Phenoxypyridinylamide derivatives, and their use in treatment of pde4-mediated disease states

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

 

The present invention relates to phenoxypropylamine 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 pyridopyrimidines derivatives described 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 described in WO 2007/050576, WO 2004/105698, US 2004/0102472, WO 2004/048374, WO 2004/047836, WO 02/094823 and WO 99/07704.

Phosphodiesterase (PDEs) are turning camp or cGMP in AMP and GMP, or inactive nucleotide form, unable to activate downstream signaling pathways. Inhibition of PDEs leads to the accumulation of camp or cGMP and subsequent activation of downstream pathways. PDEs comprise a huge family of second messengers from 11 families and over 50 isoforms. In addition, for each isoform have been described splice variants. PDEs can be camp-specific PDE4, 7, 8, 10), cGMP-specific PDE5, 6, 9) or to have dual specificity (PDE1, 2, 3, 11).

camp is produced from ATP on the inner side of the plasma membrane through the action of GPCR-regulated adenylate cyclase. Once formed a camp, the only way to end the signal is the action of phosphodiesterase, splitting of camp to 5'-AM is. 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, apparently, poorly understood and involve numerous components in the initiation of signaling cascades. It was shown that PDE4s play 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 activity of many immune cells; 2) suppression of the 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-metabolizing 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, considerable attention is 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)was reported 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 describes new phenoxypropylamine derivatives, which are inhibitors of PDE4 person, therefore, are useful in therapy.

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

where

R1represents NR7C(O)R8, NR7S(O)2R8or NR9R10;

R2represents hydrogen or C1-6alkyl;

R3represents the t of a hydrogen, halogen, C1-4alkyl or C1-4alkoxy;

R4represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3With1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl);

R5represents a C1-6alkyl (substituted NR11R12or heterocyclyl), C1-6alkoxy (substituted NR11R12or heterocyclyl)3-6cycloalkyl (substituted NR11R12or heterocyclyl) or heterocyclyl; provided that if R5includes heterocyclyl, heterocyclyl contains one or more ring nitrogen atoms; and if the specified heterocyclyl connected directly via a ring nitrogen atom or alkyl, alkoxy or cycloalkyl in R5or the phenyl ring of formula (I), with which it is directly connected R5this heterocyclyl or has at least two ring heteroatoms, or Deputy NR46R47;

R6represents hydrogen, halogen, cyano, hydroxy, SH, C1-4alkyl, C1-4alkoxy, CF3, OCF3With(O)H, C1-6alkylthio, S(O)(C1-6alkyl), S(O)2(C1-6alkyl), CO2N, CO2(C1-6alkyl), NR13R14With1-6alkyl (possibly substituted by a group halogen, HE CO 2H, NR15R16, NHC(O)O(C1-6alkyl), OS(O)2(C1-6alkyl) or heterocyclyl), C1-6alkoxy (possibly substituted by a group halogen, HE, CO2N, NR15R16or heterocyclyl)3-6cycloalkyl (possibly substituted by a group halogen, HE, CO2H, NR15R16or heterocyclyl) or heterocyclyl;

R7represents hydrogen or C1-6alkyl (possibly substituted by a group NR26R27);

R8represents a C1-6alkyl {substituted by hydroxyl, C1-6alkoxy, NR21R22, heterocyclyl {possibly substituted by a group of oxo, hydroxy, C1-6alkyl, CO2(C1-6alkyl), aryl, heteroaryl, aryl(C1-4alkyl), heterocyclyl or C(O)(C1-4alkyl)phenyl}, aryl, heteroaryl,3-7cycloalkyl, group C3-7cycloalkyl(C1-4alkyl), CO2H, CO2(C1-6alkyl), aryl(C1-4alkoxy), aryl(C1-4alkylthio), S(O)2(C1-6alkyl), NHC(O)heteroaryl or NHC(O)R23}, C1-6alkoxy, C3-6cycloalkyl {it may be substituted by hydroxyl group, NR24R25or C1-6alkyl}, heterocyclyl {possibly substituted by a group of oxo, hydroxy, C1-6alkyl, amino, aryl, heteroaryl, aryl(C1-4alkyl), heteroaryl(C1-4alkyl), heterocyclyl or C(O)(C1-4alkyl)phenyl}, aryl(C1-4alkyl) substituted amino group(C 1-4alkyl)}, aryl or heteroaryl;

R9represents hydrogen, C1-6alkyl (possibly substituted by aryl or heteroaryl), aryl or heteroaryl;

R10represents hydrogen, C1-6alkyl (possibly substituted by a hydroxyl group, a C1-6alkoxy, aryl, aryloxy, phenyl(C1-6alkoxy), heteroaryl,3-10cycloalkyl, CO2H, CO2(C1-6alkyl), NHC(O)O(C1-6alkyl or NHC(O)R23), C1-6alkoxy, C3-6cycloalkyl (possibly substituted by a hydroxy group, a C1-6alkyl, phenyl, phenyl(C1-6alkyl), heteroaryl or heteroaryl(C1-6alkyl)), heterocyclyl (possibly substituted by a group of C1-6alkyl, C(O)NH2or phenyl(C1-6alkyl), aryl or heteroaryl;

R21and R22independently represent hydrogen, C1-6alkyl or phenyl(C1-4alkyl);

R23represents a C1-6alkyl or phenyl;

where the foregoing phenyl, aryl and heteroaryl groups in R5, R8, R9, R10, R23, R21and R22independently possibly substituted by the group: halogen, cyano, nitro, CF3, hydroxy, S(O)qR26, OC(O)NR27R28, NR29R30, NR31C(O)R32, NR33C(O)NR34R35, S(O)2NR36R37, NR38S(O)2R39C(O)NR40R41C(O)R42, CO2R , NR44C(O)2R45, OS(O)(C1-6alkyl), C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane, C1-6alkoxy(C1-6)alkyl, amino(C1-4alkyl), di(C1-6)alkylamino(C1-6)alkyl, C1-6alkoxy, C1-6halogenoalkane, hydroxyl(C1-6alkoxy), heterocyclyl(C1-alkoxy), C1-6alkoxy(C1-6)alkoxy, amino(C1-4alkoxy), C1-4alkylamino(C1-4alkoxy) (which itself is possibly substituted by phenyl), di(C1-4alkyl)amino(C1-4alkoxy), C1-6alkylthio,2-6alkenyl,2-6quinil,3-10cycloalkyl (which itself is possibly substituted C1-4the alkyl or oxo), methylenedioxy, diversitronics, heterocyclyl, heterocyclyl(C1-4alkyl), phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaromatic or heteroaryl(C1-4)alkoxy; where any of the above mentioned phenyl and heteroaryl groups possibly substituted by a group halogen, hydroxy, nitro, S(O)r(C1-4alkyl), S(O)2NH2, S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, cyano, C1-4alkyl, C1-4alkoxy, C(O)NH2With(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2, CO2H, CO2(C1-4alkyl), NHC(O)(C1-4alkyl), NH(O)2(C1-4alkyl), C(O)(C1-4lcil), CF3or OCF3;

q and r independently denote 0, 1 or 2;

if not specified, heterocyclyl possibly substituted by a group of HE, C1-6alkyl, C3-7cycloalkyl, NR46R47, (C1-6alkyl)HE or (C1-6alkyl)NR48R49, NR50CO2(C1-6alkyl), CO2(C1-6alkyl), C(O)(C1-6alkyl), C(O)heterocyclyl, heteroaryl, (C1-6alkyl)C(O)NR51R52, (C1-6alkyl)C(O)NR53R54, (C1-6alkyl)C(O)heterocyclyl or heterocyclyl;

R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44and R45independently represents a C1-6alkyl {substituted by the group halogen, hydroxy or C1-6alkoxy}, CH2(C2-6alkenyl), phenyl {which itself is possibly substituted by a group halogen, hydroxy, nitro, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, S(O)2(C1-4alkyl), S(O)2NH2, S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, cyano, C1-4alkyl, C1-4alkoxy, C(O)NH2C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2, CO2H, CO2(C1-4alkyl), NHC(O)(C1-4alkyl), NH(O)2(C1-4alkyl), C(O)(C1-4alkyl), CF3or OCF3} or heteroaryl {cat is who himself is possibly substituted by a group halogen, hydroxy, nitro, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, S(O)2(C1-4alkyl), S(O)2NH2, S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, cyano, C1-4alkyl, C1-4alkoxy, C(O)NH2With(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2, CO2H, CO2(C1-4alkyl), NHC(O)(C1-4alkyl), NH(O)2(C1-4alkyl), C(O)(C1-4alkyl), CF3or OCF3};

R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R40, R41, R42, R43, R44and R45can also represent hydrogen;

R12, R14, R15, R25, R47and R49independently represent hydrogen, C1-6alkyl (possibly substituted by a hydroxy group, a C1-6alkoxy, C1-6alkylthio,3-7cycloalkyl (possibly substituted by a hydroxy group) or NR55R56)3-7cycloalkyl (possibly substituted by hydroxy group(C1-6alkyl)) or heterocyclyl (possibly substituted C1-6by alkyl);

R11, R13, R16, R24, R26, R27, R46, R48, R50, R51, R52, R53, R54R55and R56independently represent hydrogen or C1-6alkyl;

or its N-oxide; or pharmaceutically reception who will be Sol.

Some compounds of the present invention may exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention includes all such isomers and mixtures thereof in all ratios. 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) includes a salt 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, Paul the amine resin, procaine, purines, tertiary butylamine, teobrom, triethylamine, trimethylamine, Tripropylamine, tromethamine or canoemen.

Pharmaceutically acceptable salt of the compounds of formula (I) also includes Quaternary ammonium salt, for example, when the amine group in the compound of formula (I) reacts with C1-10alkylhalogenide (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 [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid salt), 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), n is Catinat, the oleate, orotate, oxalate, Pantothenate, pamoate, Panova, pectinate, 3-phenylpropionate, pivalate, propionate, pivalate, pyruvate, saccharinate, salicylate, stearate, succinate, tartrate, para-toluensulfonate, TRANS-cinnamic acid, triptorelin, xinafoate, xenoport, xilt (pair-Xylen-2-sulfonic acid), undecanoic, 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, Hemi-salt or mono - or di-Sol or tri-salt.

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

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 primary, secondary, 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.

Alkyl groups are straight or branched chain 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, OCF3or OCHF2.

Alkenyl represents, for example, vinyl or prop-2-enyl. Quinil represents, for example, propargyl.

Cycloalkyl represents a mono - or bicyclic ring system which is saturated or unsaturated, but not aromatic. It represents, for example, cyclopropyl, cyclobutyl, Cyclops is until, 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 4-to 8-membered ring, possibly condensed with one or more other non-aromatic rings and possibly condensed with the benzene ring containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl represents, for example, azetidine, pyrrolidine, piperidinyl, piperazinil, isoindolyl, morpholinyl, thiomorpholine, homomorpholine, homopiperazine, 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 or azepine, homopiperazine, 1,4-oxazepine or 1-azabicyclo[2.2.2]octyl.

Hydroxyalkyl is the 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)2NCH2or (CH3)(CH3CH2)NCH2. 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. Aryl(C1-4alkoxy) is, for example, phenylmethoxy. Aryl(C1-4alkylthio) represents, for example, fenilin2S.

Heteroaryl represents, for example, an aromatic 5 - or 6-membered ring, possibly condensed with one or more other rings (which may be carbocyclic or heterocyclic, and aromatic or non-aromatic)containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; or an N-oxide or S-oxide or S-dioxide. Heteroaryl represents, for example, furyl, thienyl (also known ka is thiophenyl), pyrrolyl, thiazolyl, isothiazolin, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [1,2,3]-thiadiazolyl, [1,2,4]-triazolyl, [1,2,3]-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as bankfull), 4,5,6,7-tetrahydrobenzo, benzo[b]thienyl (also known as Bastiani or benzothiophene), indazole, benzimidazole, 1,2,3-benzotriazolyl, benzoxazolyl, 1,3-benzothiazolyl, 1,2,3-benzothiadiazoles, thieno[3,2-b]pyridine-6-yl, 1,2,3-benzoxadiazole, benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazole, benzofurazan (also known as 2,1,3-benzoxadiazole), honokalani, pyrazolopyrimidine (e.g., 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), 1,2,3-thiadiazolyl, 1H-pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyridinyl, thieno[2,3-b]pyrazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 6,7-dihydro-6N-[1,3]thiazolo[3,2-a]pyrimidinyl or 4,5,6,7-tetrahydrobenzo; or its N-oxide or S-oxide or S-dioxide.

In one aspect of the invention, heteroaryl represents, for example, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, [1,2,4]-triazolyl, pyridinyl, pyrimidinyl, PIR is sinil, pyridazinyl, indolyl, indazoles, benzimidazoles, honokalani, pyrazolopyrimidine (e.g., 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), 1H-pyrrolo[2,3-b]pyridinyl or [1,2,4]triazolo[1,5-a]pyrimidinyl; or its N-oxide.

NHC(O)Heteroaryl represents, for example, NHC(O)pyridinyl. Heteroaryl(C1-4alkyl) is, for example, pyridinyl2.

"Maybe substituted" represents, 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 R1represents NR7C(O)R8.

In another aspect of the present invention proposed a compound of formula (I), where R1represents NR9R10.

In another aspect of the present invention proposed a compound of formula (I), where R7represents hydrogen.

In another aspect of the present invention proposed a compound of formula (I), where R9represents hydrogen.

In yet another aspect, the present and the acquisition of the proposed compound of formula (I), where R8represents aryl or heteroaryl (possibly substituted as indicated above), or With3-6cycloalkyl substituted by a group NR24R25.

In another aspect of the present invention proposed a compound of formula (I), where R10represents a C1-6alkyl (for example, C1alkyl) substituted aryl or heteroaryl (any of which may substituted, as described above).

In another aspect of the present invention, the aryl is, for example, phenyl.

In another aspect of the present invention heteroaryl represents, for example, pyrazolyl, imidazo[1,2-a]pyridinyl, or 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In yet another aspect, the aryl and heteroaryl possibly substituted, for example, the group halogen, cyano, nitro, hydroxy, NR29R30With1-6alkyl, C1-6hydroxyalkyl,1-6halogenoalkane,1-6alkoxy(C1-6)alkyl, amino(C1-4alkyl), di(C1-6)alkylamino(C1-6)alkyl, C1-6alkoxy, C1-6halogenoalkane, hydroxyl(C1-6alkoxy), heterocyclyl(C1-6alkoxy), C1-6alkoxy(C1-6)alkoxy, amino(C1-4alkoxy), C1-4alkylamino(C1-4alkoxy) (which itself is possibly substituted phenyl or di(C1-4alkyl)amino(C1-4alkoxy); where R29and R30independently represent a hydrogen Il is C 1-6alkyl.

In another aspect of the present invention proposed a compound of formula (I), where R2represents hydrogen.

In another aspect of the present invention proposed a compound of formula (I), where R3represents a halogen (e.g., fluorescent).

In another aspect of the present invention proposed a compound of formula (I), where R4represents hydrogen.

In another aspect of the present invention proposed a compound of formula (I), where R5represents a C1-6alkyl (for example, C1alkyl) substituted NR11R12or heterocyclyl (which itself is possibly substituted as indicated above); where R29and R30independently represent hydrogen or C1-6alkyl

In another aspect of the present invention heterocyclyl is piperidinyl, piperazinil, morpholinyl, homomorpholine or homopiperazine.

