was then dried over night at 40°C under vacuum to obtain specified in the title compound (214 mg).

Elemental analysis: Found: C, 55,47; N, To 5.58; N, 13,31. With38H36F2N8About3·1,SN3SO3N·1,8H2O requires C, 55,47; N, 5,32; N, 13,14%.

Example 135

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt di-methanesulfonate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.8 g, of 1.16 mmol) in EtOH (25 ml), heated to 50°C., was added methanesulfonyl acid (0.075 ml, of 1.16 mmol). This mixture was allowed to cool to room temperature for 1 hour. Solid, which was precipitate was isolated by filtration and was dried over the weekend under vacuum at 40°C with obtaining specified in the title compound (470 mg).

Elemental analysis: Found: C, 52,62; N, lower than the 5.37; N, 12,54. With38H36F2N8O3·1,SN3SO3N·1,5H2O require the em S, 52,83; N, TO 5.21; N, 12.32 PER CENT.

Example 136

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt three-methanesulfonate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.8 g, of 1.16 mmol) in ethanol (25 ml), heated to 50°C., was added methanesulfonyl acid (0,150 ml, 2.32 mmol). This mixture was allowed to cool to room temperature for 1 hour, but solid matter in the sludge is not dropped. The mixture was stirred for 48 hours, and after this time the solid was precipitate. It was isolated by filtration and dried overnight at 40°C. under vacuum to obtain specified in the title compound (620 mg).

Elemental analysis: Found: C, 49,29; N, To 5.21; N, 11,46. With38H36F2N8O3·2,SN4O3S·1,1N2O ask, 49,48; N, 5,07; N, 11,27%.

Example 137

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt benzoate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-CT is oksamida (0.8 g, to 1.16 mmol)in EtO (25 ml), heated to 50°C., was added benzoic acid (0,141 g of 1.16 mmol). This solution was stirred at room temperature over night, but solid matter in the sludge is not dropped. The ethanol is evaporated under vacuum obtaining specified in the title compound (940 mg).

Example 138

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt, mono-1,2-etandisulfonat

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) in EtOH (10 ml), heated to 50°C., was added 1,2-identicalto acid was 0.138 g, to 0.72 mmol). This mixture was allowed to cool to room temperature for 1 hour and then stirred at room temperature for 48 hours. Solid, which was precipitate was isolated by filtration and dried under vacuum at 40°C with obtaining specified in the title compound (480 mg).

Elemental analysis: Found: C, 53,56; N, From 5.29; N, 11,96. With38H36F2N8O3·0,9C2H6About6S2·1,7N2O·0.8 ethanol requires, To 53.5; H, 5,38; N, 12,06%.

Example 139

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyri is up[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a Hemi-salt of 1,2-ethicolegal acid

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) in EtOH (10 ml), heated to 50°C., was added 1,2-identicalto acid (0,069 g, 0.36 mmol). This mixture was allowed to cool to room temperature for 1 hour and then stirred at room temperature for 48 hours. Solid, which was precipitate was isolated by filtration and dried under vacuum at 40°C with obtaining specified in the title compound (440 mg).

Elemental analysis: Found: C, 58,11; N, To 5.58; N, 14,2. With38H36F2N8O3·0,45C2H6About6S2·1,7N2O requires C, To 57.9; H, 5,26; N, 13,89%.

Example 140

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 1-hydroxy-2-naphthoic acid

A solution of 1-hydroxy-2-naphthoic acid (or 0.027 g, 0.14 mmol) was dissolved in 1,2-dimethoxyethane (2 ml)was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.1 to g, 0.14 mmol) in 1,2-dimethoxyethane (2 ml) and the solution was stirred for 16 hours. The precipitate is delali by filtration and dried to obtain specified in the connection header (0,089 g) in crystalline form A. Picture XRPD of crystalline form a of example 140 presents on Fig.

Example 141

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with DL-almond acid

A solution of DL-almond acid (0,033 g, 0.22 mmol) was dissolved in 1,2-dimethoxyethane (3 ml)was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.15 g, 0.22 mmol) in 1,2-dimethoxyethane (3 ml) and the solution was stirred for 72 hours. The precipitate was isolated by filtration and dried to obtain specified in the title compound as a colourless solid (96 mg).

Example 142

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with L-tartaric acid

A solution of L-tartaric acid (0,043 g, 0.29 mmol) in methanol (2 ml) was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.20 g, 0.29 mmol) in methanol (2 ml). The resulting suspension was heated to the boil, then leave to cool and mix in ECENA 16 hours. The precipitate was isolated by filtration and dried to obtain specified in the title compound as a colourless solid (154 mg).

Example 143

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with a pair of toluensulfonate acid

A solution of para-toluensulfonate acid (0.05 g, 0.29 mmol) in 1,2-dimethoxyethane (2 ml) was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.20 g, 0.29 mmol) in 1,2-dimethoxyethane (2 ml). The resulting suspension was heated to boiling, then she was allowed to cool and was stirred for 16 hours. The precipitate was isolated by filtration and dried to obtain specified in the title compound as a colourless solid (167 mg).

Example 144

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with nicotinic acid

A solution of nicotinic acid (0.036 g, 0.29 mmol) in dichloromethane (2 ml) and methanol (0.1 ml) was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrim the DIN-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.20 g, 0.29 mmol) in dichloromethane (2 ml). The resulting suspension was stirred for 16 hours, then concentrated to obtain specified in the title compound as a colourless solid (171 mg).

Example 145

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with adipic acid

A solution of adipic acid (0,042 g, 0.29 mmol) in 1,2-dimethoxyethane (2 ml) was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.20 g, 0.29 mmol) in 1,2-dimethoxyethane (2 ml). The resulting suspension was stirred for 48 hours, then isolated by filtration to obtain specified in the title compound as a colourless solid (143 mg).

Example 146

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt trihydrochloride

Concentrated hydrochloric acid (2.2 ml) was added to a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-a]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (1.6 g, 2.32 mmol) in ethanol (20 ml). The resulting suspend the Yu was diluted with additional ethanol (750 ml) and subjected to recrystallization in the solvent, then left to suspendibility within 48 hours. The solid precipitate was then collected by filtration, washed with ethanol (200 ml) and dried in vacuum to obtain specified in the title compound as a colourless solid (1.45 g).

1H NMR (400 MHz, DMSO-d6) δ 9.89-9.59 (m, 2H), 8.84 (dd, 1H), 8.60 (d, 1H), 8.42 (s, 1H), 8.34 (dd, 1H), 7.86-7.59 (m, 9H), 7.54-7.38 (m, 2H), 4.88 (t, 1H), 4.51-4.27 (m, 2H), 4.16 (s, 1H), 3.97-3.34 (m, 8H), 2.69-2.55 (m, 2H), 2.02 (d, 2H), 1.79-1.60 (m, 4H).

Analysis on ions of chlorine: Found: Cl 12,83%. C38H36F2N8About3·3l requires Cl, 13,20%.

Example 147

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with sulfuric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved by heating in ethanol (7 ml) and this solution was allowed to cool to room temperature. Added additional amount of sulfuric acid (50%) (15 drops) and the mixture was stirred at room temperature overnight. The precipitate was recovered by filtration and dried to obtain specified in the title compound as a white solid (0.35 g).

Example 148

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)bifani the-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt of mono-bansilalpet

6-Fluoro-N-{CIS-4-[fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.3 g, 0.43 mmol) was dissolved by heating in ethanol (3 ml) and was allowed to cool to room temperature. Add benzosulfimide acid (0,069 g, 0.43 mmol) and the mixture was stirred at room temperature for 2 days. The solid is collected by filtration and dried to obtain specified in the title compound as a white solid (0.26 g).

1H NMR (400 MHz, DMSO-d6) δ 8.79 (1H, dd), 8.59 (1H, d), 8.49 (1H, s), 8.37 (1H, s), 8.34 (1H, dd), 7.79-7.71 (3H, m), 7.68-7.63 (3H, m), 7.62-7.58 (3H, m), 7.47-7.37 (4H, m), 7.34-7.28 (2H, m), 4.87 (1H, t), 4.20 (1H, s), 3.59 (2H, s), 3.30-3.29 (2H, s), 3.10-3.07 (4H, m), 2.59-2.54 (4H, m), 2.04-1.96 (2H, m), 1.76-1.62 (4H, m).

Example 149

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2.5-dichlorobenzenesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved by heating in ethanol (3 ml) and was allowed to cool to room temperature. Added 2,5-dichlorobenzenesulfonic acid (0,164 g to 0.72 mmol) and the mixture peremeshivaniya room temperature for 48 hours. The solid is collected by filtration and dried to obtain specified in the title compounds as white solids (0,289 g).

Example 150

6-Fluoro-N-{1{IP-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt, mono-malonate

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.3 g, 0.43 mmol) was dissolved by heating in ethanol (3 ml) and was allowed to cool to room temperature. Added malonic acid (0,045 g, 0.43 mmol) and the mixture was stirred at room temperature for 14 days. The solid is collected by filtration and dried to obtain specified in the title compounds as white solids (0,192 g).

1H NMR (400 MHz, DMSO-d6) δ 8.81-8.77 (1H, m), 8.59 (1H, d), 8.37 (1H, s), 8.34 (1H, dd), 7.79-7.70 (3H, m), 7.68-7.58 (4H, m), 7.47-7.36 (4H, m), 4.87 (1H, t), 4.20 (1H, s), 3.60 (2H, s), 3.07 (4H, d), 2.71 (2H, s), 2.63-2.54 (4H, m), 2.49-2.45 (4H, m), 2.03-1.96 (2H, m), 1.77-1.61 (4H, m).

Example 151

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt three-2,5-dichlorobenzenesulfonate

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]PI is kidin-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved by heating in ethanol (20 ml). While this solution is still warm solution was added 2,5-dichlorobenzenesulfonic acid (0,562 g, 2.48 mmol) in ethanol (5 ml) and the mixture was stirred at room temperature overnight. The solid is collected by filtration and dried to obtain specified in the title compound as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.93 (1H, s), 8.78 (1H, s), 8.59 (1H, d), 8.53 (1H, s), 8.34 (1H, dd), 7.96-7.92 (1H, m), 7.84 (2H, dd), 7.82-7.76 (5H, m), 7.68-7.58 (5H, m), 7.45-7.38 (6H, m), 4.88 (1H, t), 4.18 (1H, s), 4.60-3.93 (12H, m), 2.68-2.58 (2H, m), 2.08-2.01 (2H, m), 1.77-1.61 (4H, m).

Example 152

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt di-2,5-dichlorobenzenesulfonate

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved by heating in ethanol (20 ml). While this solution is still warm solution was added 2,5-dichlorobenzenesulfonic acid (0,562 g, 2.48 mmol) in ethanol (5 ml) and the mixture was stirred at room temperature overnight. The solid is collected by filtration and dried. Was added ethanol (50 ml) and the suspension was stirred at room temperature overnight to obtain specified in the header is VCE compound as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.87 (1H, s), 8.80 (1H, s), 8.59 (1H, d), 8.46 (1H, s), 8.34 (1H, dd), 7.85-7.73 (7H, m), 7.68-7.50 (4H, m), 7.45-7.37 (5H, m), 4.88 (1H, t), 4.20 (1H, s), 3.92-3.59 (12H, m), 2.69-2.55 (2H, m), 2.07-2.00 (2H, m), 1.77-1.61 (4H, m).

Example 153

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with stearic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (500 mg, 0,724 mmol) was dissolved in Meon (14 ml) under heating was added stearic acid (453 mg, of 1.59 mmol) and heating was continued until until everything went into solution. The mixture was allowed to cool to room temperature. Precipitated precipitated solid was collected, washed Meon and dried in air to obtain specified in the connection header in the form of solids.

Example 154

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2,4,6-trimethylbenzenesulfonamide acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 mg, of 0.58 mmol) and 2,4,6-trimethylbenzene is AlfaNova acid (116 mg, of 0.58 mmol) were mixed in THF (10 ml)was heated to dissolve, and then was stirred for 10 min, then evaporated to dryness to obtain specified in the connection header in the form of solids.

Example 155

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2,4,6-trimethylbenzenesulfonamide acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 mg, of 0.58 mmol) and 2,4,6-trimethylbenzenesulfonyl acid (232 mg, of 1.16 mmol) were mixed in THF (10 ml), the resulting solution was added Meon (5 ml), then was stirred for 10 min and then evaporated to dryness to obtain specified in the connection header in the form of solids.

Example 156

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2,4,6-trimethylbenzenesulfonamide acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 mg, of 0.58 mmol) and 2,4,6-trimethylbenzenesulfonyl acid (348 mg, of 1.74 mmol) were mixed in THF (10 ml), was added Meon (5ml), was heated until then, until all has passed into solution, and then was stirred for 10 min, then evaporated to dryness to obtain specified in the connection header in the form of solids.

Example 157

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt tri-phosphate

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (500 mg, 0,724 mmol) was dissolved in Meon (14 ml) was cautiously heated and added phosphoric acid (85 wt.%, 14,7 M, 0.25 ml, 3.6 mmol). The mixture was stirred, there was a thick white precipitate. Stirring was continued for 4 days at room temperature and the solid was filtered off, washed with a small amount of the Meon and dried in air to obtain specified in the title compound as a white powder.

Elemental analysis: Found: C, 45,48; N, equal to 4.97; N, 11.25 per cent. With38H36F2N8O3·3,N3PO4requires, 45,49; N, 4,58; N, 11,17%.

Example 158

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with phosphoric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazin the-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (230 mg, 0.33 mmol) was dissolved in methanol (10 ml) and treated with 1 M phosphoric acid (of 0.11 ml, 1/3 equiv.) and the mixture was left evaporated to obtain specified in the title compound as a white solid.

Example 159

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with phosphoric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (230 mg, 0.33 mmol) was dissolved in methanol (10 ml)was treated with 1 M phosphoric acid (0.33 ml, 1 equiv.) and left is evaporated to obtain specified in the title compound as a white solid.

Example 160

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with phosphoric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (230 mg, 0.33 mmol) was dissolved in methanol (10 ml)was treated with 1 M phosphoric acid (0,66 ml, 2 equiv.) and left is evaporated to obtain specified in the title compound as a white solid.

P the emer 161

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 1.5 EQ. citric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,501 g, 0.73 mmol) suspended in ethanol (16 ml) and was heated to 60°C. After 30 minutes, was added an additional amount of ethanol (10 ml). After 15 min the solution was separated into a separate flask from the remaining adhesive solids and heated at 60°C. was Added citric acid (0,139 g, 0.73 mmol), which led to the precipitate, which was gradually dissolved with the formation of a white suspension and a yellow sticky solid. Suspension decantation and left to cool to room temperature, then concentrated to obtain specified in the connection header in the form of a cream solid color (0,390 g).

Elemental analysis: Found: C, 55,19; N, 5,31; N, 10,82%. With38H36F2N8O3·1,50C6H8O7·N2O requires C, 55,08; N, 5,22; N, 10.93%per.

Example 162

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt di-citrate

6-Fluoro-N-{CIS-4-[6-fluoro-,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,506 g, 0.73 mmol) suspended in ethanol (5 ml) was added dichloromethane (2 ml). The solution was added to ethanol (20 ml) at 60°C, then added to the solution of citric acid (0,563 g of 2.93 mmol) in a mixture of water:ethanol 2:3 (5 ml). The mixture was left to cool to room temperature, after which the formed precipitate. The mixture was left to mix overnight at room temperature, then filtered to obtain specified in the connection header in the form of a cream solid color (0,636 g).

Elemental analysis: Found: C, 55,19; N, At 4.99; N, 10,42%. C38H36F2N8O3·1,90 ° C6H8O7·1,05H2O requires C, 55,21; N, 5,00; N, 10,43%.

Example 163

6-Fluoro-N-{CIS-4-[b-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt trihydrobromide

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,501 g, 0.73 mmol) suspended in ethanol (5 ml) was added dichloromethane (2 ml). Added warm ethanol (20 ml) and the solution was heated to 60°C. was added dropwise Hydrobromic acid (48% in water) (0.3 ml, to 2.65 mmol) and the solution was left to cool to room temperature. The precipitate was filtered to obtain specified in the header is VCE connection in the form of a pale yellow solid (0,527 g).

Elemental analysis: Found: C, 45,63; N, 4,80; N, 11,23%. C38H36F2N8O3·2,85HBr·4,35H2O requires C, 45,63; N, 4,79; N, 11,21%.

Example 164

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2-naphtalenesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,248 g, 0.36 mmol) suspended in ethanol (1 ml) was added dichloromethane (2 ml). The solution was added to ethanol (10 ml) at 60°C, then added to the solution of the monohydrate naphthalene-2-sulfonic acid (of 0.081 g, 0.36 mmol) in ethanol (2 ml). The mixture was left to cool to room temperature and concentrated under vacuum to obtain specified in the connection header in the form of heterogeneous beige foam/glass (0,324 g).

Example 165

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2-naphtalenesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,238 g, 0.34 mmol) suspended in ethanol (1 ml) and obavljale dichloromethane (2 ml). The solution was added to ethanol (10 ml) at 60°C, then added to the solution of the monohydrate naphthalene-2-sulfonic acid (0.156 g, 0.69 mmol) in ethanol (4 ml). The mixture immediately turned into a gel-like solid at 60°C, and it was left to cool to room temperature, then concentrated under vacuum to obtain specified in the connection header in the form of a semi-solid gel cream color (0,376 g).

Example 166

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2-naphtalenesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,225 g, 0.33 mmol) suspended in ethanol (1 ml) was added dichloromethane (2 ml). The solution was added to ethanol (10 ml) at 60°C, then added to the solution of the monohydrate naphthalene-2-sulfonic acid (0,221 g, 0.98 mmol) in ethanol (4 ml). At 60°C was formed precipitate, and the mixture was left to cool to room temperature. Volatiles were removed in vacuum to obtain specified in the connection header in the form of a cream-colored powder (0,434 g).

Example 167

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohe the forces}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with L-malic acid

6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 mg, of 0.58 mmol) in methanol (20 ml) and dichloromethane (5 ml) was added L-malic acid (78 mg, of 0.58 mmol). The resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (478 mg).

Example 168

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with L-lactic acid

6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 mg, of 0.58 mmol) in methanol (20 ml) and dichloromethane (5 ml) was added L-lactic acid (52 mg, of 0.58 mmol). The resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (452 mg).

Example 169

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with succinic acid

6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (400 m is, of 0.58 mmol) in methanol (20 ml) and dichloromethane (5 ml) was added succinic acid (68 mg, of 0.58 mmol). The resulting solution was evaporated in vacuum to obtain specified in the title compound as a solid (468 mg).

Example 170

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with TRANS-butandiol acid

TRANS-Butandiol acid (8,40 mg, 0.07 mmol) was dissolved in ethanol (1 ml) and to this solution was added 6-fluoro-N-{1{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol), pre-dissolved in ethanol (1 ml). The mixture was stirred at room temperature for 1 hour. Added an additional aliquot of ethanol (2 ml) to facilitate suspendirovanie any played in the sludge solids. The mixture is then suspended within 48 hours. The precipitate was collected by filtration and dried in vacuum at room temperature to obtain specified in the connection header.

Example 171

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with furan-2-carboxylic acid

p> Furan-2-carboxylic acid (8,11 mg, 0.07 mmol) was dissolved in ethanol (1 ml) and to this solution was added 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol), pre-dissolved in ethanol (1 ml). The mixture was stirred at room temperature for 1 hour. Added an additional aliquot of ethanol (2 ml) to facilitate suspendirovanie any played in the sludge solids. The mixture is then suspended within 48 hours. The precipitate was collected by filtration and dried in vacuum at room temperature to obtain specified in the connection header.

Example 172

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved in ethanol (10 ml) and left to stand for a period of time for which precipitate colorless solid. This solid substance was collected by filtration and dried in vacuum at room temperature, then added with acetonitrile (3 ml) for 48 hours, then ochiltree is Ali, was dried in vacuum at room temperature to obtain specified in the connection header in the form of polymorph A. XRPD Pattern of polymorph And example 172 presented on Fig.

Example 173

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with citric acid

Citric acid (anhydrous) (of 0.014 g, 0.07 mmol) was dissolved in ethanol (1 ml) and to this solution was added 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol)pre-dissolved in ethanol (1 ml). The mixture was stirred at room temperature for 1 hour. Added an additional aliquot of ethanol (2 ml) to facilitate suspendirovanie any played in the sludge solids. The mixture is then suspended within 48 hours. The precipitate was collected by filtration and dried in vacuum at room temperature to obtain specified in the connection header.

Example 174

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with maleic acid

Maleic acid (8,40 mg, 0.07 mmol) was dissolved in ethanol is (1 ml) and to this solution was added 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol), previously dissolved in ethanol (1 ml). The mixture was stirred at room temperature for 1 hour. Added an additional aliquot of ethanol (2 ml) to facilitate suspendirovanie any played in the sludge solids. The mixture is then suspended within 48 hours. The precipitate was collected by filtration and dried in vacuum at room temperature to obtain specified in the connection header.

Example 175

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with TRANS-cinnamic acid

TRANS-Cinnamic acid (0,012 ml, 0.07 mmol) was dissolved in ethanol (1 ml) and to this solution was added 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol), pre-dissolved in ethanol (1 ml). The mixture was stirred at room temperature for 1 hour. Added an additional aliquot of ethanol (2 ml) to facilitate suspendirovanie any played in the sludge solids. The mixture is then suspended within 48 hours. The precipitate was collected by filtration and dried in vacuum at room temperature to obtain specified in the connection header

Example 176

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with benzosulfimide acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol) was dissolved in methanol (1 ml) under heating, and to this solution was added benzosulfimide acid (0,023 g, 0.14 mmol), dissolved in ethanol (1,000 ml). The mixture was stirred over night. The solid substance was collected by filtration to obtain specified in the connection header.

Example 177

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with benzosulfimide acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, to 0.72 mmol) was dissolved in ethanol (10 ml) under heating, and to this solution was added benzosulfimide acid (0,343 g, 2,17 mmol). The mixture was stirred overnight, during mixing, the resin was precipitated. The solvent decantation and the residue triturated with hot ethyl acetate to obtain bestwe the aqueous solids. This solid was filtered and dried to obtain specified in the connection header.

Example 178

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 1.5-naphthalenedisulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.05 g, 0.07 mmol) was dissolved in methanol (20 ml) by boiling under reflux. To this solution was added 1,5-naphthalenedisulfonic acid (0,021 g, 0.07 mmol). The mixture was evaporated to dryness and the residue was again dissolved in a mixture of water/ethanol by boiling under reflux. The mixture was cooled between 0-5° during the night and the crystalline product was collected by filtration and dried in vacuum to obtain specified in the connection header.

Example 179

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2.5-dichlorobenzenesulfonic acid

The product of example 149 (5 mg) was recrystallized from ethanol. The solution was left to cool to room temperature and the precipitate was collected by centrifugation to obtain specified in the connection header is crystalline form A. Picture XRPD of crystalline form a of example 179 presented on Fig.