In another aspect of the present invention proposed a compound of formula (I), where R5represents methyl, ethyl or propyl, substituted by piperidinyl, piperazinil, morpholinium, homomorpholine or homopiperazine.

In another aspect of the present invention proposed a compound of formula (I), where R5represents propyl, substituted by piperidinyl, piperazinil, morpholinium, geomorphol is nil or homopiperazine.

In another aspect of the present invention proposed a compound of formula (I), where R5represents a 3-(piperazine-1-yl)propyl.

In another aspect of the present invention heterocyclyl possibly substituted C1-6the alkyl or NR46R47; where R46and R47independently represent hydrogen or C1-6alkyl.

In another aspect of the present invention proposed a compound of formula (I), where R6represents hydrogen, hydroxyl or1-4alkoxy (such as methoxy).

In another aspect of the present invention proposed a compound of formula (I), where R6represents hydrogen, hydroxyl or1-4alkoxy (such as methoxy) or (C1-6alkyl, possibly substituted by heterocyclyl.

In another aspect of the present invention proposed a compound of formula (I), where R6represents hydroxy or1-6alkyl, possibly substituted by piperidinyl, piperazinil, morpholinium, homomorpholine or homopiperazine.

In another aspect of the present invention proposed a compound of formula (I), where R6is a or C1-6alkyl, possibly substituted by morpholinyl or homomorpholine.

In another aspect of the present invention proposed a compound of formula (I), where the phenyl ring carrying the groups R5and R 6located in the meta-position of the phenyl carrying the group R4, that is, as shown directly below:

In another aspect of the present invention proposed a compound of formula (I), where R6is as defined above (for example, hydroxyl or methoxy; such as hydroxyl), and is in the para-position, and R5located in the ortho-position, i.e. as shown directly below:

In another aspect of the present invention proposed a compound of formula (I), where R6is the same as defined above, and is in the ortho-position, and R5located in the para-position, i.e. as shown directly below:

In another aspect of the present invention proposed a compound of formula (I)where the substituents are in a CIS-position to tsiklogeksilnogo ring of formula (I), that is, as shown directly below:

In another aspect of the present invention proposed a compound of formula (I)where the substituents are as shown directly below:

Compounds according to the invention described in the examples. Each of the compounds from examples is an additional aspect of this is subramania. 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.

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 another aspect of the invention, a method for obtaining compounds of formula (I), where R1, R2, R3, R4, R5and R6are as defined in formula (I), any of the methods a, b, C, D or e, as described below.

Method And

The compounds of formula (I), where R1, R2, R3, R4and R6are as defined in formula (I), and where R5represents a C1alkyl, optionally substituted NR11R12or heterocyclyl as defined in formula (I)can be obtained by reacting compounds of the formula (II), where R1, R2, R3, R4and R6are as defined in formula (I)

with suitable amines under conditions of reductive amination using, for example, a suitable reducing agent in the presence of a suitable acid catalyst and in a suitable solvent in the presence or in the absence of a suitable desiccant and at a suitable temperature. Examples of suitable reducing agents include triacetoxyborohydride sodium or cyanoborohydride sodium. Preferably, use triacetoxyborohydride sodium. Examples of suitable acid catalysts include carboxylic acids such as acetic acid, ethane or propane acid. It is preferable to use acetic acid. Examples of suitable solvents include chlorinated solvents such as DCM, chloroform or 1,2-dichloroethane, or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme. Preferably, use DCM. Examples of suitable desiccants include molecular sieves, sodium sulfate or magnesium sulfate. Preferably, use sodium sulfate. The reaction can be carried out at temperatures ranging from ambient temperature to the temperature of reflux distilled. Preferably, use the ambient temperature.

The compounds of formula (II), where R1, R2, R3, R4and R6 are as defined in formula (I)can be obtained by reacting compounds of the formula (IX), where R1, R2, R3, R4are as defined in formula (I), and X is a bromide, iodide or Bronevoy acid/ester derivative,

with compounds of the formula (X), where R6is the same as defined in formula (I), using chemistry cross-combination.

Examples of reaction conditions cross-combination comprises the conditions of palladium-mediated cross-combination, where one partner is a chloride, bromide or iodide, with Bronevoy acid or ester derivative as the other partner, or combination of conditions on Ullman, where both partners are chloride, bromide or iodide derivatives using copper catalysis. Examples of suitable palladium-mediated catalysts, ligands, salts, bases and solvents include palladium diacetate, or the complex bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM, or tetranitropentaerithrite; with ligands by tricyclohexylphosphine, or 2.2 bis-DICYCLOHEXYL-phosphino-1,1'-biphenyl or di-tert-butyl-phosphino-1,1'-biphenyl or three-tert-butylphosphino; phosphate salts of potassium (K3PO4 ) or potassium fluoride in a solvent such as tetrahydrofuran, 1,4-dioxane, water or acetonitrile.

The compounds of formula (IX), where R1, R2, R3and R4are as defined in formula (I), and X represents chloride, bromide or iodide, can be obtained from compounds of formula (XI), where R1, R2and R3are as defined in formula (I), and Y represents a suitable leaving group such as halogen, by reacting

with compounds of the formula (XII), where R4is the same as defined in formula (I), and X represents chloride, bromide or iodide, in a suitable solvent with a base and a suitable temperature. Examples of suitable solvents include N,N-dimethylformamide (DMF), N-methylpyrrolidinone, dimethylsulfoxide, acetonitrile, alcohols, such as ethanol, propanol or butanol. Examples of suitable bases include cesium carbonate, potassium carbonate, sodium carbonate or trialkylamine, such as triethylamine or N,N-diisopropylethylamine. Temperature range from ambient temperature to the temperature of reflux distilled. Preferably, using DMF as solvent with cesium carbonate as base at 60-70°C.

The compounds of formula (XI), where R1R 2and R3are as defined in formula (I), and Y represents a suitable leaving group such as halogen, can be obtained from compounds of formula (XIII)where R3is the same as defined in formula (I), and Y represents a leaving group such as halogen,

by reacting with compounds of the formula (XIV), where R and R2are as defined in formula (I), using a suitable agent combination in a suitable solvent at a suitable temperature.

Examples of suitable agents of the combination include HATU, PYBOP® (benzotriazol-1 yloxy)triprolidine hexaphosphate), Rouger® (bromo-Tris-pyrrolidinone hexaphosphate), DCCI (1,3-dicyclohexylcarbodiimide), CDI (carbonyldiimidazole), possibly in the presence of excess amine, such as triethylamine or N,N-diisopropylethylamine. Examples of suitable solvents include chlorinated solvents such DCM, chloroform or 1,2-dichloroethane, or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme, or alternately, such as acetonitrile or butyronitrile. Preferably, HATU use in acetonitrile, using an excess of N-ethyldiethanolamine as a base, with which the temperature of the environment.

Method In

The compounds of formula (I), where R1, R2, R3, R4, R5and R6are as defined in formula (I), by reacting compounds of the formula (III), where R2, R3, R4, R5and R6are as defined in formula (I), with suitable allerease agents such as acid chlorides, or with suitable carboxylic acids using suitable agents combination with obtaining the compounds where R1represents NR7C(O)R8or by interaction with appropriate sulphonylchloride with obtaining the compounds where R1represents NR7S(O)2R8or by interaction with appropriate aldehydes in suitable conditions, reductive amination with obtaining the compounds where R1represents NR9R10.

Examples of suitable agents of the combination include HATU, PYBOP®, PyBrOP®, DCCI, CDI, possibly in the presence of excess amine, such as triethylamine or N,N-diisopropylethylamine. Examples of suitable solvents include chlorinated solvents such as DCM, chloroform or 1,2-dichloroethane, or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme, or alternately, such as acetonitrile butyronitrile. Preferably, HATU use in acetonitrile, using an excess of N-ethyldiethanolamine as the base, when the ambient temperature.

Examples of suitable reductive amination include the application of a suitable reducing agent in the presence of a suitable acid catalyst and in a suitable solvent in the presence or in the absence of a suitable desiccant and at a suitable temperature. Examples of suitable reducing agents include triacetoxyborohydride sodium or cyanoborohydride sodium. Preferably, use triacetoxyborohydride sodium. Examples of suitable acid catalysts include carboxylic acids such as acetic acid, ethane or propane acid. Preferably, use acetic acid. Examples of suitable solvents include chlorinated solvents such as DCM, chloroform or 1,2-dichloroethane, or simple esiri, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme, or alcohols, such as ethanol, propanol or butanol. Preferably use DCM. Examples of suitable desiccants include molecular sieves, sodium sulfate or magnesium sulfate. Preferably using sodium sulfate. The reaction can be carried out at temperatures variouse is from ambient temperature to the temperature of reflux distilled. Preferably use the ambient temperature.

The compounds of formula (III), where R2, R3, R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (XV), where R2, R3, R4, R5and R6are as defined in formula (I), and PG is a suitable protective group. Examples of suitable protective groups include tert-butoxycarbonyl, triptorelin or benzyloxycarbonyl. Preferably using tert-butoxycarbonyl.

Use suitable conditions to remove the protection. For example, tert-butoxycarbonyl protective groups use suitable acidic reaction conditions, remove protection, such as hydrochloric acid or TFA, either in the presence or in the absence of a solvent, such as DCM or tetrahydrofuran.

The compounds of formula (XV), where R2, R3, R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (XVII), where R2, R3, R4are as defined in formula (I), and X represents chloride, bromide, iodide or Bronevoy acid/ester derived by interaction

with compounds of the formula (V), where R5and R6Vlada such as defined in the formula (I), and X represents chloride, bromide, iodide or Bronevoy acid/ester derivative, using the chemical cross-combination.

Examples of reaction conditions cross-combination comprises the conditions of palladium-mediated cross-combination, where one partner is a chloride, bromide or iodide, with Bronevoy acid or ester derivative as the other partner, or combination of conditions on Ullman, where both partners are chloride, bromide or iodide derivatives using copper catalysis. Examples of suitable catalysts based on palladium, ligands, salts, bases and solvents include palladium diacetate, or the complex bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM, or tetranitropentaerithrite; with ligands by tricyclohexylphosphine, or 2.2 bis-DICYCLOHEXYL-phosphino-1,1'-biphenyl, or di-tert-butyl-phosphino-1,1'-biphenyl, or three-tert-butylphosphino; phosphate salts of potassium (K3PO4) or potassium fluoride in a solvent such as tetrahydrofuran, 1,4-dioxane, water or acetonitrile.

Alternatively, the compounds of formula (XV), where R2, R3, R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (XVI), where R2and R3the two who are such as defined in the formula (I), and Y represents a leaving group such as halogen, by reacting with compounds of the formula (VI), where R4, R5and R6are as defined in formula (I), in a suitable solvent with a base and a suitable temperature. Examples of suitable solvents include N,N-dimethylformamide (DMF), N-methylpyrrolidinone, dimethylsulfoxide, acetonitrile, alcohols, such as ethanol, propanol or butanol. Examples of suitable bases include cesium carbonate, potassium carbonate, sodium carbonate or trialkylamine, such as triethylamine or N,N-diisopropylethylamine. Temperature range from ambient temperature to the temperature of reflux distilled.

The compounds of formula (XVII), where R2, R3, R4are as defined in formula (I), and X represents chloride, bromide or iodide, can be obtained from compounds of formula (XVIII), where R3and R4are as defined in formula (I), and X represents chloride, bromide or iodide, by interaction

with compounds of the formula (XIX)

where R2is the same as defined in formula (I), and PG is a suitable protective group, with suitable and what enta combination in a suitable solvent at a suitable temperature.

Examples of suitable agents of the combination include HATU, PYBOP®, Rougher®, DCCI, CDI is possible in the presence of excess amine, such as triethylamine or N,N-diisopropylethylamine. Examples of suitable solvents include chlorinated solvents such as DCM, chloroform or 1,2-dichloroethane, or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme, or alternately, such as acetonitrile or butyronitrile. Preferably, HATU use in acetonitrile, using an excess of N-ethyldiethanolamine as the base, when the ambient temperature.

Examples of suitable protective groups include tert-butoxycarbonyl, triptorelin or benzyloxycarbonyl. Preferably, using tert-butoxycarbonyl.

The compounds of formula (XVIII), where R3and R4are as defined in formula (I), and X represents chloride, bromide or iodide or Bronevoy acid/ester derivative, can be obtained from compounds of formula (XIII)where R3is the same as defined in formula (I), and Y represents a leaving group such as halogen, by reacting with compounds of the formula (XIII) in a suitable solvent with a base and a suitable temperature. Examples of suitable solvents include N,N-dimethyl rmaed (DMF), N-methylpyrrolidinone, dimethylsulfoxide, acetonitrile, alcohols, such as ethanol, propanol or butanol. Examples of suitable bases include cesium carbonate, potassium carbonate, sodium carbonate or trialkylamine, such as triethylamine or N,N-diisopropylethylamine. Temperature range from ambient temperature to the temperature of reflux distilled. Preferably using DMF as solvent with cesium carbonate as base at 60-70°C.

Way

The compounds of formula (I), where R1, R2, R3, R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (IV), where R1, R2, R3, R4are as defined in formula (I), and X represents chloride, bromide, iodide or Bronevoy acid/ester derivative, by reacting with compounds of the formula (V), where R4and R5are as defined in formula (I), and X represents a chloride, bromide, iodide, or Bronevoy acid/ester derivative, in a suitable reaction conditions, cross combination.

Examples of reaction conditions cross-combination comprises the conditions of palladium-mediated cross-combination, where one partner is a chloride,bromide or iodide, with Bronevoy acid or ester derivative as the other partner, or combination of conditions on Ullman, where both partners are chloride, bromide or iodide derivatives using copper catalysis. Examples of suitable palladium-mediated catalysts, ligands, salts, bases and solvents include palladium diacetate, or the complex bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM, or tetranitropentaerithrite; with ligands three-cyclohexylphenol, or 2.2 bis-DICYCLOHEXYL-phosphino-1,1'-biphenyl, or di-tert-butyl-phosphino-1,1'-biphenyl or three-tert-butylphosphino; phosphate salts of potassium (K3PO4) or potassium fluoride in a solvent such as tetrahydrofuran, 1,4-dioxane, water or acetonitrile.

The compounds of formula (IV), where R1, R2, R3and R4are as defined in formula (I), and X represents chloride, bromide or iodide, can be obtained from compounds of formula (VI), where R1, R2and R3are as defined in formula (I), and Y represents a leaving group such as halogen, by reacting with compounds of the formula (XII), where R4is the same as defined in formula (I), and X represents chloride, bromide, iodide, in a suitable solvent with a base and approach the overall temperature. Examples of suitable solvents include N,N-dimethylformamide (DMF), N-methylpyrrolidinone, dimethylsulfoxide, acetonitrile, alcohols, such as ethanol, propanol or butanol. Examples of suitable bases include cesium carbonate, potassium carbonate, sodium carbonate or trialkylamine, such as triethylamine or N,N-diisopropylethylamine. Temperature range from ambient temperature to the temperature of reflux distilled.

Method D

The compounds of formula (I), where R1, R2, R3, R4, R5and R6are as defined in formula (I)from compounds of formula (VI), where R1, R2and R3are as defined in formula (I), and Y represents a suitable leaving group such as halogen,

by reacting with compounds of the formula (VI), where R4, R5and R6are as defined in formula (I), in a suitable solvent with a base and a suitable temperature. Examples of suitable solvents include N,N-dimethylformamide (DMF), N-methylpyrrolidinone, dimethylsulfoxide, acetonitrile, alcohols, such as ethanol, propanol or butanol. Examples of suitable bases include cesium carbonate, potassium carbonate, sodium carbonate or trialkylamine, such as triethylamine or N,N-diisopropylethylamine. The pace of the atmospheric temperature range from ambient temperature to the temperature of reflux distilled.