Example 180

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt, mono-[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (2.00 g, 2,90 mmol) in ethanol (80 ml) (heated to dissolve) was added [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate acid (0,673 g, 2,90 mmol) in tO (12 ml) (heated to dissolve). The solvent was left to evaporate for 48 hours under nitrogen. The result has been specified in the header connection (2,68 g).

1H NMR (499,914 MHz, DMSO) δ 8.80-8.79 (m, 1H), 8.59 (d, 1H), 8.48 (s, 2H), 8.37 (s, 1H), 8.34 (dd, 1H), 7.78-7.60 (m, 7H), 7.46-7.38 (m, 4H), 4.90-4.85 (m, 1H), 4.17 (t, 1H), 3.59 (s, 2H), 3.10 (s, 4H), 2.86 (d, 1H), 2.72-2.57 (m, 7H), 2.36 (d, 1H), 2.26-2.20 (m, 1H), 2.00 (d, 2H), 1.93 (t, 1H), 1.87-1.82 (m, 1H), 1.79 (d, 1H), 1.75-1.64 (m, 4H), 1.30-1.24 (m, 2H), 1.05 (s, 3H), 0.74 (s, 3H).

Example 181

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with L-almond acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimi the Jn-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g) was dissolved in tO (10 ml) and (requires heat) was added L-almond acid (0,110 g, to 0.72 mmol)dissolved in ethanol. The obtained solid was filtered to obtain specified in the connection header in the form of solids.

Then some of the above salts suspended in the conditions described in the table below, with obtaining the specified crystalline form or polymorph forms, identified by x-ray diffraction on the powder (see graphics). Unless otherwise indicated, salt suspended in approximately 20 mg/ml of solvent.

Example 182

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with methanesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) was dissolved in methanol (10 ml) and dichloromethane (2 ml). Added methanesulfonyl acid (54 mg, or 0.57 mmol) and a solution of Koh which was interaval in vacuum to obtain specified in the title compound as a solid (454 mg).

Example 183

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with citric acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) was dissolved in methanol (10 ml) and dichloromethane (2 ml). Added citric acid (109 mg, or 0.57 mmol) and the solution was concentrated in vacuum to obtain specified in the title compound as a solid (509 mg).

Example 184

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt of 1,5-naphthalene-disulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) was dissolved in methanol (10 ml) and dichloromethane (2 ml). Added 1,5-naphthalene-disulfonate acid (163 mg, or 0.57 mmol) and the solution was stirred for 15 minutes, after which the formed solid substance. After the filter has been specified in the title compound as a solid (350 mg) in the crystal is form C. The filtrate was concentrated to obtain additional quantities specified in the title compound as a solid (110 mg) in crystalline form A. XRPD Pattern of crystalline form a of example 184 presented on Fig. Picture XRPD of crystalline form b of example 184 presented on Fig.

Example 185

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with benzosulfimide acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) was dissolved in methanol (10 ml) and dichloromethane (2 ml). Add benzosulfimide acid (89 mg, or 0.57 mmol) and the solution was concentrated in vacuum to obtain specified in the title compound as a solid (489 mg).

Example 186

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 1-hydroxy-2-naphthoic acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (260 mg, 0.37 to IMO is b) was dissolved in DME (2.5 ml) and to this solution was added 1-hydroxy-2-naphthoic acid (69 mg, of 0.37 mmol) in DME (2.5 ml). The resulting suspension was left to mix for 4 days, then collected by filtration and dried in vacuum to obtain specified in the title compound as a colourless solid (201 mg).

Example 187

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with a pair of toluensulfonate acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (514 mg, 0.73 mmol) was dissolved in DME (5 ml) and to this solution was added monohydrate p-toluensulfonate acid (125 mg, 0.73 mmol) in DME (5 ml). The resulting suspension was left to mix for two days, then collected by filtration and dried in vacuum to obtain specified in the title compound as a colourless solid (481 mg).

Example 188

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with hydrochloric acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-pyridin-2-carboxamide (250 mg, 0.35 mmol) was dissolved in DME (5 ml) and to this solution was added concentrated hydrochloric acid (0.2 ml, 2 mmol). The resulting suspension was left to mix for four days, then concentrated and suspended in tetrahydrofuran (5 ml) for 9 days. The resulting suspension was filtered and the solid was dried in vacuum to obtain specified in the title compound as a colourless solid (196 mg).

Example 189

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with sulfuric acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (500 mg, 0.71 mmol) was dissolved in DME (10 ml) and to this solution was added concentrated sulfuric acid (0,038 ml, 0.71 mmol). The resulting suspension was left to mix for two hours, then filtered and the solid was dried in vacuum to obtain specified in the title compound as a colourless solid (465 mg).

Example 190

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamid is in the form of a salt with D-almond acid

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]-propyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) in DME (5 ml) (heated to dissolve) was added D-almond acid (0,086 g, or 0.57 mmol) in DME (3 ml) and the reaction mixture (open to air) left mixed at 30°C for 2 hours (emitting white foam), then the solution was heated to 40°C. and blew a gaseous nitrogen up until the solvent has evaporated (20 hours). The result has been specified in the title compound in the form of solids.

Example 191

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 2.5-dichlorobenzenesulfonic acid

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]-propyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.4 g, or 0.57 mmol) in DME (5 ml) (heated to dissolve) was added 2,5-dichlorobenzenesulfonate acid (0,128 g, or 0.57 mmol) in DME (3 ml) (heated to dissolve) and the reaction mixture (open to air) left mixed at 30°C for 2 hours (emitting white foam), then the solution was heated to 4°C and blew a gaseous nitrogen until until the solvent has evaporated (20 hours). The result has been specified in the title compound in the form of solids.

Example 192

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide, salt is the hydrobromide

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (300 mg, 0.42 mmol) was dissolved by heating under reflux in a minimum quantity of ethanol (30 ml). To this solution was added a few drops of 48%aqueous Hydrobromic acid until acidic (pH 1). The mixture was left to cool over night. No precipitate was found. The mixture is then left in the refrigerator for 24 hours, during which he precipitate a pale yellow-brown solid. This substance was filtered and dried to obtain specified in the connection header in the form of solids.

Example 193

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt of benzoic acid

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-d is hydroperiod[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (300 mg, 0.42 mmol) was dissolved by heating under reflux in a minimum quantity of ethanol (30 ml). To this solution was added a solution of benzoic acid (51.8% of mg, 0.42 mmol), dissolved in tO (2 ml) and the mixture was left to cool over night. No sediment was not found, therefore the mixture was evaporated to dryness and the residue triturated with acetonitrile (10 ml) to give after stirring for several minutes colorless solid. This substance was filtered and dried to obtain specified in the connection header in the form of solids.

Example 194

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{3-[(3-hydroxypropyl)amino]propyl}-biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (of 3.64 g) was dissolved by heating in ethanol (350 ml), the solution was left to cool to room temperature to obtain specified in the title compounds as a white solid (2.37 g). Picture XRPD of polymorph And example 194 presented on Fig.

Then some of the above salts suspended in the conditions described in the table below, with obtaining the specified crystal form, identifitsirovany by using x-ray diffraction on the powder (see graphics). Unless otherwise indicated, salt suspended in approximately 20 mg/ml of solvent.

Example 195

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with sulfuric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.82 mmol) suspended in methanol (10 ml) and acetonitrile (10 ml). Added sulfuric acid (81 mg, 0.82 mmol) and the resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (581 mg).

Example 196

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with fumaric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.82 mmol) suspended in methanol (10 ml) and acetonitrile (10 ml). Added fumaric acid (95 mg, 0.82 mmol) and the obtained rest the p was concentrated in vacuum to obtain specified in the title compound as a solid (595 mg).

Example 197

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with 1-hydroxy-2-naphthoic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.82 mmol) suspended in methanol (10 ml) and acetonitrile (10 ml). Was added 1-hydroxy-2-naphthoic acid (155 mg, 0.82 mmol) and the resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (655 mg).

Example 198

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-Delco-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with methanesulfonic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.82 mmol) suspended in methanol (10 ml) and acetonitrile (10 ml). Added methanesulfonyl acid (79 mg, 0.82 mmol) and the resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (579 mg).

Example 199

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)bifani the-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with hydrochloric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.82 mmol) suspended in methanol (10 ml) and acetonitrile (10 ml). Added hydrochloric acid (10 M, 82 μl, 0.82 mmol) and the resulting solution was concentrated in vacuum to obtain specified in the title compound as a solid (582 mg).

Example 200

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with acetic acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (500 mg, 0.71 mmol) and acetic acid (85 mg, of 1.42 mmol) were combined in CH2Cl2(10 ml) and stirred, and then was evaporated to obtain specified in the connection header in the form of a brittle foam (580 mg).

Example 201

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide in the form of a salt with L-(+)-tartaric acid

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(2-pyrrolidin-1 ylethoxy)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0,502 g, 0.7 mmol) was dissolved in a mixture of dichloromethane (15 ml) and methanol (5 ml). Solution was added L-(+)-tartaric acid (0,107 g, 0.71 mmol) in methanol (6 ml) to obtain a transparent yellow solution. After 3 h the solvents were removed in vacuum to obtain a pale yellow foam (0,600 g).

Then some of the above salts suspended in the conditions described in the table below, with obtaining the specified crystal form, identified by x-ray diffraction on the powder (see graphics). Unless otherwise indicated, salt suspended in approximately 20 mg/ml of solvent.

The compounds listed in Table 5 (see below), were obtained similarly using the same methodology described above in Example 46.

Example 224

N-{CIS-4-[1-[2'-Bromo-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl{CIS-4-[1-(2'-bromo-4'-formylphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

To a solution of palladium acetate (0.035 g, 0.16 mmol)dissolved in acetonitrile (10 ml), was added 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (to 0.127 g, 0.31 mmol) and the mixture was stirred at room temperature for the period of the belts 10 minutes under nitrogen. To the resulting solution was added potassium carbonate (1,286 g of 9.30 mmol)dissolved in water (2 ml), and then 3,4-dibromosalicylic (0,818 g, 3.10 mmol) and tert-butyl{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1.8 g, 3.10 mmol)and the resulting mixture was heated at 70°C for another 2 h, the Reaction mixture was diluted with ethyl acetate (15 ml) and washed with saturated brine (10 ml). The organic layer was dried over sodium sulfate. The crude product was purified flash chromatography on silica, elwira gradient from 30 to 50% ethyl acetate in isohexane obtaining specified in the subtitle compound as a yellow resin (0,60 g).

[M-Boc]+=537/539 (multimode+).

Stage (b) Benzyl-4-({2-bromo-3'-[3-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-carboxylate

tert-Butyl{CIS-4-[1-(2'-bromo-4'-formylphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.6 g, were 0.94 mmol) and benzyl-1-piperidinecarboxylate (228 mg, 1.04 mmol) was stirred in DCM (20 ml) for 30 min, then was added triacetoxyborohydride sodium (0,259 g, 1,22 mmol) and the mixture was stirred for 4 h was Added water and the mixture was stirred for another 15 hours, the Phases were separated. The aq is the next phase was extracted with DCM and the combined organic phases were dried (Na 2SO4) and concentrated in vacuum. The crude product was purified flash chromatography on silica, elwira gradient from 40 to 60% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a colourless resin (0,60 g).

[M-BOC]+=741/743 (multimode+).

Stage (C) Benzyl-4-({2-bromo-3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-carboxylate

Benzyl-4-({2-bromo-3'-[3-{CIS-4-[(tert-butoxycarbonyl)amino]-cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-carboxylate (0.6 g, 0.71 mmol) was stirred in formic acid (16,67 ml, 434,54 mmol) for 5 h the Solution was diluted with methanol (20 ml) and evaporated in vacuum. The residue was transferred into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to obtain a colorless resin. (0.33 g). The resin was dissolved in acetonitrile (5 ml) at room temperature with 6-fluoro-imidazol[1,2A]pyridine-2-carboxylic acid (0,098 g, 0.54 mmol) and triethylamine (0,412 ml, 2,96 mmol). Dropwise within 5 minutes was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (1.57 M is THF, 0,376 ml, 0.59 mmol). The reaction mixture was stirred for 15 min, then was concentrated and suspended in water. The solid was filtered and dried in vacuum. The crude product was purified flash chromatography on silica, elwira gradient from 20 to 50% ethyl acetate in isohexane, then HPLC with reversed-phase Symmetry C8 (column 19 mm×50 mm), elwira TFA/MeOH 55%, organic isocratic gradient, obtaining specified in the subtitle compound (130 mg).

[M+H]+=903/905 (multimode+).

Stage (d) N-{CIS-4-[1-[2'-Bromo-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Benzyl-4-({2-bromo-3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperazine-1-carboxylate (80 mg, 0.09 mmol) in hydrochloric acid (5 M, 5 ml, 25,00 mmol) was heated at 80°C for 3 hours the Solution was cooled and concentrated in vacuum to obtain specified in the title compound as a solid (70 mg).

[M+H]+=769 (multimode+).

Example 225

6-Fluoro-N-{CIS-4-[6-fluoro-1-[5-methyl-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 2-[(3-Bromo-5-were)amino]--fornicative acid

The product was obtained from 2-chloro-5-fornicating acid (8.65 g, 49,29 mmol) and 3-bromo-5-methylaniline (9,17 g, 49,29 mmol) by the method of Example 241, step (a), obtaining specified in the subtitle compound as a dark brown solid (10,50 g).

1H NMR (500 MHz, DMSO) δ 10.37 (s, 1H), 8.51 (d, J=3.0 Hz, 1H), 8.11 (dd, J=8,9, and 3.2 Hz, 1H), 8.00 (d, J=12.0 Hz, 1H), 7.26 (d, J=9.7 Hz, 1H), 7.03 (s, 1H), 2.30 (s, 3H).

Stage (b) tert-Butyl{CIS-4-[({2-[(3-bromo-5-were)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}carbamate

The product was obtained from 2-[(3-bromo-5-were)amino]-5-fornicating acid (5 g, 15,38 mmol) and tert-butyl(CIS-4-aminocyclohexane)carbamate (3,30 g, 15,38 mmol) by the method of Example 241, step (b), obtaining specified in the subtitle compound (6,40 g).

1H NMR (300 MHz, CDCl3) δ 10.21 (s, 1H), 8.24 (d, J=2,9 Hz, 1H), 7.84 (d, J=1.7 Hz, 1H), 7.44 (dd, J=8,3, 2,9 Hz, 1H), 7.22 (s, 1H), 6.96 (s, 1H), 6.14 (s, 1H), 4.61 (s, 1H), 4.13 - 4.01 (m, 1H), 3.68 (s, 1H), 2.30 (s, 3H), 1.90-1.59 (m, 8H), 1.46 (s, 9H).

Stage (C) tert-Butyl{CIS-4-[1-(3-bromo-5-were)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[({2-[(3-bromo-5-were)amino]-5-herperidin-3-yl}carbonyl)amino]cyclohexyl}carbamate (6.4 g, 12,27 mmol) and 1,1'-carbonyldiimidazole (3.98 g, RUB 24.55 mmol) method and the Example 241, stage (b), heated to 70°C for 30 min with obtaining specified in the subtitle compound as a white solid (5,00 g).

1H NMR (300 MHz, DMSO) δ 8.59 (d, J=3.1 Hz, 1H), 8.28 (dd, J=7,7, 2,9 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 4.73 (t, J=18,0 Hz, 1H), 3.55 (s, 1H), 2.63-2.53 (m, 2H), 2.36 (s, 3H), 1.95-1.86 (m, 2H), 1.55-1.42 (m, 4H), 1.40 (s, 9H).

Stage (d) 3-(CIS-4-Aminocyclohexane)-1-(3-bromo-5-were)-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

Hydrogen chloride (4 M in dioxane, 10 ml, 40,00 mmol) was added to a solution of tert-butyl{CIS-4-[1-(3-bromo-5-were)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1.0 g, to 1.83 mmol) in dioxane (40 ml)and the reaction mixture was stirred for 12 hours. The solvent is evaporated, and the residue was dried to obtain hydrochloride salt specified in the subtitle compound in the form of dioxane MES (0,980 g).

1H NMR (300 MHz, DMSO) δ 8.61 (d, J=2,9 Hz, 1H), 8.29 (dd, J=7,7, 3.1 Hz, 1H), 7.97 (s, 3H), 7.52 (s, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 4.77 (t, J=16.1 Hz, 1H), 3.42-3.36 (m, 1H), 2.60-2.53 (m, 2H), 2.36 (s, 3H), 1.99-1.57 (m, 6H).

Stage (e) N-{CIS-4-[1-(3-Bromo-5-were)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

The product was obtained from 3-(CIS-4-aminocyclohexane)-1-(3-bromo-5-were)-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,98 g, 2.03 mmol) and 6-fluoro-what imidazo[1,2-a]pyridine-2-carboxylic acid (0,438 g, 2,43 mmol) by the method of Example 241, step (b), obtaining specified in the subtitle compound as not quite white solid (0.97 g).

1H NMR (300 MHz, DMSO) δ 8.80 (dd, J=3,8, 2.5 Hz, 1H), 8.60 (d, J=2,9 Hz, 1H), 8.37 (s, 1H), 8.32 (dd, J=7,9, 3.1 Hz, 1H), 7.77 (dd, J=10,0, a 5.4 Hz, 1H), 7.67 (d, J=7,3 Hz, 1H), 7.52 (s, 1H), 7.50-7.42 (m, 2H), 7.24 (s, 1H), 4.85 (t, J=and 17.9 Hz, 1H). 4.16 (s, 1H), 2.66-2.54 (m, 2H), 2.36 (s, 3H), 2.05-1.96 (m, 2H), 1.78-1.59 (m, 4H).

Stage (e) 6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formyl-5-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide

The product was obtained from N-{CIS-4-[1-(3-bromo-5-were)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (0,897 g of 1.47 mmol) and 4-formylbenzeneboronic acid (0,331 g, 2.21 mmol) by the method of Example 66, step (b), but with heating at 80°With during the night, obtaining specified in the subtitle compound as a beige solid (1.0 g).

1H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 8.79 (dd, J=4.2, and a 2.5 Hz, 1H), 8.60 (d, J=2,9 Hz, 1H), 8.36 (s, 1H), 8.33 (dd, J=7,8, 3.0 Hz, 1H), 8.00 (d, J=8,3 Hz, 2H), 7.91 (d, J=8,3 Hz, 2H), 7.78-7.63 (m, 4H), 7.44 (dd, J=18,3, 2.3 Hz, 1H), 7.29 (s, 1H), 4.95-4.79 (m, 1H), 4.20-4.12 (m, 1H), 2.70-2.53 (m, 2H), 2.45 (s, 3H), 2.07-1.94 (m, 2H), 1.80-1.56 (m, 4H).

Stage (W) 6-Fluoro-N-{CIS-4-[6-fluoro-1-[5-methyl-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-to Roxane

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-formyl-5-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.79, which mmol) and tert-butyl-1-piperidinecarboxylate (0,176 g, 0.95 mmol) were stirred together in DCM (15 ml) and acetic acid (0,047 g of 0.79 mmol) for 1 hour. To this mixture was added triacetoxyborohydride sodium (0,250 g, 1.18 mmol)and the reaction mixture was stirred for 16 h, then was poured into water and was extracted with DCM (2 x 20 ml). The extracts were combined and evaporated to dryness. The crude product was purified flash chromatography on silica, elwira gradient from 3 to 6% methanol in DCM. This product was dissolved in dioxane (10 ml) was added hydrogen chloride (4 M in dioxane, 5 ml, 20.00 mmol). The reaction mixture was stirred for 2 h, the solvent evaporated and the crude product was purified preparative HPLC on a Sunfire column using a gradient 75-50% water with 0.1% triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain salt specified in the connection header with triperoxonane acid as a white solid (80 mg).

1H NMR (300 MHz, DMSO) δ 8.80 (dd, J=4,4, 2.5 Hz, 1H), 8.59 (d, J=2,9 Hz, 1H), 8.38 (s, 1H), 8.33 (dd, J=7,9, 3.1 Hz, 1H), 7.79-7.66 (m, 4H), 7.61 (s, 1H), 7.52-7.44 (m, 4H), 7.21 (s, 1H), 4.94-4.81 (m, 1H), 4.23-4.10 (m, 1H), 3.94-3.72 (m, 4H), 3.25-3.11 (m, 4H), 2.95-2.76 (m, 2H), 2.66-2.52 (m, 2H), 2.43 (s, 3H), 2.06-1.95 (m, 2H), 1.8-1.59 (m, 4H).

[M+H]+=705 (multimode+).

Example 226

6-Fluoro-N-{CIS-4-[6-fluoro-1-[5-methyl-4'-({[2-(methylamino)ethyl]amino}methyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The product was obtained from 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formyl-5-methylbiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.79, which mmol) and Boc-N-methylethylenediamine (0,165 g, 0.95 mmol) by the method of Example 225, step (g), obtaining salt specified in the connection header with triperoxonane acid as a white solid (0,220 g).

1H NMR (300 MHz, DMSO) δ 9.33 (s, 2H), 9.10-8.80 (m, 2H), 8.86-8.81 (m, 1H), 8.61 (d, J=2,9 Hz, 1H), 8.42 (s, 1H), 8.36-8.31 (m, 1H), 7.81-7.71 (m, 4H), 7.68-7.55 (m, 4H), 7.48 (dd, J=18,3, and 2.1 Hz, 1H), 7.24 (s, 1H), 4.95-4.85 (m, 1H), 4.34 (s, 2H), 4.22-3.96 (m, 2H), 3.37-3.24 (m, 3H), 2.72-2.56 (m, 5H), 2.46 (s, 3H), 2.11-1.95 (m, 2H), 1.82-1.62 (m, 4H).

[M+H]+=693 (multimode+).

Example 227

N-{CIS-4-[6-Fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

Stage (a) tert-Butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H-yl]cyclohexyl}carbamate (10,00 g, to 17.23 mmol) and 4-formylbenzeneboronic acid (3.88 g, 25,84 mmol) by the method of Example 66, step (b), obtaining specified in the subtitle compound as a very pale yellow solid (8.44 grams).

1H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 8.59 (d, J=2,9 Hz, 1H), 8.30 (dd, J=7,9, 3.1 Hz, 1H), 8.04-8.00 (m, 2H), 7.94-7.85 (m, 4H), 7.67 (t, J=7.9 Hz, 1H), 7.48-7.45 (m, 1H), 6.53-6.49 (m, 1H), 4.81-4.73 (m, 1H), 3.58-3.53 (m, 1H), 2.67-2.54 (m, 2H), 1.91 (br d, J=13.1 Hz, 2H), 1.55-1.46 (m, 4H), 1.39 (s, 9H).

Stage (b) tert-Butyl{CIS-4-[6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,60 g of 4.66 mmol) and 1-isopropylpiperazine (1 ml of 6.99 mmol) by the method of Example 49 to obtain specified in the subtitle compound as a foam (2.55 g).

[M+H]+=671 (multimode+).

Stage (C) 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2.55 g, of 3.80 mmol) by the method of Example 225, step (g), with salt trihydrochloride specified under the head connection in the form of a white solid (2.5 to g).

[M+H]+=571 (multimode+).

Stage (d) N-{CIS-4-[6-Fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

To a solution of 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.29 mmol) in acetonitrile (5 ml) was added acetic acid (0,017 ml, 0.29 mmol) and triethylamine (298 mg, to 2.94 mmol). The mixture was stirred at room temperature for 10 min, then added anhydride papapostolou acid (1.57 M in THF, 0.2 ml, 0.29 mmol)and the mixture was stirred at room temperature for 2 hours the Mixture was poured into saturated sodium bicarbonate, and the organic substances were extracted with ethyl acetate (× 3). An ethyl acetate extracts were combined and evaporated to obtain a residue, which was purified HPLC with reversed phase (eluent: TFA(aq.)/MeCN). The appropriate fractions were combined, evaporated and triturated with ether to obtain salt triptorelin specified in the title compound as a white solid (132 mg).

1H NMR (400 MHz, DMSO) δ 8.51 (d, J=3.1 Hz, 1H), 8.23 (dd, J=7,7, 3.1 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.68-7.64 (m, 3H), 7.59 (t, J=7.8 Hz, 1H), 7.44 (d, J=8,2 Hz, 2H), 7.35 (d, J=8,2 Hz, 1H), 7.30 (s, 1H), 4.79 (t, J=13.1 Hz, 1H), 3.84 (s, 1H), 3.73 (s, 2H), 3.44-3.36 (m, 1H), 3.20-3.07 (m, 5H), 2.85-2.72 (m, 2H), 2.67-2.55 (m, 2H), 1.90 (d, J=12.0 Hz, 2H), 1.85 (s, 3H), 1.59-1.48 (m, 5H), 1.25 (d, J=6,7 Hz, 6N).

[M+H]+=613 (multimode+).

Soy is inane, in Table 6 (see the end of the description), were obtained in a similar manner in the form of solid substances from the appropriate carboxylic acid using the method described above in Example 227, stage (d).

Example 241

6-Fluoro-3-CIS-4{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage a) 5-fluoro-2-[(3-itfinal)amino]nicotinic acid

A 5 l vessel was loaded 2-chloro-5-fornicating acid (130 g, 740,55 mmol) and 3-stanlin (0,089 l, 740,55 mmol) in toluene (2.5 l) to give a brown suspension. The reaction mixture was heated under reflux to a moderate boil, then received the solution. Then portions over 6 h was added para-toluensulfonate acid (113 g, 592,44 mmol). Then the reaction mixture is boiled under reflux for 54 hours, the Reaction mixture was cooled to room temperature, was added an additional amount Lara-toluensulfonate acid (21 g) and additional toluene (1 l)and the product was heated at 105°C during the night. The resulting suspension was filtered. Was added water (7.3 l) and suspended for 16 hours. The mixture was filtered and washed with water. Then the solid was dried under vacuum to obtain ukazannoj is in the subtitle compound (192 g).

1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.50 (d, 1H), 8.23 (t, 1H), 8.11 (q, 1H), 7.59-7.57 (m, 1H), 7.36 (d, 1H), 7.11 (t, 2H).

Stage (b) tert-Butyl{CIS-4-[({5-fluoro-2-[(3-itfinal)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}carbamate

5-fluoro-2-[(3-itfinal)amino]nicotinic acid (187 g, 522,19 mmol), tert-butyl(CIS-4-aminocyclohexane)carbamate (140 g, 652,74 mmol) and triethylamine (0,524 l, 3759,77 mmol) was dissolved in DMF (1.5 l), and the solution was cooled to 5°C. the Anhydride papapostolou acid 50% in THF (0,416 l, 652,74 mmol) was added dropwise over a period of time of 1 h under nitrogen. Added additional quantity of a solution of the anhydride papapostolou acid 50% in THF (40 ml) and triethylamine (30 ml). After an additional hour at 10°C. the resulting solution was stirred at room temperature for 18 hours the Solution was poured into a mixture of 3% diethyl ether/water (7.5 l) and stirred over night. The precipitate was filtered off, washed with water and dried in vacuum. The result has been mentioned in the subtitle compound (250 g).

1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.48 (d, 1H), 8.39 (d, 1H), 8.21 (t, 1H), 8.15 (q, 1H), 7.51 (d, 1H), 7.30 (dt, 1H), 7.07 (t, 1H), 6.64 (s, 1H), 3.84 (s, 1H), 3.43 (s, 1H), 1.78-1.72 (m, 4H), 1.62-1.50 (m, 4H), 1.40 (s,, 9H).

Stage (C) tert-Butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

A 10 l vessel was loaded tert-is util-{CIS-4-[({5-fluoro-2-[(3-itfinal)amino]pyridine-3-yl}carbonyl)amino]cyclohexyl}carbamate (250 g, 450,94 mmol) in NMP (2,3 L) to give a brown solution. Added 1,1'-carbonyldiimidazole (146 g, 901,88 mmol)and the solution was cooled to 5°C. in Portions over a period of time of 2 hours was added sodium hydride (36,1 g, 901,88 mmol), maintaining the internal temperature below 10°C throughout the specified period. Was stirred for 1 hour at 15°C, then poured into water (4 l). The mixture was stirred over night at room temperature. Then was filtered, the solid, and the filter cake washed with water (0.5 l) and a mixture of 2:1 tert-BME/ISO-hexane (1 liter). Then the solid product was dried in vacuum to obtain specified in the subtitle compound (254 g).

1H NMR (400 MHz, DMSO) δ 8.58 (d, 1H), 8.28 (dd, 1H), 7.84-7.81 (m, 2H), 7.44-7.41 (m, 1H), 7.33 (t, 1H), 6.51 (s, 1H), 4.73 (t, 1H), 3.55 (s, 1H), 2.62-2.53 (m, 2H), 1.92-1.88 (m, 2H), 1.48 (m, 4H), 1.40 (s, 9H).

Stage (d) tert-Butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

tert-Butyl{CIS-4[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate was obtained from tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (13,90 g, 23,94 mmol) and 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (9 g, 23,94 mmol) by the method of Example 224, step (a), with the doctrine stated in the subtitle compound (5 g).

[M-BOC]+=475 (multimode+).

Stage (d) tert-Butyl{CIS-4-[6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

tert-Butyl{CIS-4-[6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (8 g, 13,92 mmol) and morpholine (1,457 ml, 16,71 mmol) was dissolved in DCM (100 ml) at 25°C., and the solution was left to mix for 1 hour. Then add triacetoxyborohydride sodium (4,43 g to 20.88 mmol) over a period of time of 10 min in air atmosphere. The resulting suspension was stirred for 2 h, then it was suppressed by addition of water (200 ml)and the organic layer was separated, diluted with a small amount of methanol (20 ml), dried (sodium sulfate) and concentrated to obtain specified in the subtitle compound as a brown solid (8.6 g).

1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=3.1 Hz, 1H), 8.21 (dd, J=7,2, 3.1 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.31-7.18 (m, 2H), 7.00 (d, J=2,8 Hz, 1H), 6.79 (dd, J=8,3, 2.7 Hz, 1H), 5.52-5.34 (m, 1H), 5.06-4.91 (m, 2H), 3.93 (s, 1H), 3.58 (t, J=4.4 Hz, 4H), 3.39 (s, 2H), 2.58 (d, J=12.0 Hz, 2H), 2.39 (s, 4H), 1.93 (d, J=13.3 Hz, 2H), 1.75-1.51 (m, 4H), 1.44 (s, 9H).

Stage (e) 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

[M+H]+=546 (multimode+).

Stage (W) 6 Torymidae[1,2-a]pyridine-2-carbaldehyde

Manganese oxide (IV) (1,990 ml, 115,03 mmol) portions was added to (6 torymidae[1,2-a]pyridine-2-yl)methanol (1,79 g, 10,77 mmol) in DCM (108 ml) at 25°C. for a time period of 5 minutes under nitrogen. The resulting suspension was stirred at 40°C for 30 minutes and Then was filtered solid oxidizer, and the filtrate was concentrated and triturated with ether, was isolated and washed with cold diethyl ether to obtain specified in the subtitle compound as a pale solid (0,605 g).

1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.86-8.81 (m, 1H), at 8.62 (d, J=0.5 Hz, 1H), 7.77 (dd, J=10,1, a 5.3 Hz, 1H), 7.51 (dddd, J=0,1, 10,3, to 8.2 and 2.2 Hz, 1H).

Stage (C) 6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(orphelin-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.75 g, is 3.21 mmol) and 6-torymidae[1,2-a]pyridine-2-carbaldehyde (0,684 g of 4.17 mmol) was stirred in DCM (20 ml) for 30 minutes and added triacetoxyborohydride sodium (0,884 g of 4.17 mmol). The mixture was stirred for 1 hour, then extinguished with water. The phases were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried (Na2SO4) and concentrated. The crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a yellow-brown solid (1.3 g).

1H NMR (400 MHz, DMSO) δ 8.70 (dd, J=4,4, 2.3 Hz, 1H), 8.58 (d, J=2,8 Hz, 1H), 8.28 (dd, J=7,7, 3.1 Hz, 1H), 7.83 (s, 1H), 7.58-7.49 (m, 3H), 7.41 (d, J=7.7 Hz, 1H), 7.33-7.23 (m, 2H), 7.12 (d, J=8,2 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8,3, 2.4 Hz, 1H), 4.77 (t, J=13,6 Hz, 1H), 3.80 (d, J=6,4 Hz, 2H), 3.42 (s, 4H), 3.41-3.34 (m, 1H), 3.27 (s, 2H), 2.85 (s, 1H), 2.79-2.65 (m, 2H), 2.26 (s, 4H), 1.89 (d, J=of 12.8 Hz, 2H), 1.76 (s, 1H), 1.56-1.35 (m, 4H).

[M+H]+=694 (multimode+).

Example 242

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(1-methyl-3-phenyl-1H-pyrazole-4-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and 1-methyl-3-phenyl-1H-pyrazole-4-Karbala the guide (to 61.4 mg, 0.33 mmol) was dissolved in 1,2-dichloroethane (4 ml) at 25°C., and the solution was left to mix for 10 minutes To the reaction mixture was added NMP (1 ml)and the solution was stirred for another 40 minutes Then added triacetoxyborohydride sodium (117 mg, 0.55 mmol) over a period of time of 10 min in air atmosphere. The resulting suspension was stirred at 25°C for 16 hours and Then added an additional portion of triacetoxyborohydride sodium (117 mg, 0.55 mmol)and the solution was stirred for another 4 h, then was dissolved in methanol (30 ml) and was loaded into a column of 10 g SCX. Impurities were suirable using methanol (50 ml), the product was isolated by washing 3,5 N. ammonia methanol (75 ml). The solvents were removed in vacuo and the resulting crude product was purified preparative HPLC column Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (77 mg).

1H NMR (500 MHz, DMSO) δ 9.51 (s, 1H), 8.82 (s, 1H), 8.59 (d, J=3.0 Hz, 1H), 8.29 (dd, J=7,7, 3.0 Hz, 1H), 7.92-7.50 (m, 5H), 7.45-7.08 (m, 5H), 6.88 (d, J=2.3 Hz, 1H), 6.76 (dd, J=8,4, 2.3 Hz, 1H), 4.80 (t, J=11,9 Hz, 1H), 3.86 (s, 3H), 3.74-3.48 (m, 2H), 3.42 (s, 4H), 3.27 (s, 2H), 2.78-2.74 (m, 3H), 2.25 (s, 4H), 2.02-1.81 (m, 2H), 1.71-1.24 (m, 4H).

[M+H]+=716 (multimode+).

Example 243

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-{the IP-4-[(3-phenylpropyl)amino]cyclohexyl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and 3-phenylpropionaldehyde (0,044 ml, 0.33 mmol) by the method of Example 242, but with cleaning preparative HPLC on a column (Waters X-Terra, using the gradient 95-50% water with 0.1% triperoxonane acid in acetonitrile as eluent, to obtain the salt of di-triptorelin specified in the title compound as a colourless solid (113 mg).

1H NMR (400 MHz, DMSO) δ 10.07-9.95 (m, 2H), 8.60 (d, J=2,8 Hz, 1H), 8.36-8.22 (m, 3H), 7.62 (s, 1H), 7.46-7.35 (m, 2H), 7.35-7.27 (m, 2H), 7.25-7.18 (m, 4H), 7.13-7.06 (m, 1H), 7.01-6.94 (m, 1H), 4.79 (s, 1H), 4.34-4.20 (m, 1H), 3.81-3.70 (m, 2H), 3.62-3.39 (m, 8H), 3.26-3.13 (m, 2H), 3.04-2.91 (m, 2H), 2.65 (t, J=8,1 Hz, 2H), 2.10-1.90 (m, 2H), 1.79 (d, J=14.1 Hz, 2H), 1.64 (d, J=11.0 cm Hz, 2H).

[M+H]+=664 (multimode+).

Example 244

3-{CIS-4-[(Cyclopropylmethyl)amino]cyclohexyl}-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and cyclopropanecarboxaldehyde (0,027 ml of 0.37 mmol) by the method of Example 243 from obtaining salts of di-triptorelin specified in the title compound as a colourless solid (29 mg).

1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2,8 Hz, 1H), 8.32 (dd, J=7,7, 3.1 Hz, 3H), 7.61 (s, 1H), 7.40 (d, J=7,4 Hz, 3H), 7.21 (s, 1H), 7.10 (d, J=5,9 Hz, 1H), 6.98 (s, 1H), 4.79 (d, J=12.0 Hz, 1H), 4.27 (s, 1H), 3.74 (s, 2H), 3.60-3.39 (m, 8H), 2.89 (d, J=5.6 Hz, 2H), 2.09 (d, J=14.1 Hz, 2H), 1.83-1.73 (m, 2H), 1.65 (d, J=10.5 Hz, 2H), 1.13-1.03 (m, 1H), 0.65-0.55 (m, 2H), 0.40-0.34 (m, 2H).

[M+H]+=600 (multimode+).

Example 245

3-{CIS-4-[(5-Chloro-2-hydroxybenzyl)amino]cyclohexyl}-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and 5-chloro-2-hydroxybenzaldehyde (57.4 mg, and 0.37 mmol) by the method of Example 243 from obtaining salts of di-triptorelin specified in the title compound as a colourless solid (0,226 g).

1H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 8.63-8.39 (m, 3H), 8.31 (dd, J=7,7, 3.1 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.50-7.37 (m, 4H), 7.30 (dd, J=8,7, and 2.6 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J=8,7 Hz, 2H), 4.80 (t, J=11.7 Hz, 1H), 4.26 (s, 1H), 4.13 (s, 2H), 3.81-3.46 (m, 8H), 3.33 (s, 2H), 2.64-2.55 (m, 2H), 2.14 (d, J=14.1 Hz, 2H), 1.80 (t, J=13,7 Hz, 2H), 1.66 (d, J=10,8 Hz, 2H).

[M+H]+=686 (multimode+).

Example 246

3-(CIS-4-{[(1-5-Dimethyl-1H-pyrazole-3-yl)methyl]amino}cyclohexyl)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) 1,2-Dimethyl-1H-imidazole-4-carbaldehyde

Manganese oxide (IV) (3,446 g, 39,64 mmol) portions was added to (1,2-dimethyl-1H-imidazol-4-yl)methanol (500 mg, of 3.96 mmol) in DCM (39,600 ml) at 25°C. for a time period of 5 minutes under nitrogen. The resulting suspension was stirred at 40°C for 30 minutes and Then the solid oxidizer was filtered with the use of gaskets made of fiberglass, and the filtrate was concentrated to obtain specified in the subtitle compound as a pale yellow oil, which was hardened to colorless needles upon standing (to 0.480 g).

1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 6.56 (s, 1H), 3.89 (d, J=5,1 Hz, 3H), 2.32 (d, J=0.5 Hz, 3H).

Stage (b) 3-(CIS-4-{[(1,5-Dimethyl-1H-pyrazole-3-yl)methyl]amino}cyclohexyl)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and 1,2-dimethyl-1H-imidazole-4-carbaldehyde (to 45.5 mg, and 0.37 mmol) by the method of Example 242 obtaining specified in the title compound as a colourless solid (0,117 g).

1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.58 (d, J=3.1 Hz, 1H), 8.28 (dd, J=7,8, 2,9 Hz, 1H), 7.59-7.48 (m, 2H), 7.41 (d, J=7.7 Hz, 1H), 7.35-7.25 (m, 1H), 7.13 (d, J=8,2 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8,5, and 2.6 Hz, 1H), 5.94 (s, 1H), 4.83-4.69 (m, 1H), 3.63 (s, 3H), 3.53 (s, 2H), 3.43 (s, 4H), 3.29 (s, 2H), 2.77 (s, 1H), 2.68 (d, J=9.7 Hz, 2H), 2.27 (s, 4H), 2.19 (s, 3H), 1.84 (d, J=12,8 Hz, 2H), 1.54-1.32 (m, 4H).

[M+H]+=654 (mu is Titova+).

Example 247

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-{CIS-4-[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-ylmethyl)amino]cyclohexyl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) 5,6,7,8-Tetrahydroimidazo[1,2-a]pyridine-2-ylmethanol

5,6,7,8-Tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (230 mg, 1.38 mmol) suspended in THF (2,287 ml) and was added to the complex of borane-tetrahydrofuran (6,92 ml, 6,92 mmol). The mixture was heated under reflux for 3 h, then cooled to room temperature over a period of time to 2 days, then was heated to boiling under reflux for a further 16 h and Then was added dropwise methanol (10 ml)and the reaction mixture was stirred for one hour, then concentrated in vacuo. The crude product was dissolved in methanol (5 ml) and passed through an SCX column, washing with methanol (100 ml) and elwira 3,5 N. ammonia methanol (75 ml). Basically the organic layer was concentrated to obtain specified in the subtitle compound as a yellow oil (134 mg).

1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 4.55 (s, 2H), 3.91 (t, J=5,9 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.01-1.87 (m, 4H).

Stage (b) 5,6,7,8-Tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde

Manganese dioxide (765 mg, 8,80 mmol) in portions added to 5,6,7,8-tetrahydro is dazo[1,2-a]pyridine-2-ylmethanol (134 mg, 0.88 mmol) in DCM (5 ml) at 25°C. for a time period of 5 minutes under nitrogen. The resulting suspension was stirred at 40°C for 30 minutes and Then the solid oxidizer was filtered with the use of gaskets made of fiberglass, and the filtrate was concentrated to obtain specified in the subtitle compound as a colourless oil, which was turned into a crystalline compound when standing (75 mg).

1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.51 (d, J=9.7 Hz, 1H), 4.04 (t, J=5,9 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.09-1.93 (m, 4H).

Stage (b) 6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-{CIS-4-[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-ylmethyl)amino]cyclohexyl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (215 mg, 0,39 mmol) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde (53 mg, 0.35 mmol) by the method of Example 242 obtaining specified in the title compound as a colourless solid substances (34 mg).

1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.58 (d, J=3.1 Hz, 1H), 8.27 (dd, J=7,7, 3.1 Hz, 1H), 7.56-7.48 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.30 (d, J=8,2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.80-6.72 (m, 2H), 4.76 (t, J=11.8 Hz, 1H), 3.90-3.76 (m, 1H), 3.51-3.38 (m, 7H), 3.29-3.25 (m, 4H), 2.75-2.60 (m, 4H), 2.35-2.19 (m, 4H), 1.90-1.74 (m, 5H), 1.52-1.32 (m, 4H).

[M+H]+=680 (multimode+).

Example 248

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}is illogical)-1-[4'-hydroxy-2'-(thiomorpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) tert-Butyl[(6-torymidae[1,2-a]pyridine-2-yl)methyl]{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

A suspension of 2-(chloromethyl)-6-torymidae[1,2-a]pyridine (2 g, 10,83 mmol), tert-butyl{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (5.20 g, 10,83 mmol) and substrate Hunya (EUR 7.57 ml, 43,34 mmol) in acetonitrile (20 ml) was heated at 80°C for 48 hours the Reaction mixture was cooled, filtered and concentrated in vacuum. The residue was dissolved in DCM (50 ml) was added di-tert-butyl carbonate (2,52 ml, 10,83 mmol). The mixture was stirred for 24 h, then was concentrated in vacuo, and purified flash chromatography on silica, gradient elwira 50%ethyl acetate in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow-brown resin (2,62 g).

1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=2,9 Hz, 1H), 8.16 (dd, J=7,3, 3.1 Hz, 1H), 7.99-7.95 (m, 1H), 7.84 (dt, J=7,0, 1.8 Hz, 1H), 7.63-7.61 (m, 1H), 7.47 (dd, J=9,8, and 5.2 Hz, 1H), 7.44 (s, 1H), 7.33-7.24 (m, 2H), 7.04 (dd, J=7,7, 2,1 Hz, 1H), 5.09-4.96 (m, 1H), 4.79 (s, 2H), 4.21-4.08 (m, 1H), 2.69-2.48 (m, 2H), 2.28-2.16 (m, 2H), 1.79-1.62 (m, 4H), 1.43 (s, 9H).

Stage (b) tert-Butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae,2-a]pyridine-2-yl)methyl]carbamate

The product was obtained from tert-butyl[(6-torymidae[1,2-a]pyridine-2-yl)methyl]{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.75 g, of 1.03 mmol) and 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0,255 g 1,03 mmol) by the method of Example 224, step (a), obtaining specified in the subtitle compound as a yellow-brown solid (0.625 g).

[M+H]+=723.

Stage (b) 6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(thiomorpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate (150 mg, 0.21 mmol) and thiomorpholine (28 mg, 0.27 mmol) was stirred in DCM (20 ml) for 30 minutes then added triacetoxyborohydride sodium (57 mg, 0.27 mmol). The mixture was stirred for 1 h, then added triperoxonane acid (1 ml). The mixture was stirred for 2 h and then extinguished with water. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated. The crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as Luanda, obtaining specified in the title compound as a solid (25 mg).

1H NMR (399,826 MHz, DMSO) δ 8.70 (d, J=4.4 Hz, 1H), 8.59 (d, J=2,8 Hz, 1H), 8.28 (dd, J=7,7, 2.8 Hz, 1H), 7.83 (s, 1H), 7.55-7.45 (m, 3H), 7.38 (d, J=7.9 Hz, 1H), 7.30 (d, J=8,4 Hz, 1H), 7.25 (dd, J=18.2, and 2.3 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.74 (dd, J=8,3, 2.4 Hz, 1H), 4.83-4.72 (m, 1H), 3.80 (d, J=6.2 Hz, 2H), 3.31 (s, 4H), 2.85 (s, 1H), 2.80-2.67 (m, 2H), 2.55-2.39 (m, 4H), 1.93-1.85 (m, 2H), 1.80-1.73 (m, 1H), 1.55-1.39 (m, 5H).