The compounds of formula (VI), where R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (XII), where R4is the same as defined in formula (I), and X represents chloride, bromide, iodide or Bronevoy acid/ester derivative, by reacting with compounds of the formula (X), where R5and R6are as defined in formula (I), and X is a bromide, iodide or Bronevoy acid/ester derivative, in a suitable reaction conditions, cross combination.

Examples of reaction conditions cross-combination comprises the conditions of palladium-mediated cross-combination, where one partner is a chloride, bromide or iodide, with Bronevoy acid or ester derivative as the other partner, or combination of conditions on Ullman, where both partners are chloride, bromide or iodide derivatives using copper catalysis. Examples of suitable palladium-mediated catalysts, ligands, salts, bases and solvents include palladium diacetate, or the complex bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM, or tetranitropentaerithrite; with ligands three-cyclohexylphenol, or 2.2 bis-DICYCLOHEXYL-phosphino-1,1'-b is a phenyl or di-tert-butyl-phosphino-1,1'-biphenyl or three-tert-butylphosphino; with phosphate salts of potassium (K3PO4) or potassium fluoride in a solvent such as tetrahydrofuran, 1,4-dioxane, water or acetonitrile.

Method E

The compounds of formula (I), where R1, R2, R3, R4, R5and R6are as defined in formula (I)can be obtained from compounds of formula (VII), where R3, R4, R5and R6are as defined in formula (I),

by reacting with compounds of the formula (VIII), where R1and R2are as defined in formula (I),

using a suitable agent combination of solvent and temperature.

Examples of suitable agents of the combination include HATU, PYBOP®, Rougher®, DCCI, CDI is possible in the presence of excess amine, such as triethylamine or N,N-diisopropylethylamine. Examples of suitable solvents include chlorinated solvents such as DCM, chloroform or 1,2-dichloroethane, or simple esiri, such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, glyme or diglyme, or alternately, such as acetonitrile or butyronitrile. Preferably HATU use in acetonitrile, using an excess of N-ethyldiethanolamine as the base, when the ambient temperature.

It should replace the IC, in any of the above methods a-E. the transformation of aromatic halides, such as chlorides, bromides or iodides, can be easily implemented in Bronevoy acid/ester derivatives or by using the halogen-lithium exchange using n-utility or second-utility or tert-utility in an inert solvent, such as diethyl ether or tetrahydrofuran, at low temperatures and the damping of trialkylborane, such as trimethylboron. Alternatively, the conversion of aromatic halides, such as chlorides, bromides or iodides, baronova acid/ester derivative is preferably carried out using a palladium catalyst and dioxaborolan, such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane). For example, using 1,1'-bis(diphenylphosphino)ferrocene and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM as a palladium catalyst and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) as dioxaborolane in dimethyl sulfoxide as a solvent in the presence of potassium carbonate at 80°C.

Ester derivatives Bronevoy acid can be converted into derivatives Bronevoy acid using standard acid or conditions of alkaline hydrolysis at temperatures ranging from ambient temperature up to t is mperature reflux distilled, with organic solvents with or without water conditions.

Various intermediate compounds and, in particular, the compounds of formula (V), (VIII), (X), (XII), (XIII), (XIV) or (XIX), where R1, R2, R3, R4, R5and R6are as defined in formula, PG is a suitable protective group, and X and Y represent halogen, or are commercially available, are well known in the literature or can be obtained using known literature methods or by routine adaptation of the methods described in the literature.

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

In another aspect of the present invention the methods of obtaining compounds of formula (I).

In another aspect of the present invention proposed intermediate compounds useful in producing compounds according to the invention.

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 Airways including: asthma, including bronchial, allergic, hereditary, acquired, induced physical stress induced by drugs (including induced by aspirin and NSAIDs (non-steroidal anti-inflammatory agent)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, 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 stomach is positive ways, and iatrogenic cough; acute and chronic rhinitis including rhinitis drug 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) and adenovirus;

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 tuberculosis, and pain in the lower back and neck; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing tuberculosis, psoriatic arthritis, reactive 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 kristallizovannyj 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 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 paralipomena; pain in lower back pain; familial Mediterranean fever syndrome Make-Welsh and Irish family fever, a 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, resurfacing the bone (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; seborrhoeic dermatitis, dermatitis herpetiformis, red flat zoster, sclerotic and atrophic lichen, gangrenous pyoderma, sarcoid skin, discoid lupus erythematosus, pemphigus, pemphigoid, bullous bullosa, urticaria, angioedema, vasculitis, toxic erythema, subcutaneous eosinophilia, alopecia alopecia, male pattern hair loss, sweet syndrome, disease, Weber-Christian, multimarine erythema; cellulitis, both infective and non-communicable; 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 the handbag, etc. the cue 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 urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both men and women);

9) 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 the variant of the 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 systems in 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 autoim is installed cardiomyopathy, 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 syndromes; 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 accordance with an additional aspect of the present invention, a method for treatment of a PDE4-mediated painful condition in recapitalise, such as people suffering from painful conditions specified or having a risk of developing this painful condition involving the introduction of 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 suggested that the compound of formula (I) or its pharmaceutically acceptable salt for use in therapy.

In another aspect of the invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in therapy (for example modulating the enzymatic activity of PDE4).

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

1) respiratory tract: obstructive diseases of the Airways 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 diseases of egka (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitive pneumonitis; lung fibrosis, including 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, the AK and secondary, 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 arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection arthropathy and bone disorders such as tuberculosis, including Pott disease and syndrome Ponce; acute and chronic kristallizacionnogo 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 giganticly CNY the Takayasu, 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 back pain; familial Mediterranean fever syndrome Make wells (Muckle-Wells) 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; seborrhoeic dermatitis, dermatitis herpetiformis, red flat lichen, with lanoiraude and atropinelike lichen, pyoderma gangrenosum, sarcoid skin, discoid lupus erythematosus, pemphigus, pemphigoid, congenital bullous of bullosa, urticaria, angioedema, vasculitis, toxic eritem, subcutaneous eosinophilia, alopecia areata, alopecia male pattern syndrome Retinue, syndrome, Weber-Christian, multiform (exudative) erythema; cellulitis, both infective and non-communicable; 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 copies the mA);

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 urethritis, prostatitis, epididymitis, oophoritis and salpingitis; candidiasis; Peyronie's disease; erectile dysfunction (both men and women);

9) 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 dementiaa 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, ATypI the ing 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 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, VK is uchumi 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 syndromes; or

15) of the 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 another aspect of the invention proposed 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.

In this and the finding also suggested that the use of the 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 induced by 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 comprising a 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 of this is briteney you can 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 parenteral administration. 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 from 0.001 mgkg-1to 100 mgkg-1for example, in the range from 0.1 mgkg-1up to 20 mgkg-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 arthritis, stewartry, 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 the pharmaceutical the ski 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.

The present invention also relates to combinations of compounds according to the invention, or the pharmaceutical the ski 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 5-epoxygenase-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 x 1005.

The present invention also 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 as BIIL 284260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP A), and BAY x 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.

The present invention also 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.

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

The present invention also con is seeking to combinations of the 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.

The present invention also 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.

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

The present image is the buy 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.

The present invention also 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 (lg), or drug lg, or an antagonist or antibody modulating lg function, such as anti-lgE (e.g. omalizumab).

The present invention also 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.

Now the image is giving also 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-lactam, a 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 inhibitors 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.

The present invention also relates to combinations of compounds according to the invention, or its pharmaceutically pickup is integral salt, and 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, an inhibitor of the researcher, such as tasmar, inhibitor-2, an inhibitor of the reuptake of dopamine, NMDA(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, opioid or its derivative), carbamazepine, phenytoin, valproate sodium, amitriptyline or other antidepressants, paracetamol or non-steroidal anti-inflammatory agent.

The present invention also 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 as lignocaine or its derivative.

The connection of the infusion is he to the 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, gefitinib or imatinib mesilate), serine/trionychinae (such as inhibitor MAR-kinase, such as R, JNK, protein kinase a, b or C, or IKK), 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) means that increase the secretion of growth hormone; (14) transform the respective 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 NK1- 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 T 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; (27) inhibitor activation of transcription factors such as NFkB, API, or STATS; or (28) agonist non-steroidal glucocorticoid receptor (GR-receptor).

In another embodiment of the present invention is proposed pharmaceutical product containing 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:

agonists β2-adrenergic receptors

modulator functions of the chemokine receptor,

<> inhibitor of kinase function,

- protease inhibitor

- steroid of the glucocorticoid receptor agonist,

- anticholinergic agent and

- non-steroidal agonist of the glucocorticoid receptor.

Pharmaceutical product in accordance with this embodiment can 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 according to this embodiment 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 in accordance with this embodiment 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 in accordance with this embodiment can depict ablate a β 2-long acting agonists, such as salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarata), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically 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 in accordance with this embodiment include the CCR1 receptor antagonist.

Examples of an inhibitor of kinase function, which can be used in the pharmaceutical product in accordance with this embodiment include the kinase inhibitor R and inhibi the EOS IKK.

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

Examples of steroid agonist of the glucocorticoid receptor, which can be used in the pharmaceutical product in accordance with this embodiment 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 of 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 in accordance with this embodiment include, for example, an antagonist of muscarinic receptor (e.g., antagonist of M1, M2 or M3, such as the M3 antagonist)such as ipratropium (e.g. 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 modulatorsintegrated agonist of the glucocorticoid receptor, which can be used in the pharmaceutical product in accordance with this embodiment 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) antiprolifera the active/antineoplastics 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 arabinoside, 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, orasol Il is exemestane) or inhibitor BA-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 asN_-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839),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 (CI 1033)), an inhibitor of a family of platelet-derived growth factors, or inhibitor of a family of growth factors hepatocyte;

(5) an antiangiogenic agent, the th as agent, which 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 avp3 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) an agent used in a 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 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 (CI) using a direct influence on the sample. When this ionization is produced by ionization electrospray (ES)or chemical ionization at atmospheric pressure (APCI), or multimode ionization, the combination of ES ionization and APCI. When you specify values for m/z, then usually presents tolaini, 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 ways Struct=Name 9.0.7 from CambridgeSoft Corporation;

(4) if not stated otherwise, were performed HPLC with reversed-phase column using Symmetry™, or Xterra™, Sunfire™, X-bridge™ reversed-phase silica, all available from Waters Corp.;

(5) all the title compounds of the examples provided in the form of salts or mono-or bis-triperoxonane acid via HPLC, unless specified otherwise;

(6) use the following abbreviations:

(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 materials.

Example 1

N-((1s,4s)-4-(5-fluoro-2-(4'-(piperazine-1-ylmethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexylcarbamate

A mixture of 2-chloro-5-fornicating acid (4.5 g, 25,63 mmol), cesium carbonate (16,70 g, 51,27 mmol) and 3-itfinal (5,64 g, 25,63 mmol) dissolved the Le DMF (50 ml) was heated at 60°C for 48 hours The mixture was poured into water (200 ml) and the product was extracted in EtOAc. The organic layer was dried over sodium sulfate. As a result of filtration and evaporation was obtained a brown foam (7.5 g). This solid was dissolved in DMF (50 ml) and to the solution was added DIPEA (13,43 ml, 76,90 mmol)and then HATU (9.75 g, 25,63 mmol) and the mixture was stirred at K.T. within 10 minutes To this solution was added tert-butyl(1s,4s)-4-aminocyclohexanone (5.49 g, 25,63 mmol) and the mixture was stirred over night. The reaction mixture was poured into water and the product was collected by filtration and dried in vacuum to obtain specified in the subtitle compound as a pale-dark-yellow solid. Output: 4,1,

1H NMR (300 MHz, CDCl3) δ 8.35 (dd, J=8,2, 3.2 Hz, 1H), 8.06 (d, J=3.3 Hz, 1H), 7.84 (d, J=7,1 Hz, 1H), 7.65 (dt, J=7,6, and 1.4 Hz, 1H), 7.53 (t, J=1.7 Hz, 1H), 7.23-7.11 (m, 2H), 4.41 (s, 1H), 4.21-4.10 (m, 1H), 3.63 (s, 1H), 1.87-1.75 (m, 6H), 1.75-1.62 (m, 2H), 1.44 (s, 9H).

[M+H]+- tert-Bu=500 (multimode+)

Stage (b) N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexylcarbamate (2 g, of 3.60 mmol) in DCM (10 ml) was added TFA (5,55 ml, 72,02 mmol) and the mixture was stirred at K.T. within 1 h the Mixture was evaporated to dryness, and the residue was transferred into the water, and the pH was adjusted to 10 by adding to 0.88 aqueous ammonia. The obtained solid substance was collected by filtration and dried in vacuum the floor is the group specified in the subtitle compound. Output: 1,3,

[M+H]+=456 (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)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 (0,183 g, 1.10 mmol) in dry DMF (10 ml) was added DIPEA (0,575 ml, 3,29 mmol)and then HATU (0,418 g, 1.10 mmol). The mixture was left to mix for 10 min at K.T. To this mixture was added N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (0.5 g, 1.10 mmol) and the mixture was stirred overnight, poured into water and the crude product was collected by filtration, dried in vacuum, obtaining specified in the subtitle compound. Output: 0,354,

1H NMR (300 MHz, CDCl3) δ 8.36 (dd, J=8.0 a, 3.0 Hz, 1H), 8.06 (d, J=3.1 Hz, 1H), 7.86 (d, J=7,3 Hz, 1H), 7.64 (dt, J=7,2, 1.3 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.40 (s, 1H), 7.23-7.12 (m, 2H), 6.94 (d, J=7,3 Hz, 1H), 4.20 (s, 1H), 4.08 (d, J=3.5 Hz, 1H), 3.98 (t, J=8.6 Hz, 3H), 2.85 (q, J=6.2 Hz, 2H), 2.05-1.73 (m, 11H).

[M+H]+=604 (multimode+)

Stage (d) N-((1s,4s)-4-(5-fluoro-2-(4'-(piperazine-1-ylmethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

The mixture diacetoxynaphthalene (8 mg, 0.04 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (30 mg, 0.07 mmol) was stirred for 10 min in solvent - dry acetonitrile (7 ml). To this mixture was added sequentially: a solution of potassium carbonate (151 mg, of 1.09 mmol) in water (15 ml), then N-((1s,4s-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (220 mg, 0.36 mmol) and finally 4-((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)phenylboronic acid (122 mg, 0.36 mmol). The resulting mixture was stirred and heated at 70°C for 1 h the Mixture was left to cool to K.T. Organic layer was extracted with EtOAc and well washed with water. Organic matter was separated and evaporated to dryness. The residue was transferred in TFA (7 ml) and left to stand for 1 h the Mixture was evaporated to dryness, and the crude product was purified by preparative HPLC on a column (Waters X-Terra, using as eluent 95-50%water gradient with 0.1% TFA in acetonitrile. The fractions containing the target compound, liofilizirovanny obtaining specified in the title compound as a colourless solid. Yield: 130 mg

1H NMR (300 MHz, DMSO) δ 8.90 (s, 1H), 8.39 (d, J=6,9 Hz, 1H), 8.25 (d, J=3.1 Hz, 2H), 8.06-7.94 (m, 2H), 7.70 (d, J=8,3 Hz, 2H), 7.56-7.43 (m, 4H), 7.23-7.17 (m, 1H), 4.06 (t, J=10,6 Hz, 2H), 3.91 (d, J=17.5 Hz, 4H), 3.23 (s, 4H), 2.88 (t, J=6,1 Hz, 6N), 1.99-1.83 (m, 6H), 1.79-1.63 (m, 1H).

[M+H]+=652 (multimode+)

Example 2

N-((1s,4s)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide

To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0,123 g, 0.88 mmol) in dry DMF (10 ml) was added DIPEA (0,460 ml, 2.4 mmol), then HATU (0,334 g, 0.88 mmol). The mixture was left to mix for 10 min at K.T. To this mixture was added N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (0.400 g, 0.88 mmol) and the mixture was stirred overnight, poured into water and the crude product was collected by filtration, dried and used in stage (C) without treatment.

[M+H]+=577 (multimode+)

Stage (b) 4-Hydroxy-2-(morpholinomethyl)phenylboronic acid

Morpholine (1,19 ml, 13.7 mmol) was added to a solution of 2-bromo-5-hydroxybenzaldehyde (2.5 g, 12.4 mmol) in DCM (20 ml) and was stirred for 20 minutes was Added triacetoxyborohydride sodium (2,90 g, 13.7 mmol) and was stirred for 2 h the Reaction was suppressed methanol and was stirred for 1 h the Solution was concentrated in vacuo, dissolved in methanol and applied to a SCX column (50 g), washing with methanol. As a result of elution of methanol and ammonia concentration of eluent was obtained 4-bromo-3-(morpholinomethyl)phenol (3 g, 11,02 mmol)which was dissolved in THF (60 ml)was cooled to -78°C and added dropwise tert-utility (19,45 ml, 33,07 mmol) (1.7 M). The reaction mixture was stirred for 10 min, then was heated to 0°C for 15 minutes the Reaction mixture then was cooled to -78°C and added triisopropylsilyl (7,63 ml, 33,07 mmol). The reaction mixture was heated to K.T. and was stirred for 1 h was Added saturated aqueous hydroxide Ammon is I, and the reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was diluted with EtOAc (200 ml), the phases were separated, the aqueous phase was then extracted with EtOAc. The combined organic extracts were washed with saturated brine (200 ml). Organics were dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 2,45,

MS: [M+H]+=238 (multimode+)

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

To a solution of DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (28 mg, 0.07 mmol) in acetonitrile (15,00 ml) was added palladium(II) acetate (8 mg, 0.03 mmol) and the mixture was stirred for 10 min at K.T. To this solution was added a solution of potassium carbonate (144 mg, 1.04 mmol) in water (5 ml), then N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (200 mg, 0.35 mmol) and 4-hydroxy-2-(morpholinomethyl)phenylboronic acid (82 mg, 0.35 mmol). The mixture then was heated at 70°C for 3 hours the Mixture was poured into ice water, extracted into EtOAc, and the crude product was purified by preparative HPLC on a column (Waters X-Terra, using as eluent 95-5%gradient of aqueous 0.2% ammonia in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title the connection information in the form of a brown solid. Yield: 21 mg

1H NMR (300 MHz, DMSO) δ 8.33-8.23 (m, 2H), 8.07-8.00 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.27 (s, 1H), 7.22-7.12 (m, 4H), 7.06 (d, J=8,3 Hz, 1H), 6.88 (s, 1H), 6.69 (d, J=8,3 Hz, 1H), 6.38 (s, 1H), 3.99 (s, 1H), 3.83 (s, 1H), 3.72 (d, J=1.2 Hz, 4H), 3.49-3.22 (m, 4H), 2.24 (d, J=12.9 Hz, 8H), 1.78-1.56 (m, 8H).

MS: [M+H]+=643 (multimode+)

Example 3

N-((1s,4s)-4-((1,5-Dimethyl-1H-pyrazole-3-yl)methylamino)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinereplacement

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

To a solution of DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (0,177 g, 0.43 mmol) in acetonitrile (60,0 ml) was added palladium(II) acetate (0,049 g, 0.22 mmol) and the mixture was stirred for 10 minutes at K.T. To this solution was added a solution of potassium carbonate (0,896 g, 6,48 mmol) in water (20 ml), then tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexylcarbamate (1.2 g) (from example 1, stage a) and 4-hydroxy-2-(morpholinomethyl)phenylboronic acid (0,512 g of 2.16 mmol) (from example 2, step b). The mixture then was heated at 70°C for 3 hours the Mixture was poured into ice water, extracted into EtOAc, and the crude product was purified by preparative HPLC on a column (Waters X-Terra, using as eluent 95-5%gradient of aqueous 0.2% ammonia in acetonitrile. The fractions containing the target compound were evaporated to dryness is obtaining specified in the subtitle compound as a brown solid. Yield: 490 mg

MS: [M+H]+=621 (multimode+)

Stage (b) N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nikotinamidadenindinkleotid

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (478 mg, 0.77 mmol) in DCM (3 ml) was added TFA (3 ml, up 38.94 mmol). The mixture was stirred at K.T. within 2 hours the Mixture was evaporated to dryness and added ethereal HCl. The mixture was evaporated to dryness and the method is then repeated twice more to make the connection HCl salt. The result has been a beige powder, which was used without additional purification stage (C). Output: 550 mg.

MS: [M+H]+=521 (multimode+)

Stage (C) N-((1s,4s)-4-((1,5-dimethyl-1H-pyrazole-3-yl)methylamino)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide triptorelin

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, 2HCl (100 mg, 0,17 mmol) in DCM (3 ml) was added triethylamine (0,047 ml, 0.34 mmol), 1,5-dimethyl-1H-pyrazole-3-carbaldehyde (21 mg, 0,17 mmol) and then acetic acid (9,65 ml of 0.17 mmol). The mixture was stirred at K.T. for 50 minutes Then add triacetoxyborohydride sodium (71,4 mg, 0.34 mmol)and the mixture was stirred for 3 hours the Mixture was added to a mixture of methanol/water and then purified using preparative HPLC with reversed the diversified phases (eluent = F (aq.)/MeCN, column Xbridge), the appropriate fractions were combined and concentrated in vacuum to obtain oil. When rubbing with ether there was obtained white solid, which was filtered and dried over night at 40°C To produce specified in the title compounds as white solids. Yield: 52 mg

1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J=7,9, 3.1 Hz, 1H), 8.08 (d, J=7,4 Hz, 1H), 8.01 (d, J=3.1 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.18-7.12 (m, 4H), 7.07 (d, J=7.7 Hz, 1H), 6.90 (dd, J=8,5, 1.8 Hz, 1H), 6.08 (s, 1H), 4.29 (s, 3H), 4.04 (s, 2H), 3.77-3.73 (m, 4H), 3.68 (s, 3H), 3.16-3.07 (m, 3H), 2.68-2.59 (m, 2H), 2.20 (s, 3H), 2.05-1.89 (m, 6H), 1.75-1.66 (m, 2H).

MS: [M+H]+=629 (multimode+)

Example 4

N-((1s,4s)-4-(bis((1,5-Dimethyl-1H-pyrazole-3-yl)methyl)amino)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinereplacement

To a solution/suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, 2HCl (250 mg, 0.42 mmol) in DCM (10 ml) was added 1,5-dimethyl-1H-pyrazole-3-carbaldehyde (105 mg, 0.84 mmol), triethylamine (0,059 ml, 0.42 mmol) and then acetic acid (0,024 ml, 0.42 mmol). The mixture was left to mix with K.T. for 10 min, then was added triacetoxyborohydride sodium (89 mg, 0.42 mmol)and the mixture was left to mix with K.T. within 2 hours the Mixture was concentrated in vacuo and then dissolved in ethyl acetate and washed with saturated NaHCO3(aq), dried (MgSO4) and was evaporated to obtain a residue. This residue was dissolved in methanol and purified by preparative HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil, which after rubbing with ether, filtered and dried over night at 40°C under vacuum to obtain specified in the title compounds as white solids. Yield: 120 mg

1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.7 Hz, 1H), 8.08-8.02 (m, 2H), 7.45 (t, J=7.9 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8,2, 1.8 Hz, 1H), 7.17 (t, J=1.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.04 (d, J=7,4 Hz, 1H), 6.91 (dd, J=8,5, and 2.1 Hz, 1H), 6.32 (s, 2H), 4.38-4.34 (m, 1H), 4.27 (s, 2H), 4.10 (s, 4H), 3.81 (s, 4H), 3.72 (s, 6H), 3.16-3.06 (m, 3H), 2.72-2.63 (m, 2H), 2.27-2.20 (m, 8H), 2.15-2.06 (m, 5H), 1.64-of 1.55 (m, 2H).

[M+H]+=737 (multimode+) (RASSC.=737,3173)

Example 5

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-((2-methylthiazole-4-yl)methylamino)cyclohexyl)nicotinamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, bis-trifenatate (150 mg, 0.20 mmol) in DCM (5 ml) was added triethylamine (0,056 ml, 0.40 mmol). After 5 min was added 2-methyl-1,3-thiazole-4-carbaldehyde (25,5 mg, 0.20 mmol) and acetic acid (to 0.011 ml, 0.20 mmol). The mixture was stirred at K.T. for 30 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol)and the mixture AC is stirred at K.T. throughout the night. The mixture was evaporated, and the residue was dissolved in methanol and purified by prep. HPLC with reversed phase (eluent = NH3(aq.)/MeCN). The appropriate fractions were combined and evaporated to obtain an oil. This oil was dissolved in minimal acetonitrile and then besieged, using water. This slurry is then evaporated, and the solid was dried over night at 40°C under vacuum to obtain specified in the title compounds as white solids. Yield: 32 mg

MS: [M+H]+=632,2 (RASSC.=632,2707) (multimode+)

Example 6

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-((6-methylpyridin-2-yl)methylamino)cyclohexyl)nicotinamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, bis-trifenatate (150 mg, 0.20 mmol) in DCM (5 ml) was added triethylamine (0,056 ml, 0.40 mmol). After 5 minutes was added 6-methylpyridin-2-carboxaldehyde (24,27 mg, 0.20 mmol) and acetic acid (to 0.011 ml, 0.20 mmol). The mixture was stirred at K.T. for 30 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol)and the mixture was stirred at K.T. during the night. The mixture was evaporated, and the residue was dissolved in methanol and purified by prep. HPLC with reversed phase (eluent = NH3(aq.)/MeCN). The appropriate fractions were combined and pariva is getting oil. This oil was dissolved in minimal acetonitrile and then besieged, using water. The slurry is then evaporated, and the solid was dried over night at 40°C under vacuum to obtain specified in the title compounds as white solids. Yield: 31 mg

1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=5,1 Hz, 1H), 8.11-8.03 (m, 2H), 7.46 (dt, J=33,3, 7,6 Hz, 2H), 7.25 (d, J=11.5 Hz, 2H), 7.11 (d, J=7.7 Hz, 1H), 7.06-7.00 (m, 2H), 6.91 (s, 1H), 6.63 (d, J=6.2 Hz, 1H), 4.20 (s, 1H), 3.88 (s, 2H), 3.54 (s, 4H), 3.32 (s, 2H), 2.75 (s, 1H), 2.50 (s, 3H), 2.31 (s, 4H), 1.91-1.55 (m, 8H)

MS: [M+H]+=626,2 (RASSC.=626,3142) (multimode+)

Example 7

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(2-hydroxy-5-methylbenzylamino)cyclohexyl)nicotinamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, bis-trifenatate (150 mg, 0.20 mmol) in DCM (5 ml) was added triethylamine (0,056 ml, 0.40 mmol). After 5 min was added 2-hydroxy-5-methylbenzaldehyde (27.3 mg, 0.20 mmol) and acetic acid (to 0.011 ml, 0.20 mmol). The mixture was stirred at K.T. for 30 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol) and the mixture was stirred at CTV throughout the night. The mixture was evaporated, and the residue was dissolved in methanol and purified by prep. HPLC with reversed phase (eluent =NH3(aq.)/MeCN). The appropriate fractions were combined and evaporated to obtain mA is La. This oil was dissolved in minimal acetonitrile and then besieged by adding water. The suspension was evaporated, and the solid was dried over night at 40°C under vacuum to obtain specified in the title compounds as white solids. Yield: 22 mg

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.06 (m, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.27 (d, J=6,9 Hz, 1H), 7.22 (s, 1H), 7.16-7.11 (m, 2H), 7.00 (d, J=2.3 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.78-6.73 (m, 2H), 6.67 (d, J=8,2 Hz, 1H), 4.23-4.17 (m, 1H), 3.89 (s, 2H), 3.57 (t, J=4,2 Hz, 4H), 3.37 (s, 2H), 2.72 (d, J=3.1 Hz, 1H), 2.34 (s, 4H), 2.22 (s, 3H), 1.86-1.74 (m, 6H), 1.53-1.44 (m, 2H)

MS: [M+H]+=641,2 (RASSC.=641,3139) (multimode+)

Example 8

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-((5-methylimidazo[1,2-a]pyridine-2-yl)methylamino)cyclohexyl)nicotinamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, bis-trifenatate (150 mg, 0.20 mmol) in DCM (5 ml) was added triethylamine (0,056 ml, 0.40 mmol). After 5 min was added 5-methylimidazo[1,2-a]pyridine-2-carbaldehyde (32.1 mg, 0.20 mmol) and acetic acid (to 0.011 ml, 0.20 mmol). The mixture was stirred at K.T. for 30 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol)and the mixture was stirred at K.T. during the night. The mixture was evaporated, and the residue was dissolved in methanol and purified by prep. HPLC with reversed phase (eluent = NH (aq.)/MeCN). The appropriate fractions were combined and evaporated to obtain an oil. This oil was dissolved in minimal acetonitrile and then besieged, using water. This slurry is then evaporated, and the solid was dried over night at 40°C under vacuum to obtain specified in the title compounds as white solids. Yield: 62 mg

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,2, 3.1 Hz, 1H), 8.08-8.02 (m, 2H), 7.47-7.35 (m, 3H), 7.24-7.21 (m, 2H), 7.14 (dd, J=8,8, 7,0 Hz, 1H), 7.09 (d, J=8,2 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 6.66-6.59 (m, 2H,), 4.18 (s, 1H), 3.97 (s, 2H), 3.54-3.46 (m, 4H), 3.27 (s, 2H), 2.80 (s, 1H), 2.52 (s, 3H), 2.32-2.24 (m, 4H), 1.88-1.69 (m, 6H), 1.62-1.52 (m, 2H)

MS: [M+H]+=665,3 (RASSC.=665,3251) (multimode+)

Example 9

N-((1s,4s)-4-(2-(2'-((Dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate

1,1'-Bis(diphenylphosphino)ferrocene (0,202 g, 0.36 mmol) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM (0,294 g, 0.36 mmol) were stirred together in dry dimethylsulfoxide (12 ml) for 10 min, then was added potassium acetate (2,121 g of 21.61 mmol), a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexylcarbamate (4,00 g, 7,20 mmol) in dimethyl sulfoxide (24 ml) and bis(pinacolato)LIBOR(UAH 2.432 g, 9,58 mmol) and the reaction mixture was heated at 80°C for 16 hours the Reaction mixture was left to stand for about 4 hours, then added water (about 20 ml)and the mixture was stirred for 1 h, the Solid was removed by filtration and washed with water (3×10 ml), then purified by flash chromatography on silica (Combi-Flash Companion, SNAP, 100 g), gradient elution from 50 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as painted in cream color foam. Output: 3,51,

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,2, 3.1 Hz, 1H), 8.06-8.03 (m, 2H), 7.76 (d, J=7,4 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.28-7.25 (m, 1H), 4.44-4.38 (m, 1H), 4.19-4.14 (m, 1H), 3.65-3.59 (m, 1H), 1.85-1.67 (m, 8H), 1.42 (s, 9H), 1.35 (s, 12H).