[M+H]+=710 (multimode+).

Example 249

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate (150 mg, 0.21 mmol) and hydrochloride homomorpholine (29 mg, 0.21 mmol) by the method of Example 248, step (b)obtaining specified in the title compound as a yellow solid (18 mg).

1H NMR (399,826 MHz, DMSO) δ 9.49 (s, 1H), 8.70 (dd, J=4,5, and 2.4 Hz, 1H), 8.58 (s, 1H), 8.28 (dd, J=7,7, 3.1 Hz, 1H), 7.83 (s, 1H), 7.56-7.48 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.28-7.22 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.95 (d, J=2.6 Hz, 1H), 6.73 (dd, J=8,5, and 2.6 Hz, 1H), 4.83-4.73 (m, 1H), 3.80 (d, J=5.6 Hz, 2H), 3.57 (t, J=6.0 Hz, 2H), 3.45 (d, J=7.7 Hz, 4H), 3.31 (s, 2H), 2.85 (s, 1 H), 2.79-2.65 (m, 2H), 1.94-1.84 (m, 2H), 1.81-1.72 (m, 1H), 1.67-1.58 (m, 2H), 1.54-1.37 (m, 5H).

[M+H]+=708 (multimode+).

P the emer 250

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[4'-hydroxy-2'-(piperidine-1-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate (150 mg, 0.21 mmol) and piperidine (0,021 ml, 0.21 mmol) by the method of Example 248, step (b)obtaining specified in the title compound as a yellow solid (16 mg).

1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.59 (s, 1H), 8.28 (d, J=4.4 Hz, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.56-7.47 (m, 2H), 7.45-7.36 (m, 1H), 7.34-7.19 (m, 3H), 7.12 (d, J=7.9 Hz, 1H), 6.85 (s, 1H), 6.73 (d, J=7,4 Hz, 1H), 4.85-4.69 (m, 1H), 3.80 (s, 2H), 3.19 (s, 2H), 2.85 (s, 1H), 2.80-2.66 (m, 2H), 2.28-2.15 (m, 5H), 1.95-1.82 (m, 2H), 1.81-1.71 (m, 1H), 1.55-1.37 (m, 3H), 1.36-1.20 (m, 5H).

[M+H]+=692 (multimode+).

Example 251

1-(2'-{[(2R,6S)-2,6-Dimethylmorpholine-4-yl]methyl}-4'-hydroxybiphenyl-3-yl)-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}[(6-torymidae[1,2-a]pyridine-2-yl)methyl]carbamate (150 mg, 0.21 mmol) and CIS-2,6-dimethylmorpholine (23,90 mg, 0.21 mmol) by the method of Example 248, stage (C), obtaining a decree of the frame in the title compound as a yellow-brown solid (38 mg).

1H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.70 (dd, J=4,5, 2.2 Hz, 1H), 8.60 (d, J=3.1 Hz, 1H), 8.29 (dd, J=7,7, 3.1 Hz, 1H), 7.84 (s, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.55-7.49 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.32-7.29 (m, 1H), 7.25 (ddd, J=9,9, to 8.5, 2.4 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.76 (dd, J=8,5, and 2.6 Hz, 1H), 4.82-4.72 (m, 1H), 3.80 (s, 2H), 3.43-3.18 (m, 4H), 2.85 (s, 1H), 2.81-2.66 (m, 2H), 2.65-2.56 (m, 1H), 1.89 (d, J=12,6 Hz, 2H), 1.83-1.74 (m, 1H), 1.58-1.37 (m, 6H), of 0.91 (d, J=38,2 Hz, 6N).

[M+H]+=722 (multimode+).

Example 252

5-[({CIS-4-[6-Fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)methyl]-2-methoxyphenyl-acetate

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.35 mmol) in 1,2-dichloroethane (2 ml) was added to 5-formyl-2-methoxyphenyl-acetate (102 mg, of 0.53 mmol) and was stirred for 15 min at room temperature. Added triacetoxyborohydride sodium (149 mg, 0.70 mmol)and the reaction mixture was left at room temperature over night. Was added water (2 ml), saturated sodium bicarbonate solution (3 ml) and DCM (2 ml)and the mixture was stirred 15 min, then separated. The organic solution was evaporated, and the residue was purified HPLC with reversed phase (ACE S, 0.2% aq. TFA-MeCN 95%-5% gradient). After evaporation of the fractions containing the product, trituration with ether and thorough drying in a vacuum of getting salt di-triptorelin specified what about the title compound as a white powder (70 mg).

1H NMR (300 MHz, DMSO) δ 8.79-8.64 (m, 1H), 8.60 (s, 1H), 8.35-8.25 (m, 1H), 7.82-7.56 (m, 4H), 7.54-7.25 (m, 5H), 7.23-7.12 (m, 1H), 4.89-4.74 (m, 1H), 4.48-3.83 (m, 11H), 3.79 (s, 3H), 3.54-2.94 (m, 8H), 2.26 (s, 3H), 2.15-1.98 (m, 2H), 1.88-1.55 (m, 4H), 1.24 (d, J=6.0 Hz, 6N). The remaining resonances partially hidden by the peaks of the solvent.

[M+H]+=749 (multimode+).

Example 253

Stage (a) tert-Butyl{CIS-4-[6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

tert-Butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2.234 g, 4 mmol) in 1,2-dichloroethane (30 ml) was treated with the hydrochloride 1,4-oxazepan (0,826 g, 6,00 mmol) at room temperature for 15 min, then was added triacetoxyborohydride sodium (3,39 g 16,00 mmol)and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, dried and evaporated, then the residue was again dissolved in DCM and washed with dilute aqueous Hcl. After evaporation of DCM solution was obtained is indicated in the subtitle compound as a white foam (2.3 g).

1H NMR (400 MHz, CDCl3) δ 12.66-12.55 (m, 1H), 8.38 (d, J=2,8 Hz, 1H), 8.22 (dd, J=7,2, 3.1 Hz, 1H), 7.81-7.72 (m, 2H), 7.72-7.64 (m, 3H), 7.55-7.51 (m, 1H), 7.37 (s, 2H), 5.09-4.91 (m, 2H), 4.40-4.12 (m, 2H), 3.96-3.72 (m, 3H), 3.61-3.48 (m, 1H), 3.23-2.77 (m, 2H), 2.66-2.52 (m, 6H) 2.09-1.87 (m, 2H), 1.74-1.59 (m, 4H), 1.42 (s, 9H).

Stage (b) 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,300 g of 3.57 mmol) in DCM (20 ml) was treated triperoxonane acid (3 ml, up 38.94 mmol) and stirred at room temperature overnight. All volatile materials are evaporated in vacuum, and the residue was again dissolved in DCM and thoroughly washed with saturated aqueous sodium bicarbonate solution. After drying with Na2SO4and evaporation has been specified in the subtitle compound as a white foam (2.0 g).

1H NMR (400 MHz, DMSO) δ 8.58 (d, J=2,8 Hz, 1H), 8.30 (dd, J=7,7, 3.1 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.71 (t, J=1.8 Hz, 1H), 7.66-7.57 (m, 3H), 7.42 (d, J=8,2 Hz, 2H), 7.36 (d, J=9.7 Hz, 1H), 4.76 (t, J=11.7 Hz, 1H), 3.70 (t, J=6.0 Hz, 2H), 3.66 (s, 2H), 3.63-3.58 (m, 2H), 3.13 (s, 1H), 2.75-2.57 (m, 6H), 1.85-1.76 (m, 2H), 1.74-1.65 (m, 2H), 1.65-1.53 (m, 2H), 1.52-1.43 (m, 2H). The remaining resonances partially hidden by the peaks of the solvent.

Stage (C) 3-{CIS-4-[(3-Chloro-4-methoxybenzyl)amino]cyclohexyl}-6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3M)-dione

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) and 3-chloro-4-methoxybenzyl the guide (94 mg, 0.55 mmol) by the method of Example 252 obtaining salts of di-triptorelin specified in the title compound as a white powder (69 mg).

1H NMR (400 MHz, DMSO) δ 10.29-10.15 (m, 1H), 8.82-8.66 (m, 2H), 8.61 (d, J=2,8 Hz, 1H), 8.31 (dd, J=7,7, 2.8 Hz, 1H), 7.86-7.81 (m, 1H), 7.80-7.75 (m, 2H), 7.70-7.67 (m, 1H), 7.67-7.61 (m, 2H), 7.50 (d, J=6,9 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 4.82 (t, J=11.3 Hz, 1H), 4.45 (s, 2H), 4.17 (s, 2H), 3.57-3.16 (m, 2H), 2.68-2.54 (m, 2H), 2.22-1.98 (m, 4H), 1.86-1.71 (m, 2H), 1.71-1.59 (m, 2H). Other resonances obscured the peaks of DMSO and water.

[M+H]+=698 (multimode+).

The compounds listed in Table 7 (see below), were obtained in a similar manner in the form of solid substances from the appropriate amine and aldehyde using the method described above in Example 252.

Example 263

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-{4'-[(piperidine-4-ylamino)methyl]biphenyl-3-yl}-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

A solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.8 g, 1,29 mmol) and tert-butyl-4-aminopiperidin-1-carboxylate (0,310 g, 1.55 mmol) in DCM (30 ml) was stirred for 30 minutes then added triacetoxyborohydride sodium (0,328 g, 1.55 mmol). The mixture was stirred at room temperature for 24 hours To the reaction mixture was added TFA (1 ml), the mixture was stirred course is 2 hours and then extinguished with water and methanol (0.5 ml) and concentrated in vacuum. Was added water, and then was stirred for 5 h and filtered to obtain a brown solid. The crude product was purified flash chromatography on silica, elwira gradient from 0 to 4% methanol in ethyl acetate. Pure fractions were evaporated to dryness to obtain specified in the connection header (0,230 g).

1H NMR (300 MHz, DMSO) δ 9.02 (s, 1H), 8.80 (s, 1H), 8.59 (s, 1H), 8.39-8.33 (m, 2H), 7.85-7.72 (m, 5H), 7.70-7.58 (m, 4H), 7.49-7.40 (m, 2H), 4.95-4.79 (m, 1H), 4.29-4.21 (m, 2H), 4.21-4.13 (m, 1H), 3.03-2.85 (m, 2H,), 2.65-2.53 (m, 2H), 2.32-2.20 (m, 4H), 2.08-1.96 (m, 3H), 1.80-1.61 (m, 6H).

[M+H]+=705 (multimode+).

Example 264

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[(4-methylpiperazin-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The product was obtained from 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (250 mg, 0.40 mmol) and 1-methylpiperazine (to 44.7 μl, 0.40 mmol) by the method of Example 54 to obtain specified in the title compound as a colourless solid (0,191 g).

1H NMR (400 MHz, DMSO) δ 8.83 (dd, J=4,0, 2.2 Hz, 1H), 8.59 (d, J=2,8 Hz, 1H), 8.42 (s, 1H), 8.34 (dd, J=7,7, 3.1 Hz, 1H), 7.83-7.70 (m, 6H), 7.64 (t, J=7.8 Hz, 1H), 7.55-7.45 (m, 4H), 7.41 (d, J=7.7 Hz, 1H), 4.88 (t, J=12.0 Hz, 1H), 4.17 (s, 1H), 4.02 (s, 1H), 3.49-3.06 (m, 4H), 2.82 (s, 3H), 2.61 (dd, J=35,5, to 11.9 Hz, 6H), 2.02 (d, J=12,8 Hz, 2H), 1.78-1.61 (m, 4H).

[M+H]+=705 (multimode+).

Example 265

N-{CIS-4-[1-(4'-{[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

The product was obtained from 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.81 mmol) and CIS-2,6-dimethylpiperazine (0,092 g, 0.81 mmol) by the method of Example 54 to obtain specified in the title compound as a colourless solid substances (0,379 g).

1H NMR (400 MHz, DMSO) δ 9.33 (br s, 1H), 8.83 (dd, J=4,1, 2.8 Hz, 1H), 8.59 (d, J=2,8 Hz, 2H), 8.41 (s, 1H), 8.34 (dd, J=7,7, 3.1 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.78-7.69 (m, 6H), 7.63 (t, J=7.8 Hz, 1H), 7.49 (td, J=12,1, 8,2 Hz, 3H), 7.43-7.38 (m, 1H), 4.88 (t, J=12.0 Hz, 1H), 4.17 (s, 1H), 3.99 (s, 2H), 3.43 (s, 2H), 3.26 (d, J=11.3 Hz, 2H), 2.72-2.38 (m, 4H), 2.02 (d, J=13.1 Hz, 2H), 1.79-1.59 (m, 4H), 1.20 (d, J=6,7 Hz, 6H).

[M+H]+=719 (multimode+).

Example 266

6-Fluoro-N-{CIS-4-[6-fluoro-1-(4'-{[(3S)-3-methylpiperazin-1-yl]methyl}biphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

The product was obtained from 6-fluoro-N-{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.5 g, 0.81 mmol) and tert-butyl(2S)-2-methylpiperazin-1-carboxylate (0,161 g, 0.81 mmol) by the method of Example 54 with receiving the receiving specified in the title compound as a colourless solid (0,490 g).

1H NMR (400 MHz, DMSO) δ 9.30 (br s, 1H), 8.96-8.76 (m, 2H), 8.59 (d, J=3.1 Hz, 1H), 8.41 (s, 1H), 8.34 (dd, J=7,7, 3.1 Hz, 1H), 7.84-7.37 (m, 10H), 4.88 (t, J=11,9 Hz, 1H), 4.12 (d, J=37,7 Hz, 3H), 3.51-3.06 (m, 5H), 2.86-2.55 (m, 4H), 2.02 (d, J=13.1 Hz, 2H), 1.78-1.57 (m, 4H), 1.21 (d, J=6,7 Hz, 3H).

[M+H]+=705 (multimode+).

Example 267

N-{CIS-4-[1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-(2-hydroxyethoxy)benzamide

Stage (a) N-{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]benzamide

To a stirred solution of the dihydrochloride of 3-(CIS-4-aminocyclohexane)-1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g, 0.36 mmol) in DMF (4 ml) was added 2-[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]benzoic acid (0,114 g, 0.43 mmol), base Hunya (0,187 ml, 1,07 mmol) and finally HATU (0,163 g, 0.43 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (2×30 ml). The aqueous layer was back extracted with ethyl acetate (30 ml)and the combined organic layers were washed with saturated brine (30 ml), dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound as nl is the bottom-yellow solid (0,296 g).

1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2,8 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 8.32 (dd, J=7,8, 2,9 Hz, 1H), 7.98-7.93 (m, 2H), 7.82 (d, J=14,2 Hz, 1H), 7.78-7.75 (m, 3H), 7.63 (t, J=7.9 Hz, 1H), 7.55 (d, J=8,2 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J=13,0 Hz, 1H), 7.21 (d, J=11,1 Hz, 1H), 7.06 (t, J=9.5 Hz, 1H), 4.91-4.79 (m, 1H), 4.60 (s, 1H), 4.42-4.33 (m, 2H), 4.21-4.11 (m, 2H), 3.96-3.76 (m, 2H), 3.70-3.61 (m, 1H), 3.34 (s, 2H), 2.88 (s, 6H), 2.65-2.60 (m, 6H), 1.73-1.59 (m, 4H), 1.46-1.33 (m, 4H).

Stage (b) N-{CIS-4-[1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-(2-hydroxyethoxy)benzamide

To a mixture of N-{CIS-4-[1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-[2-(tetrahydro-2H-Piran-2-yloxy)ethoxy]benzamide (0.29 grams, 0,39 mmol) in THF (2 ml) and water (1 ml) was added acetic acid (4,5 ml, 78,61 mmol)and the reaction mixture was heated at 80°C for 18 hours the Reaction mixture was left to cool to room temperature and was poured into saturated sodium bicarbonate solution (50 ml). The product was extracted with DCM (150 ml). DCM evaporated, and the residue was dissolved in methanol. The solvents were removed by evaporation in vacuo, and the residue was stirred in ether overnight. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 65-45% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compound as a white t is ejogo substances (44 mg).

1H NMR (400 MHz, DMSO) δ 8.58 (d, J=2,8 Hz, 1H), 8.43 (d, J=6.2 Hz, 1H), 8.30 (dd, J=7,7, 3.1 Hz, 1H), 7.94 (d, J=6.2 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.60 (q, J=7.9 Hz, 3H), 7.47 (t, J=7,0 Hz, 1H), 7.40-7.34 (m, 2H), 7.20 (d, J=8,2 Hz, 1H), 7.05 (t, J=7,4 Hz, 1H), 4.91-4.76 (m, 2H), 4.27 (s, 2H), 4.16 (s, 1H), 3.84-3.77 (m, 2H), 3.46 (s, 2H), 2.73-2.60 (m, 2H), 2.19 (s, 6H), 2.08-1.99 (m, 2H), 1.71-1.59 (m, 4H).

[M+H]+=652 (multimode+).

Example 268

N-{CIS-4-[1-{2'-[(Dimethylamino)methyl]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) N-{CIS-4-[1-[2'-(Aminomethyl)-4'-forbiden-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

The palladium (II) acetate (10,48 mg, 0.05 mmol) and 2-DICYCLOHEXYL-phosphino-2',6'-dimethoxybiphenyl (0,038 g, 0.09 mmol) was added acetonitrile (4 ml)and the mixture was stirred at room temperature for 10 minutes was Added potassium carbonate (0,194 g of 1.40 mmol) in water (2 ml), 6-fluoro-N-{CIS-4-[6-fluoro-1-(3-itfinal)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (0.3 g, 0.47 mmol) and (2-{[(tert-butoxycarbonyl)amino]methyl}-4-forfinal)baronova acid (0.126 g, 0.47 mmol)and the reaction mixture was heated at 80°C during the night. The reaction mixture was applied directly on a ChemElut cartridge, and the product was suirable DCM. The solvent issue is rivali, and the residue was dissolved in 1,4-dioxane (5 ml). Was added hydrogen chloride in dioxane (4 M) (5 ml, 20.00 mmol)and the reaction mixture was stirred at room temperature for 5 hours the Solvent was removed in vacuo and the residue triturated in ether overnight. The solid was removed by filtration to obtain specified in the subtitle compound as a beige solid (0,363 g).

1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.70 (d, J=3.1 Hz, 1H), 8.54-8.47 (m, 3H), 8.33 (d, J=16.1 Hz, 1H), 7.90-7.85 (m, 1H), 7.82-7.78 (m, 1H), 7.68-7.56 (m, 2H), 7.50-7.40 (m, 2H), 7.32 (d, J=13,7 Hz, 2H), 4.87 (t, J=14,7 Hz, 1H), 4.17-4.11 (m, 1H), 4.04-3.99 (m, 2H), 2.64-2.59 (m, 2H), 2.03 (d, J=29,8 Hz, 2H), 1.74-1.61 (m, 4H).

Stage (b) N-{CIS-4-[1-{2'-[(Dimethylamino)methyl]-4'-forbiden-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide

A mixture of N-{CIS-4-[1-[2'-(aminomethyl)-4'-forbiden-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]pyridine-2-carboxamide (0,363 g, or 0.57 mmol) and formaldehyde (37% wt.% in water, 0.2 ml, 2,69 mmol) in 1,2-dichloroethane (10 ml) was stirred at room temperature for 10 minutes To the mixture was added triacetoxyborohydride sodium (0,241 g to 1.14 mmol)and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuum. The residue was dissolved in methanol (5 ml) and applied to the cartridge 10g SCX. Impurities in mawali methanol (70 ml) and discarded. The product was suirable 1 N. methanolic ammonia solution (100 ml) and evaporated in vacuo. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using the gradient 55-35% water and 0.2%ammonia in acetonitrile as eluent, then flash chromatography on silica, elwira 5% methanol in DCM. Pure fractions were evaporated to dryness to obtain specified in the title compound as a white solid (60 mg).

1H NMR (400 MHz, DMSO) δ 8.80 (ddt, J=4,1, 2,6, 0.1 Hz, 1H), 8.60 (d, J=2,8 Hz, 1H), 8.37 (s, 1H), 8.32 (dd, J=7,7, 3.1 Hz, 1H), 7.74 (dd, J=9,9, a 5.3 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.59 (t, J=8,1 Hz, 1H), 7.49-7.38 (m, 4H), 7.37-7.28 (m, 2H), 7.18 (td, J=11,1, 5.0 Hz, 1H), 4.88 (t, J=16.5 Hz, 1H), 4.19 (s, 1H), 2.69-2.55 (m, 2H), 2.08-1.98 (m, 8H), 1.76-1.61 (m, 4H). Other resonances obscured by the peak of the water.

[M+H]+=668 (multimode+).

Example 269

6-Fluoro-N-{CIS-4-[6-fluoro-1-[2'-hydroxy-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]-2-hydroxybiphenyl-4-yl}methyl)piperazine-1-carboxylate

To a solution of 6-fluoro-N-{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carbox the MFA (0.25 g, 0,39 mmol) in 1,2-dichloroethane (10 ml) was added tert-butyl-1-piperidinecarboxylate (0,110 g, 0.59 mmol) and acetic acid (0,045 ml of 0.79 mmol). The reaction mixture was stirred for 10 min, then was added triacetoxyborohydride sodium (0.125 g, 0.59 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was dissolved in methanol (5 ml) and applied to the cartridge 10g SCX. Impurities were washed with methanol (70 ml) and discarded. The product was suirable 1 N. methanolic ammonia solution (100 ml) and evaporated in vacuo. The residue was left under high vacuum overnight to obtain specified in the subtitle compound (0.156 g).

[M+H]+=807.

Stage (b) 6-Fluoro-N-{CIS-4-[6-fluoro-1-[2'-hydroxy-4'-(piperazine-1-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Hydrogen chloride in 1,4-dioxane (4 M) (1 ml, 4.00 mmol) was added to a solution of tert-butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]-2-hydroxybiphenyl-4-yl}methyl)piperazine-1-carboxylate (0.15 g, 0,19 mmol) in 1,4-dioxane (10 ml)and the reaction mixture was stirred at room temperature overnight. The solvents are evaporated and the residue was purified preparative HPLC on a Sunfire column using a gradient 90-70% in the Noah 0,1% triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compound as a white solid (27 mg).

1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.58 (d, J=3.1 Hz, 1H), 8.31 (dd, J=7,7, 3.1 Hz, 1H), 7.86-7.78 (m, 3H), 7.55-7.49 (m, 3H), 7.49-7.43 (m, 1H), 7.40-7.36 (m, 2H), 7.03 (s, 1H), 6.94 (d, J=19.2 Hz, 1H), 4.86 (t, J=22,2 Hz, 1H), 4.11 (s, 1H), 3.63 (s, 2H), 3.26-3.16 (m, 4H), 2.90-2.71 (m, 4H), 2.04-1.90 (m, 4H), 1.75-1.57 (m, 4H).