MS: [M+H]+=556 (multimode+)

Stage (b) tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

The palladium(II) acetate (0,092 g, 0.41 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (0,336 g, 0.82 mmol) was stirred in acetonitrile (20 ml) for 15 min, then the solution was added potassium carbonate (4,24 g, 30,68 mmol) in water (40 ml), then 2-bromo-5-hydroxybenzaldehyde (2,467 g, 12,27 mmol) and a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (of 5.68 g, 10,23 mmol) in acetonitrile (27 ml). The reaction mixture was heated at 0°C for 8 h, then left to stand overnight. The acetonitrile is evaporated and the aqueous residue was added EtOAc. The layers were separated, and the aqueous substance was extracted with EtOAc (×8). The combined organic extracts were washed with water and saturated brine. Organics were dried over sodium sulfate and filtered to remove the desiccant, getting a thin slurry. Volatiles were evaporated, and the obtained resin was partially dissolved in acetone. The suspension was filtered to obtain a sample specified in the subtitle compound (3,646 g) in the form of not-quite-white powder. The filtrate was adsorbing on 22 g of silica and purified by flash chromatography on silica (Combi-Flash Companion, column Biotage (SNAP 100 g), gradient elution from 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain additional sample specified in the subtitle compound as a pale yellow solid (0,797 g).

Output: 4,443,

1H NMR (400 MHz, DMSO) δ 10.07 (br s, 1H), 9.88 (s, 1H), 8.26-8.25 (m, 2H), 8.02 (dd, J=7,9, 3.1 Hz, 1H), 7.54-7.50 (m, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.28 (d, J=2.6 Hz, 1H), 7.27-7.23 (m, 3H), 7.15 (dd, J=8.5 a, 2,8 Hz, 1H), 6.61-6.59 (m, 1H), 3.89-3.85 (m, 1H), 3.38-3.34 (m, 1H), 1.74-1.53 (m, 8H), 1.36 (s, 9H).

MS: [M-H]-=548 (multimode+)

Stage (C) tert-butyl(1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydro is semifinal-3-yloxy)nicotinamide)cyclohexylcarbamate (1.2 g, to 2.18 mmol) in DCM (10 ml) was added 2 M solution of dimethylamine in THF (5,46 ml, 10,92 mmol) and acetic acid (0,125 ml of 2.18 mmol). The mixture was stirred at K.T. for 10 min, then was added triacetoxyborohydride sodium (0,926 g, 4,37 mmol)and the mixture was stirred for 1 h the Mixture was diluted with DCM and washed with saturated solution of NaHCO3(aq.) (×2), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a foam. Output: 1,2,

MS: [M+H]+=579 (multimode+)

Stage (d) N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating bis hydrochloride

To a solution of tert-butyl(1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (1.2 g, 2,07 mmol) in DCM (10 ml) was added TFA (10 ml, 129,80 mmol). The mixture was stirred at K.T. during the night. The mixture was evaporated to dryness to obtain foam. The foam was then dissolved in DCM and added ethereal HCl (10 ml of 2 M HCl in ether). The resulting suspension was evaporated to dryness, and the method was repeated twice more to obtain solid, which is triturated with ether, isolated by filtration and dried overnight at 40°C. under vacuum to obtain specified in the subtitle compound. Yield: 850 mg

MS: [M+H]+=479 (multimode+)

Stage (e) N-((1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-utilitiesa-4-carboxamidotryptamine

To a solution of 2-methyl-1,3-thiazole-4-carboxylic acid (38,9 mg, 0.27 mmol) in acetonitrile (5 ml) was added DIPEA (0,095 ml, 0.54 mmol) and HATU (103 mg, 0.27 mmol). The mixture was left to mix with K.T. for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline, 2HCl (150 mg, 0.27 mmol) in MeCN (5 ml) with 2 EQ. DIPEA, and the mixture was stirred at K.T. during the night. The mixture was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with ether oil gave specified in the title compound as a colourless solid, which was dried. Yield: 105 mg

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.02 (d, J=3.3 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.92 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.25-7.19 (m, 3H), 7.13 (d, J=7.7 Hz, 1H), 7.07 (t, J=1.9 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 4.27-4.21 (m, 3H), 4.08-4.01 (m, 1H), 2.66 (s, 3H), 2.58 (s, 6H), 1.97-1.83 (m, 6H), 1.71-1.62 (m, 2H).

MS: [M+H]+=604,2 (RASSC.=604,2394) (multimode+)

Example 10

N-((1s,4s)-4-(2-(2'-((Dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-methylpyridine

To a solution of 6-metilakrilovoe acid (37,3 mg, 0.27 mmol) in acetonitrile (5 ml) was added DIPEA (0,095 ml, 0.54 mmol) and HATU (103 mg, 0.27 mmol). The mixture was left to mix with K.T. for 10 min, then was added p is the target N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline, 2HCl (150 mg, 0.27 mmol) in MeCN (5 ml) with 2 EQ. DIPEA, and the mixture was stirred at K.T. during the night. The mixture was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with ether oil gave specified in the title compound as a colourless solid, which was dried. Yield: 83 mg

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=7,4 Hz, 1H), 8.03-7.99 (m, 2H), 7.95 (d, J=7.7 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.30-7.26 (m, 2H), 7.21 (dd, J=8,2, 1.8 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.08 (d, J=1.5 Hz, 1H), 6.92 (d, J=8,2 Hz, 1H), 4.28-4.25 (m, 1H), 4.21 (s, 2H), 4.07-4.02 (m, 1H), 2.56 (s, 6H), 2.49 (s, 3H), 1.99-1.86 (m, 6H), 1.75-1.66 (m,2H).

MS: [M+H]+=598,2 (RASSC.=598,2829) (multimode+)

Example 11

N-((1s,4s)-4-(2-(2'-((Dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 5-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid (47,9 mg, 0.27 mmol) in acetonitrile (5 ml) was added DIPEA (0,095 ml, 0.54 mmol) and HATU (103 mg, 0.27 mmol). The mixture was left to mix with K.T. for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline, 2HCl (150 mg, 0.27 mmol) in MeCN (5 ml) with 2 EQ. DIPEA, and the mixture was stirred at K.T. during the night. The mixture was purified using prep. HPLC with about asenime phases (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with ether oil gave specified in the title compound as a colourless solid, which was dried overnight under vacuum at 40°C. Yield: 32 mg

1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.25 (dd, J=7,9, 3.1 Hz, 1H), 8.04 (d, J=3.1 Hz, 1H), 7.62-7.50 (m, 3H), 7.24-7.09 (m, 5H), 7.01 (d, J=6.2 Hz, 1H), 6.86 (dd, J=8,5, 2.3 Hz, 1H), 4.28-4.18 (m, 4H), 2.74 (s, 3H), 2.62 (s, 6H), 1.94-1.79 (m, 8H)

MS: [M+H]+=651,2 (RASSC.=637,2938) (multimode+)

Example 12

N-((1s,4s)-4-(2-(2'-((Dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

To a solution of 6-torymidae[1,2-a]pyridine-2-carboxylic acid, HCl (of 58.9 mg, 0.27 mmol) in acetonitrile (5 ml) was added DIPEA (0,142 ml, 0.82 mmol) and HATU (103 mg, 0.27 mmol). The mixture was left to mix with K.T. for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline, 2HCl (150 mg, 0.27 mmol) in MeCN (5 ml) with 2 EQ. DIPEA, and the mixture was stirred at K.T. during the night. The mixture was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with ether oil gave specified in the title compound as a colourless solid, which was dried over night under vacuum at 40°C. Yield: 102 mg

1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J=7,9, 3.1 Hz, 1H), 8.25 (t, J=2.7 Hz, 1H), 8.23 (s, 1H), 8.03 (d, J=3.3 Hz, 1H), 7.58 (dd, J=10,0, a 4.9 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.36 (ddd, J=9,9, and 7.8, 2.2 Hz, 1H), 7.23-7.18 (m, 2H), 7.14-7.09 (m, 3H), 6.86 (dd, J=8,5, 2.3 Hz, 1H), 4.25-4.20 (m, 3H), 4.14-4.10 (m, 1H), 2.61 (s, 6N), 1.95-1.84 (m, 6H), 1.81-1.70 (m, 2H).

MS: [M+H]+=641,2 (RASSC.=641,2688) (multimode+)

Example 13

N-((1s,4s)-4-(2-(2'-((1,4-Oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

Homomorpholine hydrochloride (0,445 g of 3.23 mmol), anhydrous sodium sulfate (3,32 g, 23,35 mmol) and tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1,281 g of 2.33 mmol) suspended in DCM (15 ml). Was added acetic acid (0,14 ml, 2.45 mmol) and the reaction mixture was stirred at K.T. for 1 h, then was added triacetoxyborohydride sodium (0,988 g of 4.66 mmol). The mixture was stirred for 1.5 h, then diluted with DCM and washed with water, saturated sodium bicarbonate, water and saturated brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain the crude product. The crude substance was dissolved in methanol and applied on a pre-p is washed cartridge 10 g SCX. A neutral substance was washed with methanol (100 ml). The product was suirable 1 N. methanolic ammonia (50 ml), and the solvent was evaporated in vacuum to obtain specified in the subtitle compound as a colourless oil. Output: 0,92,

MS: [M+H]+=635 (multimode+)

Stage (b) 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fornicating

tert-Butyl(1s,4s)-4-(2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (0,92 g, 1,45 mmol) was dissolved in DCM (3.5 ml) and cooled in ice. Was slowly added TFA (3.5 ml, 45,43 mmol), then the reaction mixture was stirred at K.T. within 3 hours the Volatiles were evaporated, and the residue was distributed between saturated sodium bicarbonate and DCM. The organic layer was washed with water and saturated brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain the crude specified in the subtitle compound (0,500 g) as a white foam, which was used without further purification. Water substance carefully re-extracted with getting more 0,232, Output: 0,732,

MS: [M+H]+=535 (multimode+)

Stage (C) N-((1s,4s)-4-(2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide triptorelin

HATU (0,089 g, 0.23 mmol) and N-is caldisorientation (0,121 ml, 0.70 mmol) was added to a solution of 6-torymidae[1,2-a]pyridine-2-carboxylic acid hydrochloride (0,051 g, 0.23 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0.125 g, 0.23 mmol) in acetonitrile (4 ml)and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header in the form of a cream solid color. Yield: 82 mg

1H NMR (400 MHz, DMSO) δ 9.57 (br s, 1H), 8.83-8.81 (m, 1H), 8.38-8.35 (m, 2H), 8.26-8.24 (m, 1H), 8.05 (dd, J=7,8, 2,9 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.67-7.63 (m, 1H), 7.54-7.46 (m, 2H), 7.26-7.23 (m, 1H), 7.19-7.09 (m, 4H), 6.92 (d, J=8.5 Hz, 1H), 4.33-4.29 (m, 2H), 3.01-2.80 (m, 2H), 1.95-1.66 (m, 10H). The remaining protons obscured by solvent peak.

MS: [M+H]+=697,2 (RASSC.=697,295) (multimode+)

Example 14

N-((1s,4s)-4-(2-(2'-((1,4-xazepam-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-methylpyridine

HATU (0,089 g, 0.23 mmol) and DIPEA (of 0.081 ml, 047 mmol) was added to a solution of 6-metilakrilovoe acid (0,032 g, 0.23 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0.125 g, 0.23 mmol) in acetonitrile (4 ml) and the reaction mixture was stirred at K.T. within two days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as pale yellow foam. Yield: 109 mg

1H NMR (400 MHz, DMSO) δ 9.90 (br s, 1H), 8.40 (d, J=7,4 Hz, 1H), 8.25 (d, J=3.1 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.90-7.83 (m, 2H), 7.52-7.46 (m, 2H), 7.25-7.22 (m, 1H), 7.17-7.10 (m, 4H), 6.90 (dd, J=8,3, 2.4 Hz, 1H), 4.35-4.27 (m, 2H), 4.04-3.99 (m, 1H), 3.93-3.88 (m, 1H), 3.64-3.46 (m, 4H), 3.02-2.80 (m, 2H), 1.94-1.68 (m, 10H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=654,2 (RASSC.=654,3091) (multimode+)

Example 15

N-((1s,4s)-4-(2-(2'-((1,4-Oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

HATU (0,089 g, 0.23 mmol) and DIPEA (of 0.081 ml, 0.47 mmol) was added to a solution of 2-methylthiazole-4-carboxylic acid the (0,033 g, 0.23 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0.125 g, 0.23 mmol) in acetonitrile (4 ml) and the reaction mixture was stirred at K.T. within 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header in the form of not-quite-white solid. Output: 0,134,

1H NMR (400 MHz, DMSO) δ 9.94 (br s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.25 (d, J=2,8 Hz, 1H), 8.08 (s, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.24-7.22 (m, 1H), 7.18-7.10 (m, 4H), 6.92 (d, J=8,3 Hz, 1 H), 4.33-4.28 (m, 2H), 4.02-3.97 (m, 1 H), 3.90-3.85 (m, 1H), 3.64-3.53 (m, 4H), 3.02-2.80 (m, 2H), 2.68 (s, 3H), 1.96-1.64 (m, 10H). The remaining protons obscured by the peak of the water.

MS: [M+H]+=660,2 (RASSC.=660,2656) (multimode+)

Example 16

2-(2'-((1,4-Oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(2-hydroxy-5-methylbenzamide)cyclohexyl)nicotinamide

HATU (0,089 g, 0.23 mmol) and DIPEA (of 0.081 ml, 0.47 mmol) was added to a solution of 2-hydroxy-5-methylbenzoic the Oh of the acid (0.036 g, 0.23 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0.125 g, 0.23 mmol) in acetonitrile (4 ml)and the reaction mixture was stirred at K.T. during the night. Added additional amount of acid (18 mg), DIPEA (0.04 ml) and HATU (45 mg)and the reaction mixture was again stirred overnight. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 16 mg

1H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 11.42 (br s, 1H), 8.45-8.39 (m, 2H), 8.24 (d, J=2,8 Hz, 1H), 8.01 (dd, J=7,8, 3.0 Hz, 1H), 7.69 (s, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.24-7.09 (m, 6H), 6.92 (d, J=8.0 Hz, 1H), 6.81 (d, J=8,2 Hz, 1H), 4.34-4.25 (m, 2H), 3.98-3.87 (m, 2H), 3.62-3.55 (m, 2H), 3.02-2.78 (m, 2H), 2.23 (s, 3H), 1.94-1.68 (m, 10H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=669,2 (RASSC.=669,3088) (multimode+)

Example 17

N-((1s,4s)-4-(1-(Dimethylamino)cyclopropanecarboxamide)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide triptorelin (250 mg, 0.33 mmol) was dissolved in methanol (1 ml) and was passed through the cartridge Stratosphere PL-HCO3 MP SPE (pre-treated with methanol, elution additional quantity of methanol 2 ml). The solvent is evaporated, and the residue was transferred in acetonitrile (2 ml) and treated with 1-(dimethylamino)cyclopropanecarboxylic acid (52 mg, 0.40 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (EMM, 1.57 M in THF) (0,277 ml, 0.43 mmol) with stirring at K.T. was Added triethylamine (0,279 ml, 2.00 mmol), and stirring was continued for 2 hours, the Solvent evaporated, and the residue was transferred into EtOAc, washed with 2 M aqueous solution of sodium bicarbonate, dried and evaporated. The residue was transferred in acetonitrile, filtered and purified by RPHPLC (column ACE S, 0.2% aq. TFA-acetonitrile, 80%-40%gradient). The product containing fractions were combined, the acetonitrile was evaporated, and the residual water was removed by lyophilization to obtain specified in the connection header in the form of a hygroscopic resin. Yield: 9 mg

1H NMR (400 MHz, CDCl3+d6-DMSO) δ 8.30 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.39 (d, J=7,4 Hz, 1H), 7.23-7.12 (m, 6H), 6.98 (dd, J=8,5, 2.3 Hz, 1H), 4.32-4.26 (m, 2H), 4.25-4.15 (m, 1 H), 3.89-3.78 (m, 6H), 2.61-2.57 (m, 4H), 1.87-1.72 (m,4H), 1.64-1.47 (m, 2H), 1.33-1.16 (m, 4). Other resonances obscured by signals DMSO and water.

MS: [M+H]+=to 632.3 (RASSC.=632,3248) (multimode+)

Example 18

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (84 mg, 0.48 mmol) in acetonitrile (5 ml) was added DIPEA (0,166 ml, 0.95 mmol) and HATU (181 mg, 0.48 mmol). The mixture was left to mix with K.T. for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (283 mg, 0.48 mmol) in MeCN (5 ml) with 2 EQ. DIPEA, and the mixture was stirred at K.T. during the night. The mixture was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with ether oil gave specified in the title compound as a colourless solid, which was dried overnight under vacuum at 40°C. Yield: 156 mg

1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.22 (dd, J=2,9, 1.2 Hz, 1H), 8.14 (d, J=6,9 Hz, 1H), 7.99 (dd, J=8,1, 2,9 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.51-7.45 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.23-7.20 (m, 1H), 7.16-7.10 (m, 3H), 7.04 (d, J=2.3 Hz, 1H), 6.91-6.87 (m, 2H), 4.12 (s, 2H), 4.02-3.96 (m, 2H), 3.64 (t, J=4,2 Hz, 4H), 2.86-2.81 (m, 4H), 2.65 (s, 3H), 1.82-1.73 (m, 8H).

MS: [M+H]+=of 679.2 (RASSC.=679,3044) (multimode+)

Example 19

2-(2'-((1,4-Oxazepan-4-yl)methyl)-4'-hydrox the biphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fornicating

HATU (0.083 g, 0.22 mmol) and DIPEA (0.075 ml, 0.43 mmol) was added to a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0,030 g, 0.22 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0,116 g, 0.22 mmol) in acetonitrile (4 ml)and the reaction mixture was stirred at K.T. within 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header in the form painted in cream color foam. Yield: 120 mg

1H NMR (400 MHz, DMSO) δ 9.93 (br s, 1H), 9.47 (br s, 1H), 8.33 (d, J=6,9 Hz, 1H), 8.25 (d, J=3.1 Hz, 1H), 8.04 (dd, J=7,8, 2,9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.19-7.10 (m, 3H), 6.93-6.91 (m, 1H), 6.39 (s, 1H), 4.35-4.26 (m, 2H), 4.00-3.95 (m, 1H), 3.85-3.80 (m, 1H), 3.74 (s, 3H), 3.01-2.80 (m, 2H), 2.26 (s, 3H), 1.95-1.61 (m, 10H). The remaining protons obscured by solvent peak.

MS: [M+H]+=657,3 (RASSC.=657,32) (multimode+)

Example 20

N-((1s,4s)-4-(2-(2'-((1,4-Oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-enthusiasm is idazo[1,2-a]pyridine-2-carboxamide

HATU (0.083 g, 0.22 mmol) and DIPEA (0.075 ml, 0.43 mmol) was added to a solution of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (0,038 g, 0.22 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexane)-5-fioricetonline (0,116 g, 0.22 mmol) in acetonitrile (4 ml)and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 21 mg

1H NMR (400 MHz, DMSO) δ 9.94 (br s, 1H), 9.45 (br s, 1H), 8.40-8.36 (m, 2H), 8.25 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.94 (s, 1H), 7.53-7.49 (m, 2H), 7.47-7.42 (m, 1H), 7.24 (dd, J=7,9, 1.8 Hz, 1H), 7.19-7.10 (m, 3H), 7.00-6.96 (m, 1H), 6.92 (dd, J=8,5, and 2.6 Hz, 1H), 4.33-4.29 (m, 2H), 4.01-3.93 (m, 2H), 3.01-2.80 (m, 2H), 2.66 (s, 3H), 1.93-1.67 (m, 10H). The remaining protons obscured by solvent peak.

MS: [M+H]+=of 693, 3 (RASSC.=693,32) (multimode+)

Example 21

6-Fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imide what about[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.52 g, 0.95 mmol) in DCM (10 ml) was added thiomorpholine (0,190 ml, 1,89 mmol) and acetic acid (0,054 ml, 0.95 mmol). The mixture was stirred at K.T. for 10 min, then was added triacetoxyborohydride sodium (0,401 g, 1,89 mmol)and the mixture was stirred for 1 h the Mixture was diluted with DCM and washed with saturated solution of NaHCO3(aq.) (×2), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a foam.

Output: 0,5 g

MS: [M+H]+=637,2 (RASSC.=637,286) (multimode+)

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.3 Hz, 1H), 8.09 (d, J=3.1 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.27-7.24 (m, 1H), 7.18-7.15 (m, 2H), 7.12 (dd, J=8,1, 1.9 Hz, 1H), 6.99 (d, J=2,8 Hz, 1H), 6.79 (dd, J=8,3, 2.7 Hz, 1H), 4.47-4.44 (m, 1H), 4.20-4.14 (m, 1H), 3.65-3.59 (m, 1H), 3.40 (s, 2H), 2.62-2.58 (m, 4H), 2.55-2.51 (m, 4H), 1.86-1.66 (m, 6H), 1.54-1.47 (m, 2H), 1.43 (s, 9H)

Stage (b) N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide (0,130 g, 0.21 mmol) dihydrochloride

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (450 mg, 0.71 mmol) in DCM (10 ml) was added hydrogen chloride, 2.0 M R is the target in ether (5 ml, 10,00 mmol). Added DCM (5 ml) and the reaction mixture was left to mix with K.T. during the night. The mixture was evaporated to dryness to obtain specified in the subtitle compound as a yellow solid. Yield: 470 mg

MS: [M+H]+=537,3 (multimode+)

Stage (C) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

HATU (of 0.081 g, 0.21 mmol) and DIPEA (0,184 ml, 1.07 mmol) was added to a suspension of 6-torymidae[1,2-a]pyridine-2-carboxylic acid hydrochloride (0,046 g, 0.21 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)the nicotinamide dihydrochloride (0,130 g, 0.21 mmol), then acetonitrile (6 ml) and the reaction mixture was stirred at K.T. during the night. Added 880 aqueous ammonia (approximately 3 ml), then a sufficient amount of methanol to move the settled solids in the solution (about 2 ml). The mixture was stirred for another 4 h, then diluted with DCM and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. Fractions containing the e target connection, was evaporated to dryness to obtain specified in the title compounds as a pale pink solid. Yield: 73 mg

1H NMR (400 MHz, DMSO) δ 9.90 (br s, 1H), 8.80 (s, 1H), 8.37-8.27 (m, 3H), 8.05 (dd, J=8,1, 2,9 Hz, 1H), 7.75-7.70 (m, 1 H), 7.66-7.62 (m, 1H), 7.53-7.45 (m, 2H), 7.24 (d, J=8.5 Hz, 1H), 7.18-7.04 (m, 4H), 6.91 (d, J=9.0 Hz, 1H), 4.27-4.23 (m, 1H), 4.02-3.90 (m, 1H), 2.87-2.61 (m, 4H), 1.80-1.66 (m, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=699,2 (RASSC.=699,2565) (multimode+)

Example 22

N-((1s,4s)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide

HATU (0,062 g, 0.16 mmol) and DIPEA (0,114 ml, 0.66 mmol) was added to a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0,023 g, 0.16 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,100 g, 0.16 mmol) in acetonitrile (4 ml)and the reaction mixture was stirred at K.T. within 2 days. Added 880 aqueous ammonia (approximately 2 ml), then an additional amount of methanol to move the settled solids in the solution (about 2 ml). The mixture was stirred for another 4 h, then diluted with DCM and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. accidenly product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the connection header in the form of painted cream color foam. Yield: 63 mg

1H NMR (400 MHz, DMSO) δ 9.93 (br s, 1H), 8.33 (d, J=6,9 Hz, 1H), 8.27 (d, J=3.1 Hz, 1H), 8.04 (dd, J=7,8, and 3.2 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.18-7.11 (m, 3H), 7.05-7.04 (m, 1H), 6.92 (d,, J=7,6 Hz, 1H), 6.39 (s, 1H), 4.28-4.23 (m, 2H), 3.99-3.95 (m, 1H), 3.85-3.80 (m, 1H), 3.74 (s, 3H), 2.87-2.61 (m, 4H), 2.26 (s, 3H), 1.75-1.62 (m, 8H). The remaining protons obscured by solvent peak.

MS; [M+H]+=659,2 (RASSC.=659,2816) (multimode+)

Example 23

N-((1s,4s)-4-(2-(2'-(Azepin-1-ylmethyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

The triethylamine (4 ml, 28,78 mmol) was added to a stirred suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (1,655 g of 3.64 mmol) and 2-methylthiazole-4-carboxylic acid (0.625 g, 4,36 mmol), after which the reaction mixture became homogeneous. It was stirred for 40 minutes, during this time, the formed precipitate, and then slowly added cyclic anhydride 1-papapostolou acid (TR, 1.57 M in THF) (3,01 ml, to 4.73 mmol). The reaction mixture was again homogeneous, and the mixture was stirred for but is I. The reaction mixture was evaporated to dryness and pererestorani in EtOAc, then washed with saturated sodium bicarbonate, 2 M hydrochloric acid, water and saturated brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound as a white foam. Output: 2,16,

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=6,9 Hz, 1H), 7.63 (dt, J=7,2, 1.7 Hz, 1H), 7.55 (t, J=1.9 Hz, 1H), 7.24-7.15 (m, 3H), 4.25-4.20 (m, 1H), 4.12-4.06 (m, 1H), 2.71 (s, 3H), 1.96-1.77 (m, 6H), 1.67-1.61 (m, 2H).

MS: [M+H]+=581 (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

1,1'-Bis(diphenylphosphino)ferrocene (0,105 g 0,19 mmol) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and DCM (0.152 g, 0,19 mmol) were stirred together in dry dimethylsulfoxide (5 ml) for 10 min, then was added potassium acetate (1,099 g, 11,20 mmol), a solution of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (2,166 g, 3.73 mmol) in dimethyl sulfoxide (10,00 ml) and bis(pinacolato)LIBOR (1,260 g, 4,96 mmol) and the reaction mixture was heated at 80°C for 17 hours, the Reaction mixture was left at K.T. within 3 days, then added water and the mixture was extracted with EtOAc (×5). The combined organic extracts were washed with water and saturated the brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica (Combi-Flash Companion cartridge Biotage (SNAP 100 g), gradient elution from 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a white foam. Output: 1,09,

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=7,4 Hz, 1H), 8.06 (d, J=3.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=7,4 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.29 (ddd, J=7,9, 2,6, 0.8 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 4.25-4.21 (m, 1H), 4.12-4.06 (m, 1H), 2.69 (s, 3H), 1.94-1.76 (m, 6H), 1.67-1.60 (m, 2H), 1.32 (s, 12H).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

The palladium(II) acetate (0,017 g, 0.08 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (holding 0.062 g, 0.15 mmol) was stirred in acetonitrile (4 ml) for 15 min, then the solution was added potassium carbonate (0,781 g, the 5.65 mmol) in water (8 ml), then 2-bromo-5-hydroxybenzaldehyde (0,454 g of 2.26 mmol) and a solution of N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (1,093 g, 1.88 mmol) in acetonitrile (8 ml). The reaction mixture was heated at 70°C for 10 h, then left to stand for 2 days. The acetonitrile is evaporated and the water on which TATKO was added EtOAc. The layers were separated, and the aqueous substance was extracted with EtOAc. The combined organic extracts were washed with water and saturated brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain the crude product. This product was purified by flash chromatography on silica (Combi-Flash Companion, 100 g column, gradient elution from 20 to 90% EtOAc in isohexane. Pure fractions were evaporated to dryness and subjected to azeotropic distillation with DCM to obtain specified in the subtitle compound as a pale brown foam. Output: 0,75,

1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.09 (d, J=3.1 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.44 (d, J=2,8 Hz, 1H), 7.33 (d, J=8,2 Hz, 1H), 7.29-7.23 (m, 2H), 7.19-7.18 (m, 1H), 7.11 (dd, J=8,2, 2.8 Hz, 1H), 6.86-6.78 (m, 1H), 4.27-4.22 (m, 1H), 4.11-4.06 (m, 1H), 2.63 (s, 3H), 1.97-1.83 (m, 6H), 1.69-1.61 (m, 2H).

MS: [M+H]+=575 (multimode+)

Stage (d) N-((1s,4s)-4-(2-(2'-(azepin-1-ylmethyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,130 g, 0.23 mmol) and anhydrous sodium sulfate (0,321 g of 2.26 mmol) was stirred in DCM (5 ml) for 20 min, then was added hexamethylenimine (homopiperazin) (0,031 ml, 0.27 mmol) and the reaction mixture was stirred for another 2 hours was Added triacetoxyborohydride the atrium (0,072 g, 0.34 mmol) and the reaction mixture was stirred at K.T. during the night. Was added methanol (2 ml), then DCM and the organic matter was washed with saturated sodium bicarbonate and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white foam. Yield: 122 mg

1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.25 (s, 1H), 8.35 (d, J=7,4 Hz, 1H), 8.25 (d, J=2,8 Hz, 1H), 8.09 (s, 1H), 8.05 (dd, J=7,9, or 2.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.24 (d, J=6,4 Hz, 1H), 7.18-7.09 (m, 4H), 6.91 (dd, J=8,3, 2.2 Hz, 1H), 4.23 (d, J=4.9 Hz, 2H), 4.02-3.97 (m, 1H), 3.90-3.85 (m, 1H), 3.19-3.12 (m, 2H), 2.82-2.75 (m, 2H), 2.68 (s, 3H), 1.76-1.64 (m, 8H), 1.49-1.44 (m, 4H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=658,2 (RASSC.=658,2863) (multimode+)

Example 24

N-((1s,4s)-4-(2-(2'-(((2S,6R)-2,6-Dimethylmorpholine)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,130 g, 0.23 mmol) and anhydrous sodium sulfate (0,321 g of 2.26 mmol) was stirred in DCM (5 ml) for 20 min, then was added CIS-2,6-dimethylmorpholine (0,034 ml, 0.27 mmol) and the reaction see what camping was stirred for another 2 hours Added triacetoxyborohydride sodium (0,072 g, 0.34 mmol). The reaction mixture was stirred at K.T. during the night, then added methanol (2 ml)and the mixture was diluted with DCM. Organic matter was washed with saturated sodium bicarbonate, water and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white foam. Yield: 54 mg

1H NMR (400 MHz, DMSO) δ 8.34 (d, J=7.2 Hz, 1H), 8.26 (d, J=2,8 Hz, 1H), 8.09 (s, 1H), 8.04 (dd, J=7,8, 2,9 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.22-7.11 (m, 4H), 7.05-7.02 (m, 1H), 6.94-6.89 (m, 1H), 4.28-4.20 (m, 1H), 4.01-3.96 (m, 1H), 3.90-3.85 (m, 1H), 3.73-3.64 (m, 1H), 3.17-3.06 (m, 2H), 2.68 (s, 3H), 2.28-2.16 (m, 2H), 1.78-1.63 (m, 8H), 1.01-0.96 (m, 6H). The remaining protons obscured by solvent peak.