[M+H]+=707 (multimode+).

Example 270

N-{CIS-4-[6-Fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-(propylamino)cyclopentanecarboxylic

1-Amino-N-{CIS-4-[6-fluoro-1-[2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}cyclopentane-carboxamide (0.54 g, 0.84 mmol) and propionic aldehyde (0,049 g, 0.84 mmol) in 1,2-dichloroethane (20 ml) was treated with triacetoxyborohydride sodium (0,214 g, 1.01 mmol)and the resulting mixture was stirred over night. The mixture was evaporated to dryness and the crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-50% water with 0.1% triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (0,372 g).

1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.07 (s, 2H), 8.59 (d, J=2,8 Hz, 1H), 8.31 (dd, J=7,7, 2.8 Hz, 1H), 7.71 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.58-7.50 (m, 3H), 7.49-7.44 (m, 1H), 7.44-7.39 (m, 1H), 4.81 (t, J=11.8 Hz, 1H), 4.33 (s, 2H), 3.89 (s, 1H), 3.79-3.53 (m, 4H), 3.27-3.06 (m, 2H), 2.81-2.55 (m, 6H), 2.37-2.23 (m, 2H), 2.05-1.91 (m, 4H), 1.85-1.69 (m, 5H), 1.68-1.51 (m, 7H), of 0.90 (t, J=7,3 Hz, 3H).

[M+H]+=683 (multimode+).

Example 271

1-{2'-[(Dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a) tert-Butyl{CIS-4-[1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.5 g, 0.87 mmol) and dimethylamine (1,305 ml, 2,61 mmol) by the method of Example 269, stage (a), obtaining specified in the subtitle compound (0.50 g).

[M+H]+=604.

Stage (b) 3-(CIS-4-Aminocyclohexane)-1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.5 g, 0.83 mmol) by the method of Example 225, step (g), obtaining specified in the subtitle compound (0,410 g).

[M+is]+=604.

Stage (C) 1-{2'-[(Dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of 6-torymidae[1,2-a]pyridine-2-carbaldehyde (0,082 g, 0.50 mmol) in 1,2-dichloroethane was added 3-(CIS-4-aminocyclohexane)-1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (to 0.263 g, 0.52 mmol) and acetic acid (0,038 g to 0.63 mmol)and the reaction mixture was stirred at 25°C for 10 minutes. Added triacetoxyborohydride sodium (0,111 g, 0.52 mmol)and the reaction mixture was stirred for 14 hours. The crude material was dissolved in methanol (5 ml) and applied on a 20g cartridge SCX. Impurities were washed with methanol (250 ml) and discarded. The product was suirable 1 N. methanolic solution of ammonia (250 ml) and was evaporated. The crude product was purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-50% water with 0.1% triperoxonane acid in acetonitrile as eluent, then further purified preparative HPLC on a column (Waters X-Terra, using the gradient 95-5% water with 0.1%ammonium acetate in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (0.104 g g).

1H NMR (400 MHz, DMSO) δ 8.71-8.70 (m, 1H), 8.59-8.58 (m, 1H), 8.29-8.26 (m, 1H), 7.84 (s, 1H), 7.55-7.50 (m, 2H), 7.43-7.41 (m, 2H), 7.32-7.23 (m, 2H), 7.10 (d, J=8,2 Hz, 1H), .92 (d, J=2.6 Hz, 1H), 6.73 (dd, J=8,2, 2.6 Hz, 1H), 4.81-4.75 (m, 1H), 3.80 (s, 2H), 3.24 (s, 2H), 2.85-2.67 (m, 3H), 2.54 (s, 1H), 2.06 (s, 3H) 1.90-1.87 (m, 7H), 1.51-1.40 (m, 4H).

[M+H]+=652 (multimode+).

The compounds listed in Table 8 (see end of description), were obtained in the form of solid substances from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and the appropriate aldehyde using the method described above in Example 242.

Example 280

6-Fluoro-3-{CIS-4-[[(6-torymidae[1,2-a]pyridine-2-yl)methyl]-(methyl)-amino]cyclohexyl}-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (184 mg, 0.34 mmol) and 6-torymidae[1,2-a]pyridine-2-carbaldehyde (55,4 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (4 ml) and N-methyl-2-pyrrolidinone (1 ml) at 25°C. and the solution was left to mix for 1 hour Then added triacetoxyborohydride sodium (117 mg, 0.55 mmol) over a period of time of 10 minutes in an air atmosphere. The resulting suspension was stirred at 25°C for 16 h, then was added formaldehyde (41 mg, 0.51 mmol) and the suspension was stirred further for 16 h Damp the suspension is then loaded on the column 10g SCX, washed with methanol (100 ml) and was suirable 3,5 N. ammonia methanol 75 ml). The crude compound was obtained after concentration in vacuo and was purified preparative HPLC column Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (0,134 g).

1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.66-8.56 (m, 2H), 8.34 (dd, J=7,8, 2,9 Hz, 1H), 7.91 (s, 1H), 7.61-7.50 (m, 3H), 7.43 (d, J=7.9 Hz, 1H), 7.35-7.29 (m, 1H), 7.29-7.20 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.88 (d,, J=2,6 Hz, 1H), 6.76 (dd, J=8,2, 2.6 Hz, 1H), 4.91-4.81 (m, 1H), 3.81 (s, 2H), 3.43 (t, J=4,1 Hz, 4H), 3.29 (s, 2H), 2.80 (dd, J=24,9, and 11.5 Hz, 2H), 2.42-2.35 (m, 1H), 2.31-2.15 (m, 9H), 1.42 (s, 4H).

[M+H]+=708 (multimode+).

Example 281

N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-N2N2-dimethylglycinamide

Stage (a): tert-Butyl{CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

1-Methyl-1,4-diazepan (0.7 ml, 5,63 mmol) was added to a solution of tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,009 g of 3.60 mmol) in DCM (40 ml). Added anhydrous sodium sulfate (approx. 0.5 g). The mixture was stirred at room temperature for 0 minutes then added triacetoxyborohydride sodium (to 1.143 g of 5.39 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated. The crude substance was dissolved in methanol and loaded onto a pre-washed SCX cartridge. Neutral impurities were removed by washing with methanol, then the product was suirable 10-20% 7 n ammonia in methanol to obtain specified in the subtitle compound as a pale yellow foam (1.66 g).

[M+H]+=657.

Stage (b): 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]-biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]-cyclohexyl}carbamate (1,661 g of 2.53 mmol) was dissolved in 1,4-dioxane (10 ml) and cooled on ice. Was added hydrogen chloride (approx. 4 M in 1,4-dioxane) (12,64 ml, 50,58 mmol)and the reaction mixture was stirred at approx. 5°C for 1 h, then at room temperature for 4 h, then concentrated in vacuo to obtain salt trihydrochloride specified in the subtitle compound as a white solid (1,985 g).

[M+H]+=557 (multimode+).

Stage (in): N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-pyrimidin-3(2H)-yl]illogical}-N2N2-dimethylglycinamide

A solution of 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,243 g, 0.36 mmol), N,N-dimethylglycine (0,040 g, 0.38 mmol) and triethylamine (with 0.55 ml, 3.96 mmol) in acetonitrile (10 ml) was stirred for 30 minutes, then was added dropwise a cyclic anhydride 1-papapostolou acid (TR, 1.57 M in THF) (0.25 ml, 0,39 mmol). The reaction mixture was stirred overnight, then poured onto saturated sodium bicarbonate (10 ml) and was extracted with ethyl acetate (× 3). The combined organic extracts were washed with water, concentrated and purified preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water and 0.2%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain di-trifenatate specified in the title compound as a white foam (0,212 g).

1H NMR (400 MHz, DMSO) δ 9.66 (br s, 1H), 8.59 (d, J=3.1 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.30 (dd, J=7,7, 3.1 Hz, 1H), 7.83-7.74 (m, 4H), 7.66-7.58 (m, MN), 7.41 (d, J=7.7 Hz, 1H), 4.79 (t, J=12.0 Hz, 1H), 4.34-4.28 (m, 1H), 3.96-3.90 (m, 2H), 2.84 (s, 3H), 2.80 (s, 6H), 2.67-2.58 (m, 2H), 2.14-2.07 (m, 2H), 1.90 (d, J=12,5 Hz, 2H), 1.67-1.55 (m, 4H). The remaining protons obscured the peaks of the solvent.

[M+H]+=642 (mult is modal+).

Example 282

N-{CIS-4-[1-{4'-[(4-Cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5-methylpyrazine-2-carboxamide

Stage (a): tert-Butyl{CIS-4-[1-{4'-[(4-cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]-pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,074 g, 3,71 mmol) and 1-cyclopentenopyridine (0,859 g, to 5.57 mmol) by the method of Example 281, stage (a), which gave specified in the subtitle compound as a pale yellow foam (2,393 g).

[M+H]+=697.

Stage (b): 3-(CIS-4-Aminocyclohexane)-1-{4'-[(4-cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[1-{4'-[(4-cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]-pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,393 g of 3.43 mmol) by the method of Example 281, stage (b), which gave salt trihydrochloride specified in the subtitle compound as a pale yellow solid (2,998 g).

[M+H]+=597.

Stage (in): N-{CIS-4-[1-{4'-[(4-Cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-what hydroperiod[2,3-d]-pyrimidine-3(2H)-yl]cyclohexyl}-5-methylpyrazine-2-carboxamide

The product was obtained from 3-(CIS-4-aminocyclohexane)-1-{4'-[(4-cyclopentylpropionyl-1-yl)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]-pyrimidine-2,4(1H,3H)-dione (0,296 g, 0.42 mmol) and 5-methylpyrazine-2-carboxylic acid (0,069 g, 0.50 mmol) by the method of Example 281, stage (C), which gave Sol di-triptorelin specified in the connection header in the form of a white foam (95 mg).

1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.64-8.59 (m, 2H), 8.33 (dd, J=7,7, 3.1 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.82-7.72 (m, 3H), 7.64 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.9 Hz, 1H), 4.89 (t, J=and 12.2 Hz, 1H), 4.21-4.17 (m, 1H), 3.56-3.49 (m, 2H), 3.30-3.08 (m, 4H), 2.67-2.54 (m, 5H), 2.04-1.97 (m, 4H), 1.77-1.54 (m, 10H). The remaining protons obscured the peaks of the solvent.

[M+H]+=717 (multimode+).

Example 283

N-{CIS-4-[1-[4'-(1,4'-Bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

Stage (a): tert-Butyl{CIS-4-[1-[4'-(1,4'-bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1,500 g, 2,69 mmol) and 1,4'-bipiperidine (0.565 g, to 3.36 mmol) by the method of Example 281, stage (a), which gave specified in the subtitle compound as a pale yellow foam (1,585 g).

[M+H]+=71.

Stage (b): 3-(CIS-4-Aminocyclohexane)-1-[4'-(1,4'-bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[1-[4'-(1,4'-bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1,585 g of 2.23 mmol) by the method of Example 281, stage (b), which gave Sol three hydrochloride is indicated in the subtitle compound in the form of a cream solid color (1,944 g).

[M+H]+=611.

Stage (in): N-{CIS-4-[1-[4'-(1,4'-Bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

The product was obtained from 3-(CIS-4-aminocyclohexane)-1-[4'-(1,4'-bipiperidine-1'-ylmethyl)biphenyl-3-yl]-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,221 g, 0.31 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0,052 g and 0.37 mmol) by the method of Example 281, stage (C), which gave Sol di-triptorelin specified in the title compounds as a white foam (0,164 g).

1H NMR (400 MHz, DMSO) δ 8.58 (d, J=3.1 Hz, 1H), 8.34 (dd, J=7,8, 2,9 Hz, 1H), 7.84-7.77 (m, 4H), 7.65 (t, J=7.8 Hz, 1H), 7.60 (d, J=7,4 Hz, 2H), 7.43 (d, J=8.5 Hz, 1 H), 7.20 (d, J=6,9 Hz, 1 H), 6.42 (s, 1 H), 4.88-4.81 (m, 1 H), 4.37-4.32 (m, 2H), 4.10-4.07 (m, 1H), 3.75 (s, 3H), 3.02-2.88 (m, 4H), 2.57-2.51 (m, 2H), 2.25-2.21 (m, 5H), 1.98-1.83 (m, 6H), 1.72-1.60 (m, 6H), 1.44-1.27 (m, 2H). The remaining protons obscured the peaks of the solvent.

[M+H]+=733 (multimode+).

P the emer 284

N-{CIS-4-[1-(4'-{[(3R,5S) - for 3,5-Dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]-cyclohexyl}-6-methylpyridin-2-carboxamide

Stage (a): tert-Butyl{CIS-4-[1-(4'-{[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]-pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,000 g, 3.58 mmol) and CIS-2,6-dimethylpiperazine (0,409 g, 3.58 mmol) by the method of Example 281, stage (a), which gave specified in the subtitle compound as a foam (1.92 g).

[M+H]+=657 (multimode+).

Stage (b): 3-(CIS-4-Aminocyclohexane)-1-(4'-{[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained tert-butyl-{CIS-4-[1-(4'-{[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1.88 g, of 2.86 mmol) by the method of Example 281, stage (b), which gave salt trihydrochloride specified in the subtitle compound as a white solids (2,05 g).

[M+H]+=557.

Stage (in): N-{CIS-4-[1-(4'-{[(3R,5S) - for 3,5-Dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3d]pyrimidine-3(2H)-yl]cyclohexyl}-6-methylpyridin-2-carboxamide

The product was obtained from 3-(CIS-4-aminocyclohexane)-1-(4'-{[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]methyl}biphenyl-3-yl)-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,200 g, 0.34 mmol) and 6-metilakrilovoe acid (46 mg, 0.34 mmol) by the method of Example 281, stage (C), which gave Sol di-triptorelin specified in the connection header in the form of a white solid (98 mg).

1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=8.7 Hz, 1H), 8.37 (d, J=3.1 Hz, 1H), 8.23 (dd, J=7,2, 3.1 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.75-7.63 (m, 5H), 7.53 (t, J=1.8 Hz, 1H), 7.47 (d, J=8,2 Hz, 2H), 7.34 (ddt, J=7,8, 0,2, 1.3 Hz, 1H), 7.26-7.22 (m, 1H), 5.13-5.03 (m, 1H), 4.43-4.39 (m, 1H), 4.05 (s, 2H), 3.71-3.65 (m, 2H), 3.24 (d, J=10.3 Hz, 2H), 3.05 (t, J=12.0 Hz, 2H), 2.84-2.74 (m, 2H), 2.49 (s, 3H), 2.07 (d, J=13.3 Hz, 2H), 1.82-1.71 (m, 4H), 1.32 (d, J=6,4 Hz, 6N).

[M+H]+=676 (multimode+).

The compounds listed in Table 9 (see at the end of the description), were obtained in a similar manner in the form of solid substances from sootvetstvujushij amine and acid using the method described above in Example 281, stage (b).

Example 305

N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-methylalanine

Stage (a): tert-Butyl[2-({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate

Product poluchalis 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,245 g, of 0.37 mmol) and 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (0,078 g 0,39 mmol) by the method of Example 281, stage (C), without purification by HPLC, which gave specified in the subtitle compound as a white foam (0,226 g).

[M+H]+=742.

Stage (b): N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-methylalanine

Hydrogen chloride (4 M in 1,4-dioxane) (1.5 ml, 6,00 mmol) was added dropwise to a stirred solution of tert-butyl[2-({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)-1,1-dimethyl-2-oxoethyl]-carbamate (0,226 g, 0.30 mmol) in 1,4-dioxane (3 ml). The resulting mixture was stirred at room temperature for 6 h, then concentrated under vacuum. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 85-15% water and 0.2%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin, in the form of a white foam (60 mg).

1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2,8 Hz, 1H), 8.32 (dd, J=7,7, 3.1 Hz, 1H), 8.14-8.09 (m, 3H), 7.83 (d, J=8,3 Hz, 1H), 7.78-7.75 (m, 3H), 7.69-7.58 (m, 5H), 7.41 (d, J=7.7 Hz, 1H), 4.81 (t, J=11.7 Hz, 1H), 4.36-4.30 (m, 1H), 3.83-3.79 (m, 1H), 2.84 (s, 3H), 2.70-2.62 (m, 2H), 2.14-2.01 (m, 4H), 1.64-1.53 (m, 10H) the Remaining protons obscured the peaks of the solvent.

[M+H]+=642 (multimode+).

Example 306

N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-L-phenylalaninamide

Stage (a): tert-Butyl[(1S)-1-benzyl-2-({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)-2-oxoethyl]carbamate

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,244 g and 0.37 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-phenylpropane acid (0,097 g and 0.37 mmol)using the method of Example 305, stage (a)given specified in the subtitle compound as a colourless glass (0,249 g).

[M-BOC]+=704.

Stage (b): N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-L-phenylalaninamide

The product was obtained from tert-butyl[(1S)-1-benzyl-2-({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)-2-oxoethyl]carbamate (0,249 g, 0.31 mmol)using the method of Example 305, stage (b), which gave specified in the title compound, salt di-triptorelin, in the form of a white foam (0,192 g).

1H NMR (400 MHz, DSO) δ 8.59 (d, J=2,8 Hz, 1H), 8.30 (dd, J=7,8, 2,9 Hz, 1H), 8.21-8.11 (m, 4H), 7.83-7.73 (m, 4H), 7.66-7.54 (m, 3H), 7.41 (d, J=7.2 Hz, 1H), 7.31-7.20 (m, 5H), 4.79-4.70 (m, 1H), 4.36-4.13 (m, 2H), 3.87-3.82 (m, 1H), 3.07-2.97 (m, 4H), 2.83 (s, 3H), 2.67-2.61 (m, 2H), 2.14-2.05 (m, 2H), 1.87 (d, J=14.1 Hz, 2H), 1.70-1.44 (m, 4H). The remaining protons obscured the peaks of the solvent.

[M+H]+=704 (multimode+).

Example 307

N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-D-valinamide

Stage (a): tert-Butyl{(1R)-1-[({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)carbonyl]-2-methylpropyl}carbamate

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,242 g, 0.36 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.083 g, 0.38 mmol)using the method of Example 305, stage (a)given specified in the subtitle compound as a colourless oil (0,240 g).

[M+H]+=756.

Stage (b): N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-D-valinamide

The product was obtained from tert-butyl{(1R)-1-[({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohex the}amino)carbonyl]-2-methylpropyl}carbamate (0,275 g, 0.31 mmol)using the method of Example 305, stage (b), which gave specified in the title compound, salt di-triptorelin, in the form of a white foam (strength of 0.159 g).

1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2,8 Hz, 1H), 8.31-8.27 (m, 2H), 8.10-8.04 (m, 3H), 7.82 (d, J=7.9 Hz, 1H), 7.78-7.75 (m, 2H), 7.66-7.58 (m, 3H), 7.41 (d, J=7.9 Hz, 1 H), 4.82-4.76 (m, 1H), 4.36-4.28 (m, 1H), 3.94-3.89 (m, 1H), 3.74-3.69 (m, 1H), 2.84 (s, 3H), 2.71-2.58 (m, 2H), 2.15-2.05 (m, 2H), 1.95-1.84 (m, 2H), 1.72-1.53 (m, 4H), of 0.95 (d, J=6,4 Hz, 6N). The remaining protons obscured the peaks of the solvent.

[M+H]+=656 (multimode+).

Example 308

N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1-valinamide

Stage (a): tert-Butyl{(1S)-1-[({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)carbonyl]-2-methylpropyl}carbamate

The product was obtained from 3-(CIS-4-aminocyclohexane)-6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,248 g and 0.37 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (of 0.085 g, 0,39 mmol)using the method of Example 305, stage (a)given specified in the subtitle compound as a colourless oil (0,247 g).

[M+H]+=756.

Stage (b): N-{CIS-4-[6-Fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrim the DIN-3(2H)-yl]cyclohexyl}-L-valinamide

The product was obtained from tert-butyl{(1S)-1-[({CIS-4-[6-fluoro-1-{4'-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}amino)carbonyl]-2-methylpropyl}carbamate (0,281 g and 0.37 mmol)using the method of Example 305 stage (b), which gave specified in the title compound salt of di-triptorelin, in the form of a white foam (0,181 g).

1H NMR (400 MHz, DMSO) δ 8.59 (d, J=3.1 Hz, 1H), 8.31-8.27 (m, 2H), 8.09-8.04 (m, 3H), 7.82 (d, J=7,4 Hz, 1H), 7.78-7.75 (m, 2H), 7.66-7.58 (m, 3H), 7.41 (d, J=7,4 Hz, 1H), 4.82-4.76 (m, 1H), 4.33-4.23 (m, 1H), 3.94-3.89 (m, 1H), 3.74-3.69 (m, 1H), 2.84 (s, 3H), 2.71-2.58 (m, 2H), 2.09 (m, 2H), 1.96-1.84 (m, 2H), 1.72-1.53 (m, 4H), of 0.96 (d, J=6,7 Hz, 6N). The remaining protons obscured the peaks of the solvent.

[M+H]+=656 (multimode+).

Example 309

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]-amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[(1S)-2-methoxy-1-methylethyl]-(methyl)amino]-methyl} - biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A mixture of (S)-1-methoxypropan-2-amine (140 mg, 1.57 mmol), tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) and triacetoxyborohydride sodium (332 mg, 1.57 mmol) was stirred in DCE (20 ml) during the night. To this solution was added formaldehyde (in 0.288 ml, 4,18 mmol), and then an additional aliquot of triacetoxyborohydride sodium (332 mg, 1.57 mmol). Then the mixture was left were ivalsa within 2 hours The reaction mixture was washed with 10%sodium bicarbonate solution (30 ml) and dried over sodium sulfate. The organic phase was filtered and evaporated to dryness. The residue is then transferred into a 50:50 mix D:triperoxonane acid (10 ml) and left to stand for 2 hours the Mixture was evaporated to dryness, extracted with DCM and washed with 10%sodium bicarbonate solution (30 ml) and dried over sodium sulfate. The organic phase was filtered and evaporated to dryness. This residue was transferred to a DCE (20 ml) and the resulting solution was added 6-torymidae[1,2-a]pyridine-2-carbaldehyde (206 mg, 1.25 mmol) and the mixture was left to mix for 1 hour, then added triacetoxyborohydride sodium (332 mg, 1.57 mmol) and the resulting mixture was stirred over night. The organic phase washed with 10%sodium bicarbonate solution (30 ml) and dried over sodium sulfate. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (0,176 g).

1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.70 (dd, J=4,6, and 2.6 Hz, 1H), 8.57 (d, J=3.1 Hz, 1H), 8.28 (dd, J=7,8, 2,9 Hz, 1H), 7.83 (s, 1H), 7.52 (dd, J=15,2, 1.9 Hz, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.33-7.20 (m, 2H), 7.12 (d, J=8.5 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.73 (dd, J=8,5, 2,6 is C, 1H), 4.77 (t, J=37.6 Hz, 1H), 3.80 (s, 2H), 3.42 (s, 2H), 3.32 (s, 3H), 3.24 (dd, J=a 9.6, 6.3 Hz, 1H), 3.12-2.95 (m, 4H), 2.88-2.64 (m, 4H), 2.00 (s, 3H), 1.89 (d, J=13.1 Hz, 2H), 1.46 (dd, J=29,3, of 13.7 Hz, 4H)that was 0.77 (d, J=6,7 Hz, 3H).