MS: [M+H]+=674,2 (RASSC.=674,2812) (multimode+)

Example 25

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-((4-isopropylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,130 g, 0.23 mmol) and anhydrous sodium sulfate (0,321 g of 2.26 mmol) was stirred in DCM (5 ml) for 20 min, then was added 1-from propylpiperazine (0.035 g, 0.27 mmol) and the reaction mixture was stirred for another 2 hours was Added triacetoxyborohydride sodium (0,072 g, 0.34 mmol) and the reaction mixture was stirred at K.T. during the night. Was added methanol (2 ml) and DCM and the organic matter was washed with saturated sodium bicarbonate, water and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white foam. Output: 161 mg.

1H NMR (400 MHz, DMSO) δ 8.34 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.09 (s, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.19-7.14 (m, 3H), 7.09 (d, J=8,2 Hz, 1H), 6.88-6.86 (m, 1H), 6.76 (d, J=8.5 Hz, 1H), 4.03-3.98 (m, 1H), 3.52-3.25 (m, 6H), 2.90-2.80 (m, 4H), 2.67 (s, 3H), 2.31-2.21 (m, 2H), 1.78-1.63 (m, 8H), 1.19 (d, J=6,7 Hz, 6N). The remaining protons obscured by solvent peak.

MS: [M+H]+=687,3 (RASSC.=687,3129) (multimode+)

Example 26

N-((1s,4s)-4-(2-(2'-((tert-Butyl(methyl)amino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,130 g, 0.23 mmol) and anhydrous sodium sulfate (0,321 g of 2.26 mmol) peremeshivayu DCM (5 ml) for 20 min, then was added N-tert-butylamine (0,033 ml, 0.27 mmol) and the reaction mixture was stirred for another 2 hours was Added triacetoxyborohydride sodium (0,072 g, 0.34 mmol) and the reaction mixture was stirred at K.T. during the night. Added an additional amount of N-methyl-tert-butylamine (0,033 ml, 0.27 mmol) and anhydrous sodium sulfate (0,321 g of 2.26 mmol), then after 2 h an additional amount of triacetoxyborohydride sodium (0,072 g, 0.34 mmol) and the mixture was stirred over night. Was added methanol (2 ml) and DCM and the organic matter was washed with saturated sodium bicarbonate, water and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 75-25%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 53 mg

1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 8.59 (s, 1H), 8.33 (d, J=7,0, 1H), 8.23 (d, J=3,0, 1H), 8.09 (s, 1H), 8.05 (dd, J=3,0, 8,0, 1H), 7.59 (d, J=8,2, 1H), 7.52 (t, J=7,9, 1H), 7.24 (dd, J=1,7, 8,0, 1H), 7.21-7.09 (m, 3H), 6.99 (s, 1H), 6.93 (dd, J=2,4, and 8.4,1H), 4.51 (d, J=12,6, 1H), 4.00 (s, 1H), 3.92-3.78 (m, 2H), 2.71 (s, 3H), 2.32 (d, J=4,9, 3H), 1.78-1.61 (m, 8H), 1.19 (s, 9H).

MS: [M+H]+=646,2 (RASSC.=646,2863) (multimode+)

Example 27

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)qi is logical)quinoline-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (750 mg, about 1.36 mmol) and 1-methyl-1,4-diazepan (0,255 ml, 2.05 mmol) were stirred together in dichloromethane (20 ml) at K.T. within 15 minutes was Added triacetoxyborohydride sodium (868 mg, 4.09 to mmol) and one drop of glacial acetic acid and the reaction mixture was stirred over night. Was added water (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml) and the mixture was stirred for 1 hour. The organic phase was separated and evaporated to obtain specified in the subtitle compound as a yellow-brown foam, which was used without further purification. Yield: 760 mg

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 8.04 (d, J=7,4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.27 (d, J=9,2 Hz, 1H), 7.22 (t, J=1.9 Hz, 1H), 7.15 (d, J=8,2 Hz, 1H), 7.13-7.09 (m, 1H), 7.06 (d,, J=2,6 Hz, 1H), 6.78 (dd, J=8,2, 2.6 Hz, 1H), 4.52-4.40 (m, 1H), 4.21-4.12 (m, 1H), 3.68-3.56 (m, 1H), 3.51 (s, 2H), 2.76-2.56 (m, 9H), 2.34 (s, 3H), 1.88-1.64 (m, 9H), 1.53-1.45 (m, 1H), 1.42 (s, 9H).

Stage (b) N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)the nicotinamide dihydrochloride

A solution of 10% TFA in DCM (10 ml) was added to tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-what diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (750 mg, to 1.16 mmol) at 25°C. the resulting solution was stirred at 25°C for 2 hours. Was added TFA (2 ml), and stirring was continued over night. All volatiles were removed in vacuo, and the residue pererestorani in DCM, the solution was washed with saturated aqueous sodium bicarbonate solution and brine and then was dried. The combined aqueous solutions were extracted in EtOAc, and then the aqueous solution was evaporated to dryness. The solid residue was thoroughly washed with warm acetone trilam, which was filtered and was evaporated. Sticky foamy residue was dissolved in warm isopropanol and acidified with HCl. The precipitate was removed and the filtrate was evaporated to dryness. Was added conc. HCl, and the resulting solution again was carefully evaporated to dryness to obtain specified in the subtitle compound as a foam. Output: 550 mg.

1H NMR (400 MHz, DMSO) δ 11.85-11.03 (m, 2H), 8.48-8.23 (m, 5H), 8.12-8.01 (m, 1H), 7.56-7.44 (m, 1H), 7.42-7.31 (m, 1H), 7.25 (d, J=9.5 Hz, 1H), 7.22-7.13 (m, 3H), 6.98 (dd, J=8,5, and 2.6 Hz, 1H), 3.79-2.94 (m, 10H), 2.76-2.60 (m, 2H), 2.08-1.58 (m, 10H). Other resonances obscured by the wide signal is water.

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)quinoline-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (110 mg, 0.18 mmol) in acetonitrile (1 ml) at K.T. added Hino is in 2-carboxylic acid (to 33.8 mg, 0,19 mmol) and cyclic anhydride 1-papapostolou acid (TR, 1.57 M in THF) (0,141 ml, 0.22 mmol) with stirring. After 20 min was added triethylamine (0,247 ml, 1.77 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with EtOAc (5 ml) was added saturated aqueous sodium bicarbonate solution (2 ml). After stirring for 15 min the homogeneous solution was concentrated to remove organic solvents, and aqueous residue was carefully extracted in DCM. Evaporation of the organic solvent gave a foam, which pererestorani in acetonitrile, filtered and purified (column RPHPLC ACE S, 80-40% 0.2% aqueous TFA-acetonitrile). The product containing fractions were combined and evaporated to dryness. The residue is triturated with ether to obtain specified in the title compound as a white powder. Yield: 11 mg

1H NMR (400 MHz, DMSO) δ 8.56 (d, J=8.5 Hz, 1H), 8.40 (d, J=7.2 Hz, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.10-8.00 (m, 3H), 7.88-7.83 (m, 1H), 7.74-7.69 (m, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.21-7.08 (m, 3H), 7.08-7.00 (m, 1H), 6.95-6.85 (m, 1H), 6.78-6.62 (m, 1H), 4.12-3.93 (m, 2H), 2.71 (s, 3H), 1.92-1.69 (m, 8H). Other resonances obscured by signals DMSO and water.

MS: [M+H]+=703,3 (RASSC.=703,3408) (multimode+)

Example 28

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(2-hydroxy-5-methylbenzamide)cyclohexyl)nicotinamide

To a solution of 2-hydrox the-5-methylbenzoic acid (61,5 mg, 0.40 mmol) in THF (1 ml) was added HOBt (61,9 mg, 0.40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64,6 mg, 0.34 mmol), the mixture was stirred for 10 min at K.T. This mixture then was added to a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide, dihydrochloride (200 mg, 0.34 mmol) and triethylamine (0,188 ml, 1.35 mmol) in THF (1 ml) and N-methyl-2-pyrrolidinone (1 ml). The reaction mixture was stirred at K.T. during the night. The mixture was diluted with acetonitrile and purified using prep. HPLC with reversed phase (eluent = TFA(aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil, which after rubbing with ether gave specified in the header connection. Yield: 84 mg

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,2, 3.1 Hz, 1H), 8.04 (d, J=3.1 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.22-7.13 (m, 4H), 7.08-7.04 (m, 2H), 6.92 (d, J=8,2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.36 (d, J=7.2 Hz, 1H), 4.28-4.22 (m, 3H), 4.06-4.01 (m, 1H), 3.80-3.76 (m, 4H), 3.14-2.48 (m, 4H), 2.24 (s, 3H), 1.98-1.86 (m, 6H), 1.75-1.66 (m, 2H)

MS: [M+H]+=655,2 (RASSC.=655,2932) (multimode+)

Example 29

N-((1s,4s)-4-(2-(2'-((4-Acetylpiperidine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,109 g 0,19 mmol) and anhydrous self is tons of sodium (0,269 g, 1,90 mmol) was stirred in DCM (5 ml) for 20 min, then was added 1-acetylpiperidine (0,039 g, 0.30 mmol) and the reaction mixture was stirred for another 2 hours was Added triacetoxyborohydride sodium (to 0.060 g, 0.28 mmol). The reaction mixture was stirred at K.T. within 3 days, then was added methanol (2 ml) and the mixture was diluted with EtOAc. Organic matter was washed with saturated sodium bicarbonate, water and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white foam. Yield: 111 mg

1H NMR (400 MHz, DMSO) δ 9.92 (br s, 1H), 9.67 (s, 1H), 8.34 (d, J=7,1 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.09 (s, 1H), 8.03 (dd, J=3,0, 7.9 Hz, 1H), 7.61 (d, J=8,4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.26-7.01 (m, 6H), 6.90 (d, J=6,6 Hz, 1H), 4.39-4.08 (m, 2H), 4.02-3.96 (m, 1H), 3.90-3.74 (m, 2H), 2.93-2.80 (m, 2H), 2.62 (s, 3H), 1.91 (s, 3H), 1.83-1.58 (m, 8H). The remaining protons obscured by solvent peak.

MS: [M+H]+=687,2 (RASSC.=687,2765) (multimode+)

Example 30

N-((1s,4s)-4-(2-(2'-(((2-(Dimethylamino)-2-oxoethyl)(methyl)amino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(2'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohex the l)-2-methylthiazole-4-carboxamide (0,109 g, 0,19 mmol) and anhydrous sodium sulfate (0,269 g, 1,90 mmol) was stirred in 1,2-dichloroethane (5 ml) for 20 min, then was added N,N-dimethyl-2-(methylamino)ndimethylacetamide (0,026 g, 0.23 mmol) and the reaction mixture was stirred for another 2 hours was Added triacetoxyborohydride sodium (to 0.060 g, 0.28 mmol). The reaction mixture was stirred at K.T. within 3 days, then was added methanol (2 ml)and the mixture was diluted with EtOAc. Organic matter was washed with saturated sodium bicarbonate, water and saturated brine. The solvent is evaporated, and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compound as a white foam. The output 103 mg.

1H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 9.38 (s, 1H), 8.34 (d, J=7,2, 1H), 8.25 (d, J=3,1, 1H), 8.09 (s, 1H), 8.03 (dd, J=3,1, 7,9, 1H), 7.63 (d, J=8,1, 1H), 7.49 (t, J=8,1, 1H), 7.22-7.11 (m, 5H), 6.91 (dd, J=2,4, and 8.4, 1H), 4.37-4.27 (m, 1H), 4.22-4.13 (m, 1H), 4.05-3.97 (m, 3H), 3.91-3.83 (m, 1H), 2.84 (s, 3H), 2.81 (s, 3H), 2.69 (s, 3H), 2.47 (s, 3H), 1.80-1.64 (m, 8H).

MS: [M+H]+=675,2 (RASSC.=675,2765) (multimode+)

Example 31

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(4-hydroxybenzamide)cyclohexyl)nicotinamide

N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotina is Yes dihydrochloride (150 mg, 0.25 mmol), 4-hydroxybenzoic acid (41,9 mg, 0.30 mmol), N1-((ethylimino)methylene)-N3,N3-DIMETHYLPROPANE-1,3-diamine hydrochloride (53,3 mg, 0.28 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol hydrate (46.4 mg, 0.30 mmol) were combined in acetonitrile (2.5 ml) and stirred and then added triethylamine (0,176 ml of 1.26 mmol). The solution was stirred at K.T. during the night. The reaction mixture was evaporated to dryness, and the residue was distributed between DCM and saturated aqueous sodium bicarbonate. The organic phase was separated and evaporated. The remainder of pererestorani in acetonitrile, filtered and purified (column RPHPLC ACE S, 95-25% 0.2% aqueous TFA-acetonitrile). The product containing fractions were combined (transferred by washing with methanol) and evaporated to dryness to obtain specified in the connection header in the form of solids. Yield: 64 mg

1H NMR (400 MHz, DMSO) δ 10.02-9.86 (m, 2H), 9.82-9.65 (m, 1H), 8.34 (d, J=6,7 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.03 (dd, J=7,9, 3.1 Hz, 1H), 7.77 (d, J=6,7 Hz, 1H), 7.67 (d, J=9,2 Hz, 2H), 7.49 (t, J=7.7 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.20-7.02 (m, 4H), 6.97-6.84 (m, 1H), 6.77 (d, J=8.7 Hz, 2H), 4.39-4.19 (m, 2H), 4.01-3.87 (m, 1H), 3.87-3.66 (m, 4H), 2.81-2.61 (m, 2H), 1.87-1.57 (m, 8H). Other resonances obscured by signals DMSO and water. NMR showed the presence of 1 mol of methanol.

MS: [M+H]+=641,2 (RASSC.=641,2775) (multimode+)

Example 32

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(3-hydroxybenzamide)cyclohexyl)nicotinamide

p> N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)the nicotinamide dihydrochloride (150 mg, 0.25 mmol), 3-hydroxybenzoic acid (41,9 mg, 0.30 mmol), HOBt (46.4 mg, 0.30 mmol) and EDCl (53,3 mg, 0.28 mmol) were combined in acetonitrile (2.5 ml) and stirred. Was added triethylamine (0,176 ml of 1.26 mmol)and the solution was stirred at K.T. during the night. Was added HOBt (46 mg) and EDCl (53 mg), and stirring was continued over night. Was added water (1 ml) and the reaction mixture was stirred for 1 h, then evaporated to dryness. The remainder of pererestorani in acetonitrile, filtered and purified (column RPHPLC ACE S, 95-25% 0.2% aqueous TFA-acetonitrile). The product containing fractions were combined (transferred by washing with methanol) and evaporated to dryness to obtain specified in the connection header in the form of glass. Yield: 37 mg

1H NMR (400 MHz, DMSO) δ 10.02-9.80 (m, 1H), 9.67-9.57 (m, 1H), 8.33 (d, J=6,7 Hz, 1H), 8.27 (d, J=2,8 Hz, 1H), 8.03 (dd, J=7,9, 3.1 Hz, 1H), 7.96 (d, J=6,7 Hz, 1H), 7.55-7.43 (m, 1H), 7.27-7.09 (m, 8H), 6.95-6.84 (m, 2H), 4.34-4.18 (m, 1H), 4.01-3.88 (m, 1H), 3.85-3.57 (m, 5H), 2.78-2.57 (m, 1H), 1.90-1.57 (m, 10H). Other resonances obscured by signals DMSO and water. NMR shows the presence of 1 mol of methanol.