[M+H]+=710 (multimode+).

Example 310

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[(3R)-3-methylmorpholin-4-yl]methyl}biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a mixture of tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (568 mg, 0,99 mmol) and (R)-3-methylmorpholine hydrochloride (200 mg, to 1.98 mmol) in DCE (10 ml) was added triethylamine (0,276 ml of 1.98 mmol) and the mixture was stirred for 1 hour at room temperature. To this mixture was then added triacetoxyborohydride sodium (419 mg, to 1.98 mmol) and the mixture was stirred over night. The mixture was washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The organic phase was evaporated to dryness and the residue was transferred into DCM (20 ml). To this solution was added TFA (10 ml) and the mixture was left to stand at room temperature for 1 hour, then evaporated to dryness. The residue was dissolved in water (30 ml), neutralized to 0.88 ammonium hydroxide. The solid was filtered and dried. A mixture of this crude compound, 6-torymidae[1,2-a]pyridine-2-carbaldehyde (138 mg, 0.84 mmol) and triacetoxy drid sodium (178 mg, 0.84 mmol) in DCE as solvent (20 ml) was stirred over night. The reaction mixture was washed with 10%sodium bicarbonate solution and the organic layer was separated and dried over sodium sulfate. The crude product was purified by preparative HPLC on a column (Waters X-Terra, using the gradient 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin, in the form of a colorless solid (0,247 g).

1H NMR (299.947 MHz, DMSO) δ 8.78 (ddd, J=4,6, 2,5, 0.8 Hz, 1H), 8.52 (d, J=3.1 Hz, 1H), 8.23 (dd, J=7,7, 3.1 Hz, 1H), 8.06 (s, 1H), 7.65-7.53 (m, 2H), 7.43-7.30 (m, 4H), 7.16 (d, J=8,3 Hz, 1H), 7.06 (1, J=2.3 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 4.83 (t, J=11,4 Hz, 2H), 4.34 (s, 5H), 3.77-3.26 (m, 5H), 2.86-2.52 (m, 5H), 2.15 (d, J=14.6 Hz, 2H), 1.87-1.58 (m, 4H), 1.03 (d, J=5.6 Hz, 3H).

[M+H]+=708 (multimode+).

Example 311

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[(3S)-3-methylmorpholin-4-yl]methyl}biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0,450 g, 0.78 mmol) and hydrochloride (S)-3-methylmorpholine (158 mg, 1.57 mmol) by the method of Example 310, but the crude product was purified by HPLC with a reversed f the th column Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (0,143 g).

1H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 8.70 (dd, J=4,6, and 2.3 Hz, 1H), 8.56 (d, J=2,8 Hz, 1H), 8.28 (dd, J=7,7, 3.1 Hz, 1H), 7.83 (s, 1H), 7.57-7.48 (m, 2H), 7.43-7.35 (m, 3H), 7.33-7.21 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 6.97 (d, J=2.6 Hz, 1H), 6.71 (dd, J=8,2, 2.6 Hz, 1H), 4.78 (t, J=29,6 Hz, 1H), 3.79 (d, J=12,8 Hz, 3H), 3.49 (s, 2H), 3.41-3.27 (m, 1H), 3.07 (d, J=13.3 Hz, 2H), 2.85 (s, 1H), 2.74 (d, J=12,6 Hz, 2H), 2.36-2.24 (m, 1H), 1.97 (m, 1H), 1.89 (d, J=13.1 Hz, 2H), 1.55-1.39 (m, 4H), to 0.80 (s, 3H).

[M+H]+=708 (multimode+).

Example 312

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[(2S)-2-hydroxypropyl](methyl)amino]methyl}-biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from (S)-1-aminopropan-2-ol (78 mg, 1.04 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin (0,130 g)

1H NMR (300 MHz, DMSO) δ 9.2 (s, 1H), 8.91 (dd, J=4,6, 2,5 Hz, 3H), 8.61 (d, J=2.7 Hz, 1H), 8.31 (dd, J=7,6, 3.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.71-7.58 (m, 2H), 7.48-7.34 (m, 4H), 7.25-7.15 (m, 2H), 6.97 (dd, J=an 8.4 and 2.2 Hz, 1H), 4.78 (t, J=20.4 Hz, 1H), 4.36 (s, 3H), 3.92 (s, 1H), 3.38 (s, 1H), 2.67-2.52 (m, 9H), 2.19-2.06 (m, 2H), 1.81-1.56 (m, 4H), 1.10-of 0.85 (m, 3H).

[M+H]+=696 (multimode+).

Example 313

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[(1R)-2-hydroxy-1-methylethyl](methyl)amino]-methyl} - biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from (R)-2-aminopropan-1-ol (78 mg, 1.04 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin, in the form of a colorless solid (0,163 g).

1H NMR (300 MHz, DMSO) δ 8.90 (dd, J=4,5, 2,4 Hz, 3H), 8.57 (s, 1H), 8.31 (dd, J=7,7, 2,9 Hz, 1H), 8.10 (s, 1H), 7.71-7.57 (m, 2H), 7.47-7.32 (m, 4H), 7.22 (d, J=8,3 Hz, 2H), 6.97 (dd, J=8,3, 2,3 Hz, 2H), 4.79 (s, 1H), 4.41 - 4.18 (m, 4H), 3.41 (d, J=26,3 Hz, 3H), 2.65-2.26 (m, 8H), 2.13 (d, J=14.4 Hz, 1H), 1.83-1.56 (m, 5H), 1.10-0,98 (d, 1H), 0,69 (d, 2H).

[M+H]+=696 (multimode+).

Example 314

The product was obtained from (R)-1-aminopropan-2-ol (78 mg, 1.04 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin, in the form of a colorless solid (0,114 g).

1H NMR (300 MHz, DMSO) δ 9.2 (s, 1H), 8.91 (dd, J=4,6, 2,5 Hz, 3H), 8.61 (d, J=2.7 Hz, 1H), 8.31 (dd, J=7,6, 3.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.71-7.58 (m, 2H), 7.48-7.34 (m, 4H), 7.25-7.15 (m, 2H), 6.97 (dd, J=an 8.4 and 2.2 Hz, 1H), 4.78 (t, J=20.4 Hz, 1H), 4.36 (s, 3H), 3.92 (s, 1H), 3.38 (s, 1H), 2.67-2.52 (m, 9H), 2.19-2.06 (m, 2H), 1.81-1.56 (m, 4H), 1.10-of 0.85 (m, 3H).

[M+H]+=696 (multimode+).

Example 315

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[1-(hydroxymethyl)cyclopropyl](methyl)amino]-methyl} - biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from (1-aminocyclopropane)methanol (91 mg, 1.04 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by way of Note the RA 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%ammonium acetate in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a colourless solid (41 mg).

1H NMR (300 MHz, DMSO) δ 9.35 (s, 1H), 8.71 (s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.32-8.23 (m, 1H), 7.84 (s, 1H), 7.57-7.47 (m, 2H), 7.37-7.21 (m, 3H), 7.01 (d, J=8,3 Hz, 1H), 6.87 (s, 1H), 6.67 (d, J=8,1 Hz, 1H), 4.78 (t, J=27,2 Hz, 1H), 4.36 (d, J=5.0 Hz, 1H), 3.79 (d, J=8,3 Hz, 4H), 2.88-2.80 (m, 2H), 2.72 (s, 2H), 2.15 (s, 3H), 1.90 (d, J=12.3 Hz, 3H), 1.49 (d, J=23,5 Hz, 4H), 0,43 (d, J=26,0 Hz, 4H).

[M+H]+=708 (multimode+).

Example 316

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[(1-hydroxyisopropyl)methyl](methyl)-amino]methyl}biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from 1-(aminomethyl)cyclopropanol (0,136 g, 1.57 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 90-40% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-t is itterated (20 mg).

1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 9.49 (s, 1H), 9.00-8.86 (m, 2H), 8.59 (d, J=2,8 Hz, 1H), 8.31 (dd, J=7,7, 2.8 Hz, 1H), 8.10 (s, 1H), 7.71-7.57 (m, 2H), 7.45-7.33 (m, 4H), 7.25-7.08 (m, 2H), 6.97 (dd, J=8,5, 2.3 Hz, 1H), 4.81-4.72 (m, 1H), 4.36 (s, 2H), 4.29-4.20 (m, 1H), 3.40-3.35 (m, 3H), 3.07 (d, J=27,1 Hz, 1H), 2.78-2.69 (m, 1H), 2.59 (s, 3H), 2.13 (d, J=14.1 Hz, 2H), 1.78-1.60 (m, 4H), 1.25 (s, 1H), 0,78-0,56 (m, 4H).

[M+H]+=708 (multimode+).

Example 317

1-(2'-{[Cyclopropyl(methyl)amino]methyl}-4'-hydroxybiphenyl-3-yl)-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from cyclopropylamine (0,089 g, 1.57 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 90-40% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin (25 mg).

1H NMR (400 MHz, DMSO) δ 9.05-8.92 (m, 2H), 8.66 (d, J=3.1 Hz, 1H), 8.36 (dd, J=7,7, 3.1 Hz, 1H), 8.16 (s, 1H), 7.76-7.63 (m, 2H), 7.52-7.43 (m, 3H), 7.28 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J=6,9 Hz, 1H), 4.84 (t, J=a 13.9 Hz, 1H), 4.50-4.39 (m, 3H), 3.48 (s, 1H), 2.74-2.59 (m, 5H), 2.48-2.40 (m, 1H), 2.19 (d, J=14.1 Hz, 2H), 1.81 (t, J=14,2 Hz, 2H), 1.70 (d, J=10.5 Hz, 2H), 0,92-of 0.48 (m, 5H).

[M+H]+=678 (multimode+).

Example 318

6-Fluoro-3-(CIS-4-{[(6-what torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]-methyl} - biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from (S)-2-aminopropan-1-ol (amount of 0.118 g, 1.57 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 90-40% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin (0,132 g).

1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.90 (dd, J=4,4, 2.3 Hz, 2H), 8.63-8.53 (m, 1H), 8.31 (d, J=4.9 Hz, 1H), 8.10 (s, 1H), 7.70-7.58 (m, 2H), 7.47-7.39 (m, 3H), 7.35 (s, 1H), 7.26-7.19 (m, 2H), 6.97 (dd, J=8,5, 2.3 Hz, 1H), 4.78 (t, J=16.2 Hz, 1H), 4.39 (s, 3H), 3.52-3.30 (m, 4H), 3.04 (s, 1H), 2.63-2.55 (m, 2H), 2.54 (d, J=3.3 Hz, 3H), 2.33 (d, J=1.8 Hz, 1H), 2.13 (d, J=14.6 Hz, 2H), 1.77 (d, J=14.6 Hz, 2H), 1.68-1.60 (m, 2H), 1.09-1.01 (m, 1H), 0,73 is 0.67 (m, 2H).

[M+H]+=696 (multimode+).

Example 319

1-(2'-{[(Cyclopropylmethyl)(methyl)amino]methyl}-4'-hydroxybiphenyl-3-yl)-6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The product was obtained from cyclopropylalanine (0,111 g, 1.57 mmol) and tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (600 mg, 1.04 mmol) by the method of Example 309. The crude product is about what imali by preparative HPLC on a column of Phenomenex Gemini, using the gradient 90-40% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin (0,130 g).

1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.82 (s, 1H), 8.67 (dd, J=4,4, 2.6 Hz, 1H), 8.33 (d, J=2,8 Hz, 1H), 8.05 (dd, J=7,7, 3.1 Hz, 1H), 7.87 (s, 1H), 7.43 (dd, J=9,9, a 5.3 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.23-7.11 (m, 4H), 6.98 (d, J=8.5 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.73 (dd, J=8,5, 2.3 Hz, 1H), 4.53 (t, J=11.7 Hz, 1H), 4.07-3.90 (m, 4H), 3.14 (s, 1H), 2.67-2.59 (m, 1H), 2.51-2.42 (m, 1H), 2.42-2.27 (m, 5H), 1.89 (d, J=13,8 Hz, 2H), 1.50 (t, J=13,8 Hz, 2H), 1.40 (d, J=11.3 Hz, 2H), 0,65 is 0.58 (m, 1H), 0,26 (s, 2H), 0,10 (s, 2H).

[M+H]+=692 (multimode+).

Example 320

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-(4'-hydroxy-2'-{[(3R)-3-hydroxypyrrolidine-1-yl]methyl}-biphenyl-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (300 mg, 0.52 mmol) and (R)-pyrrolidin-3-ol (50.0 mg, or 0.57 mmol) was stirred at room temperature in DCM (20 ml) for 15 minutes, then added triacetoxyborohydride sodium (133 mg, to 0.63 mmol). The mixture was stirred at room temperature for 20 h, then was added TFA (2 ml, 25,96 mmol). The mixture was stirred for 3 h and concentrated in vacuum. Was added saturated sodium bicarbonate and the mixture was extracted with et is lacerata, which was dried with sodium sulfate and concentrated to obtain a solid (100 mg). This substance was mixed with 6 torymidae[1,2-a]pyridine-2-carbaldehyde (30 mg, 0.18 mmol) at room temperature in DCM (20 ml) for 15 minutes, then added triacetoxyborohydride sodium (47 mg, 0.22 mmol). The mixture was stirred for 3 h and concentrated in vacuum. Added water and the mixture was extracted with ethyl acetate, which was dried with sodium sulfate and concentrated in vacuum. The crude product was purified by preparative HPLC on a column (Waters X-Terra, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a solid (56 mg).

1H NMR (300 MHz, DMSO) δ 8.70 (dd, J=4,7, 2.4 Hz, 1H), 8.58 (d, J=3.1 Hz, 1H), 8.27 (dd, J=7,7, 2,9 Hz, 1H), 7.83 (s, 1H), 7.58-7.47 (m, 3H), 7.44 (d, J=7.7 Hz, 1H), 7.32-7.20 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.72 (dd, J=8,4. the 2.4 Hz, 1H), 4.86-4.70 (m, 1H), 4.11-4.02 (m, 1H), 3.80 (d. J=6,7 Hz, 2H), 3.37 (s, 2H), 2.89-2.80 (m, 1H), 2.79-2.65 (m, 2H), 2.33-2.19 (m, 3H), 1.96-1.82 (m, 2H), 1.81-1.71 (m, 1H), 1.55-1.35 (m, 4H).

[M+H]+=694 (multimode+).

The compounds listed in Table 10 (see end of description), were obtained in a similar manner in the form of solid substances from tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate, 6-is torymidae[1,2-a]pyridine-2-carbaldehyde and sootvetstvuyuschego amine using the method described above in Example 320.

Example 327

N-{CIS-4-[6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-piperidine-1-ylacetamide

To a solution of 2-(piperidine-1-yl)acetic acid (0,052 g and 0.37 mmol) in NMP (4 ml) was added N-ethyldiethanolamine (0,190 ml, 1.10 mmol)and then HATU (0.167 g, 0.44 mmol) and the reaction mixture was stirred for 5 minutes. Then added 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g, and 0.37 mmol) and the reaction mixture was stirred for 3 h at room temperature. Was added water (20 ml) and the reaction mixture was stirred for 5 minutes. The precipitate was separated by filtration. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a solid (70 mg).

1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.59 (d, J=2,8 Hz, 1H), 8.26 (dd, J=7,7, 2.8 Hz, 1H), 7.76 (d, J=8,2 Hz, 1H), 7.58-7.57 (m, 1H), 7.54-7.50 (m, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.31 (dd, J=8,1, 1.4 Hz, 1H), 7.11 (d, J=8,2 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8,5, and 2.6 Hz, 1H), 4.88-4.82 (m, 1H), 4.02-4.00 (m, 1H), 3.45-3.43 (m, 4H), 3.28 (s, 1H), 2.84 (s, 2H), 2.55-2.52 (m, 1H), 2.38 (s, 4H), 2.28 (s, 4H), 1.78-1.73 (m, 2H), 1.65-1.7 (m, 5H), 1.48 (s, 4H), 1.24 (s, 2H).

[M+H]+=671 (multimode+).

Example 328

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(6-methylimidazo[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyridine-2,4(1H,3H)-dione

Stage (a): ethyl-6-methylimidazo[1,2-a]pyridine-2-carboxylate

Ethylbromide (10,04 g, 55,48 mmol) was slowly added to 5-methylpyridin-2-amine (4 g, 36,99 mmol) in ethanol (60 ml) at ambient temperature. The reaction mixture was stirred while boiling under reflux for 19 hours Added ethylbromide (2,321 ml, be 18.49 mmol) and the reaction mixture is boiled under reflux for 19 hours, the Solvent was evaporated and to the residue was added 1 N. HCl (100 ml). The aqueous layer was washed with ethyl acetate, podslushivaet aq. a saturated solution of sodium bicarbonate and the product was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on silica, elwira gradient 40% ethyl acetate in DCM. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow solid (1.1 g).

1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.90 (d, 1H), 7.57 (d, J=9,2 Hz, 1H), 7.09 (dd, 1H), 4.45 (q, 2H, 2.33 (d, 3H), 1.44 (t, 3H).

[M+H]+=205.

Stage (b): 6-Methylimidazo[1,2-a]pyridine-2-yl)methanol

A solution of ethyl-6-methylimidazo[1,2-a]pyridine-2-carboxylate (1,11 g, 5,44 mmol) in tetrahydrofuran (20 ml) was added dropwise to lithium aluminum hydride (1 M in THF) (5,44 ml, 5,44 mmol) at 5°C and the reaction mixture was stirred at 5°C for 1 h, the Reaction mixture was extinguished drip by adding ethyl acetate. After heating to room temperature the mixture was distributed between DCM and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the title compounds as a pale brown solid (0.84 g).

1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.47-7.44 (m, 2H), 7.02 (dd, J=9,1, 1.2 Hz, 1H), 4.82 (s, 2H), 2.31 (s, 3H).

[M+H]+=163

Stage (in): 6 Methylimidazo[1,2-a]pyridine-2-carbaldehyde

To a solution of (6-methylimidazo[1,2-a]pyridine-2-yl)methanol (0.84 g, 5.18 mmol) in DCM (15 ml) was added manganese dioxide (0,450 g, 5.18 mmol) and the reaction mixture was stirred in nitrogen atmosphere at ambient temperature for 1.5 h and left to stand for a further 18 h, the Reaction mixture was heated to boiling under reflux for 3 h, after which was added an additional amount of manganese dioxide (2.5 g, 28,76 mmol) and DCM (15,00 ml). The reaction mixture was stirred the boiling under reflux for 3 h and left to stand at room temperature for 67 hours The mixture was filtered through a layer of celite, washed with DCM. The filtrate was concentrated, triturated with ether and filtered to obtain specified in the subtitle compound as a beige solid (0,283 g).

1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.07 (s, 1H), 7.94 (d, J=1.3 Hz, 1H), 7.58 (d, J=9.5 Hz, 1H), 7.14 (dd, J=9,5, 1.5 Hz, 1H), 2.38 (s, 3H).

[M+H]=161.

Stage (d): 6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(6-methylimidazo[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g, 0.46 mmol) was added DCE (20 ml) and NMP (1 ml) and the suspension was intensively stirred for 1.5 hours was Added 6-methylimidazo[1,2-a]pyridine-2-carbaldehyde (of 0.066 g, 0.41 mmol) and the reaction mixture was stirred at ambient temperature for 1 h was Added four drops of acetic acid and the reaction mixture was stirred at ambient temperature for 17 hours was Added triacetoxyborohydride sodium (0,194 g to 0.92 mmol) and the reaction mixture was stirred at ambient temperature for another 3 h and left to stand at ambient temperature for 19 hours, the Reaction mixture was diluted with DCM and the organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, F. literaly and the solvent was evaporated. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compounds as white solids (0,160 g).

1H NMR (400 MHz, DMSO) δ 8.58 (d, J=3.1 Hz, 1H), 8.30-8.23 (m, 2H), 7.70 (s, 1H), 7.59-7.49 (m, 2H), 7.43-7.34 (m, 2H), 7.31 (d, 1H), 7.13 (d, 1H), 7.03 (dd, 1H), 6.88 (d, 1H), 6.75 (dd, 1H), 4.78 (t, 1H), 3.77 (d,, 2H), 3.43 (s, 4H), 3.28 (s, 2H), 2.85 (s, 1H), 2.80-2.67 (m, 2H), 2.25 (s, 7H), 1.92-1.85 (m, 2H), 1.72 (s, 1H), 1.53-1.38 (m, 4H).

[M+H]+=690 (multimode+).

Example 329

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(5-methylimidazo[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g, 0.46 mmol) in DCE (20 ml) was added 5-methylimidazo[1,2-a]pyridine-2-carbaldehyde (of 0.066 g, 0.41 mmol) and four drops of acetic acid. The reaction mixture was stirred at ambient temperature for 17 hours was Added triacetoxyborohydride sodium (0,194 g to 0.92 mmol) and the reaction mixture was stirred at ambient temperature for about 6.5 hours, the Reaction mixture was diluted with DCM and the organic phase was washed with saturated aqueous sodium bicarbonate, brine, was dried in the magnesium sulfate and the solvent was evaporated. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compounds as white solids (0,161 g).

1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.58 (d, 1H), 8.27 (dd, 1H), 7.71 (s, 1H), 7.58-7.49 (m, 2H), 7.44-7.35 (m, 2H), 7.33-7.29 (m, 1H), 7.18-7.11 (m, 2H), 6.88 (d, 1H), 6.75 (dd, 1H), 6.70 (d, 1H), 4.80 (t, 1H), 3.83 (s, 2H), 3.42 (t, 4H), 3.27 (s, 2H), 2.89 (s, 1H), 2.84-2.71 (m, 2H), 2.53 (s, 3H), 2.26 (s, 4H), 1.90 (d, 2H), 1.77 (d, 1H), 1.54-1.38 (m, 4H).

[M+H]+=690 (multimode+).

Example 330

6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(3-methylimidazo[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): Methyl - and ethyl-3-methylimidazo[1,2-a]pyridine-2-carboxylate

To a solution of methyl 3-bromo-2-oxobutanoate (6,23 g, 31,95 mmol) in ethanol (50 ml) was added pyridine-2-amine (2,506 g, 26,62 mmol) and the mixture was heated under reflux for 6 h, then stirred at ambient temperature for 2 days. The suspension was heated under reflux for a further 6 h, then stirred at ambient temperature for 17 hours, the Solvent was evaporated and the crude product was purified by flash HRO is ecografia on the silicon dioxide, elwira 3% (10% methanolic ammonia in 90% methanol) in 97% DCM. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as an orange oil, which is a mixture of methyl and ethyl esters (2,48 g).

1H NMR (400 MHz, CDCl3) δ 7.91 (dd, 1H), 7.68-7.63 (m, 1H), 7.27-7.19 (m, 1H), 6.90 (tdd, 1H), 4.47 (q, 2H), 4.00 (s, 3H), 2.81 (s, 3H), 1.46 (t, 3H).

[M+H]+=191 corresponds to the methyl ether complex; [M+H]+=204 corresponds ethyl ether complex.

Stage (b): (3 Methylimidazo[1,2-a]pyridine-2-yl)methanol

A solution of methyl - and ethyl-3-methylimidazo[1,2-a]pyridine-2-carboxylate (2,48 g, 12,14 mmol) in tetrahydrofuran (40 ml) was added dropwise to lithium aluminum hydride (1 M in THF) (12,14 ml, 12,14 mmol) at 5°C and the reaction mixture was stirred at 5°C for 1 h To the reaction mixture was added dropwise a saturated aqueous solution of salt of Rosella (Rochelle's) and the mixture was filtered. The filtrate was dried over magnesium sulfate, filtered and the solvent evaporated to obtain specified in the subtitle compound (1,590 g).

1H NMR (400 MHz, CDCl3) δ 7.83 (d, 1H), 7.56 (d, 1H), 7.15 (ddd, 1H), 6.82 (td, 1H), 4.85 (s, 2H), 2.49 (s, 3H).

[M+H]+=163.

Stage (in): 3-Methylimidazo[1,2-a]pyridine-2-carbaldehyde

Manganese dioxide (charged 8.52 g, 98,03 mmol) in portions over 5 minutes was added to a solution of (3-methylimidazo[1,2-a]pyridine-2-yl)meta is Ola (1,59 g, 9,80 mmol) in DCM (100 ml) under nitrogen atmosphere. The reaction mixture was heated to boiling under reflux for 3 hours the Mixture was filtered through a layer of celite, then further filtered the filtrate through 3 fiberglass filter, washing DCM. The filtrate was concentrated to obtain specified in the subtitle compound as a yellow solid (1.20 g).

1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 7.95 (d, 1H), 7.66 (d, 1H), 7.30-7.25 (m, 1H), 6.94 (dd, 1H), 2.80 (s, 3H).

[M+H]+=161.

Stage (d): 6-Fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-3-(CIS-4-{[(3-methylimidazo[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

(CIS-4-aminocyclohexane)-6-fluoro-1-[4'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g, 0.46 mmol) in DCE (20 ml) was added 3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (of 0.066 g, 0.41 mmol) and 4 drops of acetic acid. The reaction mixture was stirred at ambient temperature for 19 hours Added triacetoxyborohydride sodium (0,194 g to 0.92 mmol) and the reaction mixture was stirred at ambient temperature for 5 hours the Reaction mixture was diluted with DCM and the organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate and the solvent evaporated. The crude product was purified by preparative HPLC on a column of Phenomenex emini, using the gradient 75-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compound as off-white solids (0,120 g).

1H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.58 (d, 1H), 8.27 (dd, 1H), 8.19 (d, 1H), 7.57-7.45 (m, 3H), 7.41 (d, 1H), 7.30 (d, 1H), 7.19-7.11 (m, 2H), 6.91-6.86 (m, 2H), 6.76 (dd, 1H), 4.77 (t, 1H), 3.79 (s, 2H), 3.43 (t, 4H), 3.28 (s, 2H), 2.83 (s, 1H), 2.79-2.68 (m, 2H), 2.46 (s, 3H), 2.27 (s, 4H), 1.93-1.85 (m, 2H), 1.64 (s, 1H), 1.53-1.38 (m, 4H).

[M+H]+=690 (multimode+).

Example 331

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-[5'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): tert-Butyl{CIS-4-[6-fluoro-1-(2'-formyl-5'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-carbamate

A mixture of palladium diacetate (19 mg, 0.09 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (71 mg, 0,17 mmol) was stirred for 10 minutes in dry acetonitrile as solvent (16 ml). To this mixture was sequentially added a solution of potassium carbonate (0,357 g, 2.58 mmol) in water (5 ml), 2-chloro-4-hydroxybenzaldehyde (is 0.135 g, 0.86 mmol) and tert-butyl{CIS-4-16-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (0.5 g, 0.6 mmol). The resulting mixture was stirred and heated at 70°C for 4 h the Mixture was left to cool to room temperature and concentrated in vacuum. The crude product was applied on silicagel column and suirable a mixture of from 30% to 50% ethyl acetate: isohexane. Pure fractions were combined and evaporated to dryness to obtain specified in the subtitle compound as a pale yellow solid (0,255 g).

1H NMR (300 MHz, CDCl3) δ 9.87 (s, 1H), 8.33-8.27 (m, 1H), 8.13 (dd, J=6,8, and 2.6 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.49-7.42 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.27-7.22 (m, 1H), 6.90-6.81 (m, 2H), 4.99-4.80 (m, 2H), 3.84 (s, 1H), 2.59-2.40 (m, 2H), 1.90-1.71 (m, 2H), 1.65-1.46 (m, 4H), 1.35 (s, N).

[M+H]+=646.

Stage (b): 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[5'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-5'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (250 mg, 0.44 mmol) and research (0,042 ml, 0.48 mmol) was stirred for 15 minutes and added triacetoxyborohydride sodium (101 mg, 0.48 mmol). The mixture was stirred for 2 hours was Added morpholine (20 mg) and after 15 minutes triacetoxyborohydride sodium (50 mg). The reaction mixture was stirred for 1 h was Added triperoxonane acid (1 ml, 12,98 mmol) and the mixture was stirred for another 2 h, then was concentrated in vacuo the e with obtaining solids (0,280 g).

[M+H]+=546.

Stage (in): 6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]-amino}cyclohexyl)-1-[5'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of 3'-(3-((1s,4s)-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl)-5-hydroxybiphenyl-2-carbaldehyde (250 mg, of 0.53 mmol) and 6-torymidae[1,2-a]pyridine-2-carbaldehyde (104 mg, to 0.63 mmol) in dichloromethane (20 ml) was stirred for 15 minutes, was added triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred for 2 hours was Added methanol (1 ml)was stirred for 2 h and concentrated in vacuum to obtain a solid substance. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using a gradient of 83% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white solid (79 mg).

1H NMR (300 MHz, DMSO) δ 10.19-10.00 (m, 1H), 9.01-8.82 (m, 2H), 8.59 (s, 1H), 8.33 (dd, J=7,7, 1.2 Hz, 1H), 8.11 (s, 1H), 7.71-7.59 (m, 2H), 7.55-7.40 (m, 5H), 6.91 (d, J=8.7 Hz, 1H), 6.78 (s, 1H), 4.84-4.71 (m, 1H), 4.37 (s, 2H), 4.21 (s, 2H), 3.83-3.67 (m, 2H), 3.65-3.49 (m, 2H), 3.43-3.32 (m, 1H), 3.21-3.03 (m, 2H), 2.72-2.53 (m, 4H), 2.19-2.04 (m, 2H), 1.85-1.59 (m, 4H).

[M+H]+=694 (multimode+).

Example 332

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-the l]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)-biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, and 0.37 mmol) in DCE (2 ml) was treated with 6-torymidae[1,2-a]pyridine-2-carbaldehyde (75 mg, 0.46 mmol) and was stirred for 15 minutes at room temperature. Added triacetoxyborohydride sodium (156 mg, of 0.74 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted in DCM (3 ml), was added water (2 ml) and saturated aqueous sodium hydrogen carbonate solution (3 ml) and the mixture was intensively stirred for 15 minutes. The organic phase was separated and evaporated. The residue was transferred into a small amount of acetonitrile, filtered and purified by preparative HPLC on a column of ACE S using gradient 95-25% water and 0.2%triperoxonane acid in acetonitrile as eluent. The fractions containing the product were combined and evaporated to obtain specified in the title compound, salt di-triptorelin, in the form of fluffy cream powder (78 mg).

1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=3.1 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 8.18 (dd, J=7,2, 3.1 Hz, 1H), 7.78 (dd, J=10,0, 4.6 Hz, 1H), 7.69-7.62 (m, 3H), 7.59 (t, J=7.8 Hz, 1H), 7.52-7.45 (m, 4H), 7.29-7.27 (m, 1H), 5.13-4.98 (m, 1H), 4.55 (s, 2H), 4.29 (s, 2H), 3.96-3.85 (m, 2H), 3.82 (t, J=6.3 Hz, 2H), 3.60-3.52 (m, 1H), 2.78-2.62 (m, 2H), 2.45-2.34 (m, 3H), 1.92-1.76 (m, 4H). The remaining protons obscured the peaks of the solvent.

Example 333

3-(CIS-4-{Bis[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-6-fluoro-1-[4'-(1,4-oxazepan-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

From the reaction mixture to obtain the compound of Example 332 also been allocated is specified in the title compound, salt di-triptorelin, in the form of a white powder (19 mg).

1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.40 (d, J=3.1 Hz, 1H), 8.26 (dd, J=6,9, 3.1 Hz, 1H), 8.19 (s, 2H), 7.90-7.83 (m, 3H), 7.74 (t, J=7,6 Hz, 1H), 7.71 (d, J=8,2 Hz, 2H), 7.61-7.59 (m, 1H), 7.53 (d, J=8,2 Hz, 2H), 7.47 (dt, J=2,1, to 8.7 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H), 5.26-5.14 (m, 1H), 4.29 (s, 2H), 4.14 (s, 4H), 3.96-3.89 (m, 2H), 3.83 (t, J=6.3 Hz, 2H), 2.97-2.91 (m, 1H), 2.89-2.75 (m, 2H), 2.32 (d, J=14.6 Hz, 3H), 1.79-1.58 (m, 5H).

[M+H]+=840 (multimode+).

Example 334

N-{4-[2-(Diethylamino)ethoxy]benzyl}-N-{CIS-4-16-fluoro-1-{4'-[(4-isopropyl-piperazine-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}ndimethylacetamide

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)-methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.35 mmol) in DCE (2 ml) was treated with 4-(2-(diethylamino)ethoxy)benzaldehyde (97 mg, 0.44 mmol) at room temperature for 15 minutes, then added triacetoxyborohydride sodium 149 mg, 0.70 mmol) and the whole mixture was stirred at room temperature for 3 days. The reaction mixture was diluted in DCM (3 ml) and water (2 the l), was added a saturated aqueous solution of sodium bicarbonate (3 ml) and the mixture was intensively stirred for 15 minutes. The organic phase was separated and evaporated, and the residue is transferred in acetonitrile (3 ml) and treated with acetylchloride (0,031 ml, 0.44 mmol) and triethylamine (0,073 ml of 0.53 mmol). The mixture was stirred at room temperature for 24 h, then diluted with DCM and thoroughly mixed with water and saturated aqueous sodium bicarbonate. The organic phase was separated and evaporated. The crude substance was purified by preparative HPLC on a column of ACE S using gradient 95-5% 0,2%aqueous ammonia in acetonitrile as eluent, followed by preparative HPLC on a column of ACE S using gradient 95-25% 0,2%water triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound evaporated from receiving specified in the title compound, salt di-triptorelin, in the form of a white solid (36 mg).

1H NMR (400 MHz, Dl3) δ 8.37 (d, J=2,8 Hz, 1H), 8.22 (dd, J=7,2, 3.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.72-7.64 (m, 4H), 7.55-7.48 (m, 4H), 7.40-7.30 (m, 1H), 7.14 (d, J=8,2 Hz, 2H), 6.91-6.73 (m, 3H), 5.17-5.06 (m, 1H), 4.86 (s,, 2H), 4.35 (s, 2H), 4.25 (s, 2H), 3.79-3.41 (m, 12H), 3.40-3.17 (m, 4H), 2.64-2.45 (m, 2H), 2.15-1.93 (m, 4H), 1.82-1.60 (m, 4H), 1.42-1.30 (m, 12H).

[M+H]+=818 (multimode+).

Example 335

3-(CIS-4-{Bis[(1-acetyl-1H-indol-3-yl)methyl]amino}cyclohexyl)-6-fluoro-1-{4'-[(4-isopropyi the Razin-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-[(4-isopropylpiperazine-1-yl)-methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.35 mmol) in DCE (2 ml) was added 1-acetyl-1H-indole-3-carbaldehyde (98 mg, of 0.53 mmol) and was stirred for 15 minutes at room temperature. Added triacetoxyborohydride sodium (149 mg, 0.70 mmol) and the reaction mixture was left to stand at room temperature overnight. Was added water (2 ml), saturated aqueous sodium bicarbonate solution (3 ml) and DCM (2 ml) and the mixture was stirred for 15 minutes, then separated. The organic solution is evaporated and the crude substance was purified by preparative HPLC on a column of ACE S using gradient 75-5% 0,2%water triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound evaporated from receiving specified in the title compound, salt di-triptorelin, in the form of a pale pink solid (51 mg).

1H NMR (400 MHz, DMSO) δ 9.93-9.84 (m, 1H), 8.64-8.58 (m, 1H), 8.33 (dd, J=7,7, 2.8 Hz, 1H), 8.27-8.19 (m, 1H), 8.13-8.03 (m, 2H), 7.93-7.84 (m, 1H), 7.83-7.66 (m, 7H), 7.57-7.43 (m, 3H), 7.37-7.26 (m, 2H), 7.16-7.07 (m, 1H), 7.05-6.99 (m, 1H), 5.11-4.99 (m, 1H), 4.80-4.68 (m, 1H), 4.68-4.58 (m, 1H), 3.24-2.99 (m, 6H), 2.84-2.61 (m, 2H), 2.35-2.20 (m, 1H), 2.17-1.99 (m, 4H), 1.23 (d, J=6,4 Hz, 6N). Other resonances obscured by signals DMSO and water.

[M+H]+=913 (multimode+).

Example 336

6-Fluoro-N-{CIS-4-[6-fluoro-1-{4'-[2-(isopropylamino)ATOC and]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-imidazo[1,2-a]pyridine-2-carboxamide

N-{CIS-4-[1-[4'-(2-Chloroethoxy)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-di hydroperiod[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-6-torymidae[1,2-a]-pyridine-2-carboxamide (0.2 g, 0.30 mmol), potassium carbonate (0,412 g, 2,98 mmol), potassium iodide (0.05 g, 0.30 mmol) and 2-aminopropan (1 ml, 11,74 mmol) suspended in acetonitrile (5 ml) and was heated up to 80°C for 5 hours was Added an additional portion of 2-aminopropane (1 ml, 11,74 mmol) and the reaction mixture was heated for another 16 h, then was poured into water and was extracted with ethyl acetate. The combined extracts were washed with brine and the solvent evaporated. The crude product was purified by preparative HPLC on a Sunfire column using a gradient of 95-50% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt triptorelin, in the form of a pale pink solid (30 mg).

1H NMR (500 MHz, DMSO) δ 8.82 (d, J=2.3 Hz, 1H), 8.66 (s, 2H), 8.59 (d, J=3.0 Hz, 1H), 8.40 (s, 1H), 8.34 (dd, J=7,7, 3.0 Hz, 1H), 7.76-7.65 (m, 5H), 7.59 (t, J=7.9 Hz, 1H), 7.48 (dd, J=18,4, 2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.7 Hz, 2H), 4.88 (t, J=11,9 Hz, 1H), 4.28 (t, J=5.0 Hz, 2H), 4.16 (d, J=3.0 Hz, 1H), 3.44-3.34 (m, 3H), 2.66-2.57 (m, 2H), 2.02 (d, J=13,0 Hz, 2H), 1.76-1.63 (m, 4H), 1.27 (d, J=6.3 Hz, 6H).

[M+H]+=694 (multimode+).

Example 337

1-{4'-[(Dimethylamino)methyl]biphenyl-3-yl}-6-fluoro-3-{CIS-4-[(imidazo-[1,2-a]pyridine-2-ylmethyl)AMI is about]cyclohexyl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of imidazo[1,2-a]pyridine-2-carbaldehyde (71 mg, 0.49 mmol)dissolved in DCE (20 ml), was added 3-(CIS-4-aminocyclohexane)-1-{4'-[(dimethylamino)methyl]biphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,238 g, 0.49 mmol), and then triacetoxyborohydride sodium (0,103 g, 0.49 mmol). The resulting mixture peremeshivayu for 4 h at room temperature. The reaction mixture was diluted with DCM (10 ml) and washed with saturated brine (20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to obtain crude product. The crude product was purified by preparative HPLC on a column (Waters X-Terra, using the gradient 50-5% water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound, salt di-triptorelin, in the form of a colorless solid (0,351 g).

1H NMR (300 MHz, DMSO) δ 10.08 (s, 1H), 8.96 (s, 1H), 8.68 (d, J=6,9 Hz, 1H), 8.61 (d, J=3.1 Hz, 1H), 8.31 (dd, J=7,7, 3.1 Hz, 1H), 8.13 (s, 1H), 7.87-7.74 (m, 4H), 7.67-7.56 (m, 4H), 7.46-7.37 (m, 2H), 7.04 (t, J=6,8 Hz, 1H), 4.82 (t, J=11.5 Hz, 1H), 4.44-4.27 (m, 4H), 3.40 (s, 1H), 2.76 (d, J=3,7 Hz, 6N), 2.67-2.52 (m, 3H), 2.20-2.07 (m, 2H), 1.84-1.58 (m, 4H).

[M+H]+=618 (multimode+).

Example 338

1-Amino-N-[CIS-4-(1-biphenyl-3-yl-6-fluoro-2,4-dioxo-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl)cyclohexyl]cyclopropanecarboxamide

To a mixture of 1-BOC-amino-cyclopropanecarboxylic acid (68 mg, 0.34 mmol) and substrate Hunya (0,194 g, 1.5 mmol) in dry DMF (5 ml) was added HATU (128 mg, 0.34 mmol). The mixture was left to mix for 10 minutes at room temperature. To this mixture was added 3-(CIS-4-aminocyclohexane)-1-biphenyl-3-yl-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (115 mg, 0.31 mmol) and the mixture was stirred over night. The mixture was poured into water and the solid collected. This solid is then dissolved in a mixture of 4 N. HCl/dioxane (2 ml) and left for 1 hour, evaporated to dryness and the crude product was purified by preparative HPLC on a column (Waters X-Terra, using the gradient 70-50% water 0.1%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (65 mg).

1H NMR (300 MHz, DMSO) δ 8.68 (m, 2H), 8.60 (m, 1H), 8.32 (m, 1H), 7.70 (m, 4H), 7.49 (m, 2H), 7.39 (m, 2H), 7.12 (s, 1H), 4.82 (m, 1H), 3.80 (m, 1H), 3.41 (m, 3H), 2.61 (m, 2H), 2.02 (d, J=13.1 Hz, 2H), 1.54 (m, 4H), 1.28 (m, 2H).

[M+H]+=514 (multimode+).

Example 339

6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperidine-4-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide

Stage (a): tert-Butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbonyl]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-the l] - biphenyl-4-yl}methyl)piperidine-1-carboxylate

To a suspension of palladium (II) acetate (0.035 g, 0.16 mmol) in acetonitrile (15 ml) was added 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (0,149 g, 0.31 mmol). The mixture was stirred in nitrogen atmosphere for 10 minutes. Then was added potassium carbonate (0,282 ml, and 4.68 mmol) in solution in water (10 ml), and then 6-fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}imidazo[1,2-a]pyridine-2-carboxamide (1,002 g, 1.56 mmol) and then tert-butyl 4-(4-bromobenzyl)piperidine-1-carboxylate (0,663 g of 1.87 mmol). The mixture was heated up to 80°C for 4 hours. The mixture was cooled and left to mix at room temperature over night. The mixture is then poured into water. Attempted extraction with ethyl acetate resulted in the formation of the emulsion. Then the mixture was filtered, separated, and the organic layer was evaporated to obtain crude product. It was purified by column chromatography using ethyl acetate as eluent, to obtain specified in the subtitle compound (450 mg).

[M+H]+=790 (multimode+).

Stage (b): 6-Fluoro-N-{CIS-4-[6-fluoro-2,4-dioxo-1-[4'-(piperidine-4-ylmethyl)biphenyl-3-yl]-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclo-hexyl}imidazo[1,2-a]pyridine-2-carboxamide

To a solution of tert-butyl 4-({3'-[6-fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)carbon is l]amino}cyclohexyl)-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)piperidine-1-carboxylate in DCM (2 ml) was added triperoxonane acid (2 ml, 25,96 mmol). The mixture was stirred at room temperature for 2 hours. The solvents were removed in vacuum. The crude product was purified by preparative HPLC with a reversed phase column ACE (available from Highchrom Limited - www.highchrom.co.uk using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain solid, which was dried overnight at 40°C. under vacuum to obtain specified in the title compound (15 mg).

[M+H]+=690 (multimode+).

Example 340

6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}-cyclohexyl)-1-[3'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): 2-Formyl-3-methoxyphenyl-triftorbyenzola

To a solution of 2-hydroxy-6-methoxybenzaldehyde (2.70 g, 17,72 mmol) and pyridine (1,720 ml, 21,27 mmol) in dichloromethane (50 ml) at 0°C was added triftormetilfullerenov anhydride (2,98 ml, 17,72 mmol). The orange suspension was left to slowly warm and was stirred for 20 hours was Added water and was acidified aqueous HCl (1 M). The organic phase was separated and washed a feast upon. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated to obtain specified in the subtitle compound (3.5 g)

GCMS [M] 84.

Stage (b): 3-Methoxy-2-(morpholine-4-ylmethyl)phenyl-triftorbyenzola

2-Formyl-3-methoxyphenyl-triftorbyenzola (216 mg, from 0.76 mmol) and morpholine (0,079 ml of 0.91 mmol) was stirred at room temperature in dichloromethane (20 ml) for 15 minutes, then added triacetoxyborohydride sodium (193 mg, of 0.91 mmol). The mixture was stirred at room temperature for 20 h and was added triperoxonane acid (2 ml, 25,96 mmol). The mixture was stirred for 3 h and concentrated in vacuum. Was added saturated sodium bicarbonate and then extracted with ethyl acetate, which was dried and concentrated to obtain a solid substance. The crude product was purified by flash chromatography on silica with elution with a gradient of 70% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow oil (100 mg).

[M+H]+=356 (multimode+).

Stage (in): 3-Hydroxy-2-(morpholine-4-ylmethyl)phenyl-triftorbyenzola

Tribromide boron (7,60 ml of 7.60 mmol, 1 M in DCM) was added to a solution of 3-methoxy-2-(morpholinomethyl)phenyl-triftoratsetata (2.7 g, 7,60 mmol) in dichloromethane (20 ml) and was stirred for 24 h was Added HCl (2 M) and was stirred for 2 hours, the Phases were separated and the aqueous phase extragear the Wali DCM. The combined organic phases were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica with elution with 10% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow-brown solid (1.10 g)

[M+H]+=342 (multimode+).

Stage (d): tert-Butyl{CIS-4-[6-fluoro-1-[3'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate

The mixture diacetoxynaphthalene (0,039 g, 0,17 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (0,141 g, 0.34 mmol) was stirred for 10 minutes in dry acetonitrile as solvent (16 ml). To this mixture was sequentially added a solution of potassium carbonate (0,714 g, 5.17 mmol) in water (5 ml), 3-hydroxy-2-(morpholinomethyl)phenyl-triftorbyenzola (0,588 g, 1,72 mmol) and tert-butyl{4-[6-fluoro-2,4-dioxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro-pyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (1 g, 1,72 mmol). The resulting mixture was stirred and heated at 70°C for 4 h the Mixture was left to cool to room temperature and concentrated in vacuum. The crude product was applied on silicagel column and suirable a mixture of from 30% to 50% ethyl acetate: isohexane. Net fra is tion were combined and evaporated to dryness to obtain specified in the title compound (1.0 g).

[M+H]+=646 (multimode+).

Stage (d): 3-(CIS-4-aminocyclohexane)-6-fluoro-1-[3'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-spiramycin-2,4(1H,3H)-dione

Triperoxonane acid (3 ml, up 38.94 mmol) was added to tert-butyl{CIS-4-[6-fluoro-1-[3'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (500 mg, 0.77 mmol) in dichloromethane (10 ml) and was stirred for 3 hours then Concentrated in vacuum to obtain specified in subheading compound as an orange oil (600 mg).

[M+H]+=546 (multimode+).

Stage (e): 6-Fluoro-3-(CIS-4-{[(6-torymidae[1,2-a]pyridine-2-yl)methyl]amino}cyclohexyl)-1-[3'-hydroxy-2'-(morpholine-4-ylmethyl)biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-[3'-hydroxy-2'-(morpholine-4-yl-methyl) - biphenyl-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0,420 g, 0.77 mmol) and 6-torymidae[1,2-a]pyridine-2-carbaldehyde (0,063 g 0,39 mmol) in dichloromethane (20 ml) was stirred for 30 minutes. Added triacetoxyborohydride sodium (0,082 g 0,39 mmol) and the mixture was stirred for 2 hours was Added an additional amount of 6-torymidae[1,2-a]pyridine-2-carbaldehyde (0,063 g 0,39 mmol) and after 5 minutes was added triacetoxyborohydride sodium (0,082 g 0,39 mmol). Was stirred for 2 h and was added methanol (1 ml). Was stirred for 1 and concentrated in vacuum. The crude product was purified by preparative HPLC on a column (Waters X-Terra, using 85% isocratic water with 0.1%triperoxonane acid in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound (30 mg).

1H NMR (300 MHz, DMSO) δ 8.97-8.86 (m, 3H), 8.63-8.58 (m, 1H), 8.37-8.30 (m, 1H), 8.12-8.08 (m, 1H), 7.71-7.62 (m, 2H), 7.51-7.36 (m, 5H), 7.08-7.01 (m, 1H), 6.88-6.81 (m, 1H), 4.85-4.71 (m, 1H), 4.37 (s, 2H), 4.23 (s,, 2H), 3.67 (s, 5H), 3.44-3.34 (m, 2H), 2.64-2.55 (m, 4H), 2.20-2.08 (m, 2H), 1.83-1.59 (m, 4H).

[M+H]+=694 (multimode+).

Example 341

N-{CIS-4-[1-{2'-[(Dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (0,099 g to 0.60 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine (0,311 ml, to 1.79 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,272 g, 0.71 mmol) and the reaction mixture was stirred for 5 minutes. Then added 3-(CIS-4-aminocyclohexane)-1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g, of 0.60 mmol) and the reaction mixture was left to mix for 5 hours. Added water and the resulting precipitate was filtered and dried. The crude product was purified via preparative the Oh HPLC column Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain a solid substance. The connection is then suspended in the air for 48 hours, was filtered and dried to obtain specified in the title compound (0.083 g).

1H NMR (299.947 MHz, DMSO) δ 8.59 (d, J=2,9 Hz, 1H), 8.30 (dd, J=7,8, 3.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.44-7.42 (m, 3H), 7.33-7.28 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.92 (d, J=2.7 Hz, 1H), 6.73 (dd, J=8,4, and 2.6 Hz, 1H), 4.83 (t, J=11.7 Hz, 1H), 4.08 (s, 1H), 3.98-3.94 (m, 2H), 3.25 (s, 2H), 2.76-2.72 (m, 3H), 2.07 (s, 6H), 1.93-1.80 (m, 6H), 1.71-1.58 (m, 4H).

[M+H]+=652 (multimode+).

Example 342

N-{CIS-4-[1-{2'-[(Dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide

To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.083 g, of 0.60 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine (0,311 ml, to 1.79 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (0,272 g, 0.71 mmol) and the reaction mixture was stirred for 5 minutes. Then added 3-(CIS-4-aminocyclohexane)-1-{2'-[(dimethylamino)methyl]-4'-hydroxybiphenyl-3-yl}-6-torpedo[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g, of 0.60 mmol) and the reaction mixture was left to mix for 5 hours. Added water and the resulting precipitate was filtered and dried. The crude product is ciali by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header (0,045 g).

1H NMR (299,947 MHz, DMSO) δ 9.47 (s, 1H), at 8.62-8.61 (m, 1H), 8.34-8.30 (m, 1H), 7.54 (d, J=8,1 Hz, 1H), 7.46-7.43 (m, 2H), 7.34 (d, J=1.0 Hz, 1H), 7.21 (d, J=7,1 Hz, 1H), 7.13 (d, J=8,3 Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.77 (s, 1H), 6.43 (s, 1H), 4.90-4.82 (m, 1H), 4.10 (s, 1H), 3.78 (s, 3H), 3.27 (s, 2H), 2.62-2.58 (m, 2H), 2.28 (s, 3H), 2.08 (s, 6H), 1.98-1.94 (m, 2H), 1.71-1.59 (m, 4H).

[M+H]+=626 (multimode+).

Example 343

N-{CIS-4-[1-[4'-(1,4-Diazepan-1-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-methyl-1,3-thiazole-4-carboxamide

Stage (a): Benzyl-4-({3'-[3-{CIS-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)-1,4-diazepan-1-carboxylate

To a solution of tert-butyl{CIS-4-[6-fluoro-1-(4'-formylphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (3,013 g of 5.39 mmol) in DCM (60 ml) was added sodium sulfate (anhydrous) (0,766 g of 5.39 mmol) and benzyl-1,4-diazepan-1-carboxylate (1,789 ml, 8,63 mmol). The mixture was stirred at room temperature for 30 minutes and then added triacetoxyborohydride sodium (to 1.143 g of 5.39 mmol) and the reaction mixture was allowed to mix at the temperature of the environment during the night. The reaction mixture was diluted with CH2Cl2(50 ml), thoroughly washed with saturated aq. solution Panso3, dried and evaporated at 40°C with getting a grey foam. This foam is dissolved in the Meon) was applied on a large SCX cartridge (pre-washed Meon), thoroughly washed Meon and suirable mixture Meon-7 n ammonia in the Meon (4:1), obtaining mentioned in the subtitle compound (3.03 g). It was used without additional purification.

1H NMR (400 MHz, CDCL3) δ 8.37 (d, J=2,8 Hz, 1H), 8.21 (dd, J=3.3, which is 7.2 Hz, 1H), 7.77-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.59-7.53 (m, 2H), 7.53-7.49 (m, 1H), 7.41-7.26 (m, 16H), 5.14 (s, 4H), 5.04-4.93 (m, 2H), 3.97-3.89 (m, 1H), 2.97-2.80 (m, 5H), 2.73-2.52 (m, 7H), 2.06 (s, 2H), 1.97-1.57 (m, 16H), 1.43 (s, 9H), 1.26 (t, J=7,1 Hz, 3H). The spectrum shows the presence of 1 mol EtOAc and about 1 mol of N-Cbz-homopiperazine.

Stage (b): Benzyl-4-({3'-[3-(CIS-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)-1,4-diazepan-1-carboxylate

To a solution of benzyl-4-({3'-[3-{CIS-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)-1,4-diazepan-1-carboxylate (2.3 g, 2,96 mmol) in 1,4-dioxane (10 ml) was added 4.0 M hydrogen chloride in 1,4-dioxane (10 ml, 40,00 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness to obtain a white solid substance ( g). It was used without additional purification.

[M+H]+=677 (multimode+).

Stage (in): N-{CIS-4-[1-[4'-(1,4-Diazepan-1-ylmethyl)biphenyl-3-yl]-6-fluoro-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}-2-methyl-1,3-thiazole-4-carboxamide

To a suspension of benzyl 4-({3'-[3-(CIS-4-aminocyclohexane)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidine-1(2H)-yl]biphenyl-4-yl}methyl)-1,4-diazepan-1-carboxylate (300 mg, 0.44 mmol) and 2-methylthiazole-4-carboxylic acid (63.5 mg, 0.44 mmol) in acetonitrile (5 ml) was added triethylamine (0,309 ml, 2.22 mmol). After stirring at room temperature for 10 minutes was added 1.57 M solution of cyclic anhydride 1-papapostolou acid in THF (0,296 ml, 0.47 mmol) and the mixture was left to mix for 2 hours. The mixture was poured into a feast upon. NaHCO3(aq.) and the organic phase was extracted with ethyl acetate. An ethyl acetate extracts were combined and evaporated to obtain crude product. It was dissolved in acetic acid (2 ml) was added 33% Nug in acetic acid (2 ml). The reaction mixture was stirred for 10 minutes. The solvent was removed in vacuum. The crude product was purified by preparative HPLC with a reversed phase column ACE (available from Highchrom Limited - www.highchrom.co.uk using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. Sootvetstvuyushie fractions were combined, evaporated to dryness and raster is whether with ether to obtain white solids. This solid was isolated by filtration and dried overnight under vacuum at 40°C with obtaining specified in the title compound (111 mg).

1H NMR (400 MHz, CDCL3) δ 8.36 (d, J=3.1 Hz, 1H), 8.22 (dd, J=7,0, 2,9 Hz, 1H), 7.90 (s, 1H), 7.72 (d, J=7.9 Hz, 2H), 7.68-7.64 (m, 3H), 7.55-7.50 (m, 3H), 7.34 (d, J=7.7 Hz, 1H), 5.03 (t, J=12.0 Hz, 1H), 4.37-4.32 (m, 1H), 4.25 (s, 2H), 3.73-3.64 (m, 4H), 3.46-3.36 (m, 4H), 2.76-2.65 (m, 5H), 2.34-2.26 (m, 2H), 2.08 (d, J=13.1 Hz, 2H), 1.81-1.68 (m, 4H).

[M+H]+=668 (multimode+).

The compounds listed in Table 11 (see end of description), were obtained in a similar manner in the form of solid substances from sootvetstvujushej carboxylic acid using the method described in Example 343, stage (b).

The compounds listed in Table 12 (see end of description), were obtained similarly using the methods described in Example 227.

Example 363

3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-hydroxy-2'-[(5-oxo-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Stage (a): tert-Butyl{CIS-4-[6-fluoro-1-{4'-hydroxy-2'-[(5-oxo-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]Piri-midin-3(2H)-yl]cyclohexyl}carbamate

To a solution of tert-butyl{CIS-4-[6-fluoro-1-(2'-formyl-4'-hydroxybiphenyl-3-yl)-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2.5 g, 4.35 mmol) in 1,2-dichloroethane (30 ml) was added 1,4-di is sepan-5-he (0,596 g, with 5.22 mmol) and acetic acid (0,249 ml, 4.35 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours was Added triacetoxyborohydride sodium (1,844 g to 8.70 mmol), and then 1,2-dichloroethane (30 ml) and the reaction mixture was stirred at ambient temperature for 24 hours the Mixture was washed with saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The organic phase was evaporated to dryness. The crude product was purified by flash chromatography on silica, elwira gradient from 3 to 5% (7 N. methanolic ammonia in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in the connection header (2,21 g).

[M+H]+=673 (multimode+).

Stage (b): 3-(CIS-4-Aminocyclohexane)-6-fluoro-1-{4'-hydroxy-2'-[(5-oxo-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

The mixture triperoxonane acid (25 ml, 324,49 mmol) and dichloromethane (25 ml) was added to tert-butyl{CIS-4-[6-fluoro-1-{4'-hydroxy-2'-[(5-oxo-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}-2,4-dioxo-1,4-dihydropyrido[2,3-d]-pyrimidine-3(2H)-yl]cyclohexyl}carbamate (2,21 g, 3,29 mmol) and the mixture was left to stand at room temperature for 1 h, the Solvents evaporated and the residue was dissolved in water and podslushivaet putem adding aqueous ammonia. The precipitate was filtered and dried in an oven at 40°C for 16 h with getting wet is specified on the title product (1.19 g). The crude product (0.1 g) was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water and 0.2%ammonia in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids (0,088 g).

1H NMR (399,826 MHz, DMSO) δ 8.56 (d, J=2,8 Hz, 1H), 8.29 (dd, J=7,7, 3.1 Hz, 1H), 7.55-7.48 (m, 2H), 7.46 (t, J=5.4 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.11 (d, J=8,2 Hz, 1H), 6.90 (d, J=2,6 Hz, 1H), 6.75 (dd, J=8,3, 2.4 Hz, 1H), 4.74 (ddd, J=12,2, 8,6, and 3.7 Hz, 1H), 3.43-3.38 (m, 2H), 3.06 (s, 1H), 2.96 (s, 2H), 2.70 (td, J=12,8, and 9.3 Hz, 2H), 2.39 (s, 4H), 2.23 (d, J=4,6 Hz, 2H), 1.64 (d, J=12.0 Hz, 2H,), 1.53 (t, J=13.1 Hz, 2H), 1.42 (d, J=10.3 Hz, 2H).

[M+H]+=573 (multimode+).

Compounds shown in table 13 (see end of description), were obtained similarly using the methodology described in Example 241.

EXAMPLE

Analysis for screening of human phosphodiesterase B2 alpha

In the analysis using recombinant human phosphodiesterase B2 (PDE4B2)produced in the host (PrAZL0133), which is stored at -20°C. as the substrate, use of camp (adenosine 3',5 cyclophosphate), part of a set Alpha Screen camp (Perkin Elmer, cat. room # M), which was stored at 4°C. the Set Alpha Screen also includes biotinylated camp, acceptor and donor granules.

The procedure of addition was as follows. In white 384-well flat-bottomed plates (Greiner, ka is. room # 781075) was added to the test compounds and controls (0,2 ál of 100%DMSO)and then added 10 μl of PDE4B2 in the reaction buffer. The reaction buffer had the following composition: 50 mm Tris (pH 7.5), 8.3 mm MgCl2, 1.7 mm EGTA (etilenvinilatsetata acid) and 0.01% (wt./about.) Brij®35. Enzyme and compounds were incubated at room temperature for 15 minutes. Then add 10 ál of camp in the reaction buffer. The analysis was stopped after 60 minutes incubation at room temperature by adding 10 ál acceptor beads in buffer for detection with 40 mm EDTA (ethylenediaminetetraacetic acid). Buffer for detection had the following composition: 5 mm Tris (pH 7.5), 0.1 percent (wt./about.) BSA (bovine serum albumin) and 0.1% (vol./about.) Tween-20. For this addition was performed with the addition of 10 ál donor beads in buffer for detection with biotinylated camp. Then the plates were incubated in the dark at room temperature for 5 hours, followed by measurement on the analyzer Fusion™-α. Values pIC50(shown in Table 14) was determined using the graphing XIfit using the model 205.

Table 14
ExamplePDE4B2 pIC50
79,2
87,3
98,5

The EXAMPLE IN

Radiometric analysis of human phosphodiesterase B2

In the analysis using recombinant human phosphodiesterase B2 (PDE4B2)produced in the host (PrAZL0163), which is stored at -20°C. This analysis is based on the observation that 5 AMR, the product of the interaction catalyzed PDE4, preferably associated with SPA (analysis of scintillation proximity) granules of yttrium silicate (Amersham Biosciences, UK) compared with the substrate, camp. Connection sootvetstvujushej concentrations were subjected to pre-incubation at 30°C for 30 minutes with buffer for analysis containing 50 mm HEPES (pH 7.5), 8.3 mm MgCl2, 1.7 mm EGTA, 0.01 percent (wt./about.) Brij®35 and 0.1 μl/ml recombinant PDE4B2. The interaction was initiated by addition of [3H]cyclic AMP obtaining a final concentration of 8 nm, and stopped 20 minutes after addition of the substrate by adding SPA granules of yttrium silicate, containing 18 mm ZnSO4. Bound [3H]cyclic AMP was measured using a Topcount NXT (Packard Biosciences, UK). Values pIC50presented in Table 15 (see end of description), was determined using the graphing XIfit using the model 205.

The PATH AND

1. The compound of formula (I)

g is e
And represents the CA1;
E represents CE1;
W represents (CH2)n;
Y is (CH2)p;
n and p are independently 0 or 1;
R1represents phenyl substituted by phenyl {which is possibly substituted with halogen, hydroxy, CH(O)CO2H, C1-4the alkyl, C1-4alkyl-N(C1-4alkyl)2)1-4alkyl(NH2)1-4alkyl(NN(C1-4alkyl)),1-4hydroxyalkyl, CF3With1-4alkylthio,1-4alkyl(heterocyclyl) or C1-4NHC(O)O(C1-4alkyl)} or heterocyclyl; and heterocyclyl possibly substituted C1-6by alkyl;
R2represents NHC(O)R3; and R3represents a C1-4alkyl {substituted NR7R8or heterocyclyl}3-7cycloalkyl (possibly substituted by a group NR43R44or heteroaryl; where R7, R8, R43and R44are as defined in claim 1; heteroaryl possibly substituted with halogen, C1-4the alkyl, CF3With1-4alkoxy, F3, heterocyclyl or amino group(C1-4alkyl);
R7and R8independently represent a1-6alkyl;
And1E1and G1independently represent hydrogen or halogen;
unless otherwise stated, heterocyclyl possibly substituted C1-6alkyl is m;
R25represents a C1-6alkyl;
R50represents hydrogen or C1-6alkyl (possibly substituted by a group NR51R52);
R30, R36, R40, R42or R44independently represent hydrogen, C1-6alkyl (possibly substituted by hydroxy, C1-6alkoxy, C1-6alkylthio,3-7cycloalkyl (which is possibly substituted by hydroxy) or NR45R46)3-7cycloalkyl (possibly substituted by hydroxy group(C1-6alkyl)) or heterocyclyl (possibly replaced With1-6by alkyl);
R29, R35, R39, R41, R43, R45, R46and R51independently represent hydrogen or C1-6alkyl;
or its pharmaceutically acceptable salt;
where heterocyclyl represents a non-aromatic 5 - or 6-membered ring containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen; and
where aryl represents phenyl or naphthyl; and
where heteroaryl represents an aromatic 5 - or 6-membered ring, possibly condensed with other ring (which may be carbocyclic and aromatic or non-aromatic, containing one or two heteroatoms selected from the group consisting of nitrogen.

2. The compound of formula (I) according to claim 1, where a represents CH.

3. Link the formula (I) according to claim 1 or 2, where n and p are both equal to 1.

4. The compound of formula (I) according to claim 1, where a represents CA1; E represents CE1; W and Y both represent CH2; and G1And1and E1independently represent a hydrogen or halogen.

5. Pharmaceutical composition having activity as an inhibitor of PDE4 (phosphodiesterase 4), containing the compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

6. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 for use as PDE4 inhibitor.

7. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 for the manufacture of a medicinal product for use in the treatment of D4-mediated disease condition.

8. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 for the treatment D4-mediated disease condition.

9. The compound of formula (I) according to claim 1, which is a

its pharmaceutically acceptable salt.

10. The compound of formula (I) according to claim 1, which is a

its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one and a method for production thereof. 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one is obtained by condensation of acetone with 1,3,5-tri-(tert-butyl)-1,3,5-triazacyclohexane while heating in an alcohol in the presence of acetic acid. The reaction is carried out while heating in ethanol or another alcohol. The obtained product is extracted after condensation of the reaction mass in a vacuum with hot toluene and recrystallised from ethyl alcohol.

EFFECT: obtaining a novel compound which can be used as a starting substance when producing bispidine and 1,3-diazaadamantane derivatives.

2 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds in the form of a free base or a pharmaceutically acceptable acid addition salt specified in a group including: (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-azabicyclo[3.3.1]nonane, 5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydroindol-2-one, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[1.3.1]nonane and 5-{6-[(4S,5R)-(1-azabicyclo[3,3,1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-one, possess nAChR α7 agonist activity.

EFFECT: using them in pharmaceutical compositions and for preparing a drug applicable for preventing and treating a memory disorder.

21 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having antibacterial properties, a method for synthesis thereof, use thereof and a pharmaceutical composition based on said compounds. In general formula (I) R1 is a (CH2)n-NH2 or (CH2)n-NHR radical, where R is (C1-C6)alkyl and n equals 1 or 2; R2 is a hydrogen atom; R3 and R4 together form a nitrogen-containing aromatic 5-member heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted with one or more R' groups, where R' is selected from a group consisting of a hydrogen atom and alkyl radicals with 1-6 carbon atoms.

EFFECT: improved method.

13 cl, 4 ex

Liquid hardening // 2447114

FIELD: chemistry.

SUBSTANCE: invention relates to curing agents for air-drying alkyd-based resins, coating compositions, such as paint, varnish, wood stain, inks and linoleum floor coverings. Described is a curable liquid medium containing a) from 1 to 90 wt % of an alkyd-based resin and b) from 0.0001 to 0.1 wt % of a siccative in form of an iron or manganese complex with a tetradentate, pentadentate or hexadentate nitrogen donor ligand.

EFFECT: said siccative has high activity and enables hardening of compositions at relatively low concentration in a curable liquid medium.

19 cl, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (III) in form of a free base or an acid addition salt, use thereof as a pharmaceutical agent for preventing, treating and/or inhibiting progression of psychotic and neurodegenerative disorders, as well as pharmaceutical compositions based on said compound.

EFFECT: novel compound which can be used to prevent, treat or inhibit progression of diseases or a pathologic condition in which nAChR α7 activation participates or plays a role.

8 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazolyl derivatives of formula I or to their pharmaceutically acceptable salts; where Ar represents a phenyl group substituted by methylene dioxy or ethylene dioxy. Also, the invention refers to a pharmaceutical composition exhibiting cholinergic receptor activity on the basis of said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can be effective for treating various diseases or disorders, such as those associated with the cholinergic system of the central nervous system, peripheral nervous system, diseases or disorders associated with smooth muscle contracture, endocrine diseases or disorders, neurodegenerative diseases or disorders, inflammatory diseases or disorders, pain and withdrawal syndromes caused by addictive chemical withdrawal.

10 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

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