MS: [M+H]+=641,2 (RASSC.=641,2775) (multimode+)

Example 33

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-methylthiazole-5-carboxamide

N-((1s,4s)-4-Aminol logical)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)the nicotinamide dihydrochloride (150 mg, 0.25 mmol) suspended in acetonitrile (2 ml) and was treated with 4-methylthiazole-5-carboxylic acid (43,4 mg, 0.30 mmol). After stirring for several minutes added cyclic anhydride 1-papapostolou acid (TR, 1.57 M in THF) (0,241 ml, 0.38 mmol) and then triethylamine (0,281 ml, 2.02 mmol) and the reaction mixture was stirred over night. Added additional amount TR (0,24 ml) and triethylamine (0,28 ml), and stirring was continued over night. Added additional amount of 4-methylthiazole-5-carboxylic acid (43,4 mg, 0.30 mmol), and stirring is continued during the weekend. Added additional amount of 4-methylthiazole-5-carboxylic acid (43,4 mg, 0.30 mmol), EMM (0,24 ml) and triethylamine (0,28 ml), and stirring was continued over night. Adding more thiazole-carboxylic acid (215 mg), EMM (1.2 ml) and triethylamine (2 ml) and the mixture was stirred at K.T. during the night. All volatiles evaporated, and the oily residue was transferred in acetonitrile, filtered and purified (column RPHPLC ACE S, 95-25% 0.2% aqueous TFA-acetonitrile). The product containing fractions were combined (transferred by washing with methanol) and evaporated to dryness to obtain specified in the connection header in the form of glass. Yield: 26 mg

1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.38 (d, J=6,9 Hz, 1H), 8.25 (d, J=3.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.28-7.04 (m, 5H), 6.93 (d, J=6,9 G is, 1H), 3.66-3.43 (m, 2H), 3.26-3.04 (m, 2H), 2.85-2.61 (m, 2H), 1.85-1.58 (m, 8H). Other resonances obscured by signals DMSO and water.

MS: [M+H]+=646,2 (RASSC.=646,2499) (multimode+)

Example 34

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

HATU (0,064 g, 0,17 mmol) and DIPEA (0.06 ml, 0.34 mmol) was added to a solution of 2-methylthiazole-4-carboxylic acid (0,024 g, 0,17 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,100 g, 0,17 mmol) and DIPEA (and 0.09 ml, 0.52 mmol) in acetonitrile (4 ml) and the reaction mixture was stirred at K.T. within 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 87 mg

1H NMR (500 MHz, DMSO) δ 9.92 (br s, 1H), 9.67 (br s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.08 (s, 1H), 8.04 (dd, J=3,0, 7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.19-7.09 m, 3H), 7.05 (s, 1H), 6.91 (d, J=6,7 Hz, 1H), 4.32-4.18 (m, 2H), 4.01-3.96 (m, 1H), 3.91-3.84 (m, 1H), 3.78-3.66 (m, 2H), 3.62-3.51 (m, 2H), 3.20-3.07 (m, 2H), 2.77-2.62 (m, 5H), 1.78-1.63 (m, 8H).

MS: [M+H]+=646,2 (RASSC.=646,2499) (multimode+)

Example 35

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-3-hydroxyproline

EDCl (0,043 g, 0.22 mmol) and HOBt (0.037 g, 0.24 mmol) was added to a stirred suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,120 g, 0.20 mmol) and 3-hydroxypyridones acid (0,034 g, 0.24 mmol) in acetonitrile (4 ml). Was slowly added triethylamine (0.15 ml, at 1.08 mmol), then the additional amount of acetonitrile (4 ml) to give a yellow solution. The reaction mixture was stirred at K.T. within 5 days, then diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 38 mg

1H NMR (500 MHz, DMSO) δ 12.45 (br s, 1H), 9.93 (br s, 1H), 9.65 (br s, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.36 (d, J=7,0 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.13 (dd, =1,0, the 4.3 Hz, 1H), 8.05 (dd, J=2,9, 7.9 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (d, J=8,2 Hz, 1H), 7.24 (dd, J=1,7, 8,2 Hz, 1H), 7.18-7.10 (m, 3H), 7.06 (d, J=1.8 Hz, 1H), 6.92 (dd, J=1,4, and 8.4 Hz, 1H), 4.32-4.20 (m, 2H), 4.03-3.88 (m, 2H), 3.79-3.65 (m, 2H), 3.19-3.06 (m, 2H), 2.76-2.61 (m, 2H), 1.86-1.66 (m, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=642,2 (RASSC.=642,2728) (multimode+)

Example 36

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(trifluoromethyl)thiazole-4-carboxamide

EDCl (0.036 g, 0,19 mmol) and HOBt (0,031 g, 0.20 mmol) was added to a stirred suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,100 g, 0,17 mmol) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (Atlantic Research Chemicals Ltd) (0,040 g, 0.20 mmol) in acetonitrile (8 ml). Was slowly added triethylamine (0,141 ml, 1.01 mmol). The reaction mixture was stirred at K.T. overnight, then diluted with EtOAc and washed with water and saturated brine. Organic matter was evaporated to obtain the crude product. The crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent 95-5%gradient of aqueous 0.2% of TFA in acetonitrile. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as a pale orange solid. Yield: 41 mg

1H NMR (500 M is C, DMSO) δ 9.92 (br s, 1H),9.79 (brs, 1H), 8.68 (s, 1H), 8.34 (d, J=7,0 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.04 (dd, J=3,0, 7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.18-7.02 (m, 4H), 6.90 (d, J=7,3 Hz, 1H), 4.32-4.16 (m, 2H), 4.02-3.96 (m, 1H), 3.93-3.85 (m, 1H), 3.20-3.05 (m, 2H), 2.80-2.62 (m, 2H), 1.83-1.62 (m, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=700,2 (RASSC.=700,2217) (multimode+)

Example 37

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-isopropylthiazole-5-carboxamid

To a stirred solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (100 mg, 0,17 mmol) and 2-isopropylthiazole-5-carboxylic acid (37.5 mg, 0.22 mmol) in acetonitrile (2 ml) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatridecane-2,4,6-trioxide (TR, 1.57 M in THF) (0,215 ml, 0.34 mmol) and then introduced triethylamine (0,234 ml, 1,68 mmol). The reaction mixture was stirred at K.T. during the night. Added additional amount of 2-isopropylthiazole-5-carboxylic acid (37 mg), TR (0,215 ml) and triethylamine (0.5 ml), and stirring was continued over night. Carried out the second supplementary Appendix 2-isopropylthiazole-5-carboxylic acid (37 mg), TR (0,215 ml) and triethylamine (0.5 ml) and the reaction mixture was stirred over night. All volatile components were evaporated, and the residue was transferred into DCM and washed with saturated waters is the first sodium bicarbonate solution, was dried and evaporated. The remaining resinous substance was dissolved in acetonitrile, filtered and purified by RPHPLC (ACE S column, 95-25% 0.2% aqueous TFA-acetonitrile). The product containing fractions were combined (washing together with methanol) and evaporated to obtain specified in the connection header in the form of a resin. Yield: 26 mg

1H NMR (400 MHz, DMSO) δ 8.37 (d, J=6,4 Hz, 1H), 8.28-8.25 (m, 2H), 8.23 (d, J=6,4 Hz, 1H), 8.02 (dd, J=7,9, 3.1 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.26-7.03 (m, 5H), 6.97-6.86 (m, 1H), 4.36-4.22 (m, 2H), 4.01-3.89 (m, 2H), 3.84-3.65 (m, 4H), 2.80-2.62 (m, 2H), 1.87-1.58 (m, 8H), 1.32 (d, J=6,9 Hz, 6N). Other resonances obscured by signals DMSO and water. NMR shows that the substance contains 1 mol of methanol.

MS: [M+H]+=674,2 (RASSC.=674,2812) (multimode+)

Example 38

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(2-hydroxybenzamide)cyclohexyl)nicotinamide

To a solution of 2-hydroxybenzoic acid (27.9 mg, 0.20 mmol) in THF (1 ml) was added HOBt (37,2 mg, 0.24 mmol) and EDCl (38,8 mg, 0.20 mmol) and the mixture was stirred for 10 min at K.T. This mixture then was added to a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (120 mg, 0.20 mmol) and triethylamine (0,113 ml, 0.81 mmol) in THF (1 ml) and N-methyl-2-pyrrolidinone (3 ml). The reaction mixture was stirred at K.T. during the night. The mixture was diluted with 1 ml of water and was purified using prep. HPLC OBR is placed phases (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain an oil, which after rubbing with ether gave specified in the header connection. Yield: 58 mg

1H NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 8.43 (dd, J=19,5, 6,7 Hz, 2H), 8.26 (d, J=2,8 Hz, 1H), 8.02 (dd, J=7,9, 3.1 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.38 (t, J=7,4 Hz, 1H), 7.21 (d, J=7,7 Hz, 1H), 7.17-7.10 (m, 3H), 7.03 (d, J=15,9 Hz, 1H), 6.95-6.86 (m, 4H), 4.17-4.07 (m, 1H), 3.98-3.88 (m, 2H), 3.66-3.56 (m, 3H), 3.49-3.33 (m, 6H), 1.83-1.65 (m, 8H).

MS: [M+H]+=641,2 (RASSC.=641,2775) (multimode+)

Example 39

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-isopropylthiazole-4-carboxamid

HATU (0,064 g, 0,17 mmol) and DIPEA (0.06 ml, 0.34 mmol) was added to a solution of 2-isopropylthiazole-4-carboxylic acid (ChemBridge Corporation) (0,029 g, 0,17 mmol) in acetonitrile (4 ml). The mixture was stirred for 10 minutes, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,100 g, 0,17 mmol) and DIPEA (and 0.09 ml, 0.52 mmol) in acetonitrile (4 ml) and the reaction mixture was stirred at K.T. within 2 days. The reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic substances evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent a gradient 955% water and 0.2%TFA in acetonitrile. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 59 mg

1H NMR (400 MHz, DMSO) δ 10.00-9.61 (m, 2H), 8.38 (d, J=7,4 Hz, 1H), 8.28-8.24 (m, 1H), 8.15-8.11 (m, 1H), 8.04 (dd, J=1,9, and 7.8 Hz, 1H), 7.56 (d, J=8,2 Hz, 1H), 7.49 (t, J=7,6 Hz, 1H), 7.25-7.03 (m, 5H), 6.93-6.88 (m, 1H), 4.31-4.15 (m, 1H), 4.03-3.98 (m, 1H), 3.90-3.83 (m, 1H), 2.85-2.64 (m, 2H), 1.82-1.65 (m, 8H), 1.34 (d, J=6,8 Hz, 6N). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=674,2 (RASSC.=674,2812) (multimode+)

Example 40

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-6-hydroxyproline

EDCl (0,039 g, 0.20 mmol) and HOBt (0,034 g, 0.22 mmol) was added to a stirred suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,110 g 0,19 mmol) and 6-hydroxypyridones acid (0,031 g, 0.22 mmol) in acetonitrile (4 ml). Was added triethylamine (0,129 ml of 0.93 mmol), then the additional amount of acetonitrile (4 ml). The reaction mixture was stirred at K.T. within 2 days, then was added an additional amount of EDCl (40 mg). The reaction mixture was stirred overnight, then was added HATU (0,070 g 0,19 mmol) and the mixture was stirred over night. Added 880 ammonia and the mixture was stirred for an additional night, and then the mixture was diluted with EtOAc and prom is Wali water and saturated brine. Organic substances evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent a gradient 95-5% water and 0.2%TFA in acetonitrile. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 13 mg

1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=7,1 Hz, 1H), 8.13 (d, J=3.0 Hz, 1H), 8.06 (dd, J=3,1, 7.9 Hz, 1H), 7.67 (dd, J=7,4, and 8.4 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.27-7.11 (m, 5H), 7.06-7.04 (m, 1H), 6.92 (dd, J=2,5, and 8.4 Hz, 1H), 6.74 (d, J=8,8 Hz, 1H), 4.34 (s, 2H), 4.14-4.08 (m, 1H), 3.97-3.51 (m, 5H), 2.91-2.74 (m, 2H), 1.93-1.71 (m, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=642,2 (RASSC.=642,2728) (multimode+)

Example 41

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-hydroxyquinolin-2-carboxamide

To a solution of hydrate of 4-hydroxyquinolin-2-carboxylic acid (38,2 mg, 0.20 mmol) in N-methyl-2-pyrrolidinone (2 ml) was added HOBt (37,2 mg, 0.24 mmol) and EDCl (38,8 mg, 0.20 mmol). The mixture was stirred for 10 min at K.T. This mixture then was added to a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (120 mg, 0.20 mmol) and triethylamine (0,113 ml, 0.81 mmol) in N-methyl-2-pyrrolidinone (2 ml). The reaction mixture was premesis what does K.T. throughout the night. Prepared additional aliquot of 0.5 EQ. acid, EDCl and HOBt and then added to the reaction mixture. The mixture was diluted approximately 1 ml of water and purified by prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain the oil, the anointing which ether has been specified in the header connection. Yield: 23 mg

1H NMR (600 MHz, CD3OD) δ 8.48 (d, J=7,0 Hz, 1H), 8.23 (dd, J=8,2 Hz, 0.9 Hz, 1H), 8.15 (d, J=3.1 Hz, 1H), 8.11-8.07 (m, 1H), 7.82 (d, J=8,4 Hz, 1H), 7.77-7.73 (m, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.46 (t, J=7,6 Hz, 1H), 7.28 (dd, J=8,1 Hz, 2.2 Hz, 1H), 7.23-7.16 (m, 3H), 7.04 (d, J=2.5 Hz, 1H), 6.92 (dd, J=8,4 Hz, 2.4 Hz, 1H), 6.73 (s, 1H), 4.33 (s, 2H), 4.16 (s, 1H), 4.06-3.98 (m, 1H), 3.87-3.57 (m, 4H), 3.22-2.78 (m, 4H), 1.99-1.76 (m, 8H).

MS: [M+H]+=692,2 (RASSC.=692,2884) (multimode+)

Example 42

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-hydroxyquinolin-3-carboxamide

EDCl (0,039 g, 0.20 mmol) and HOBt (0,034 g, 0.22 mmol) was added to a stirred suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide dihydrochloride (0,110 g 0,19 mmol) and 2-hydroxyquinolin-3-carboxylic acid (Maybridge Chemical Company) (0,042 g, 0.22 mmol) in acetonitrile (4 ml). Was added triethylamine (0,129 ml of 0.93 mmol), then the additional amount of acetonitrile (4 ml). The reaction mixture was stirred at K.T. for the tion 2 days then add the additional number of EDCl (40 mg). The reaction mixture was stirred overnight, then was added HATU (0,070 g 0,19 mmol) and the mixture was stirred over night. Added 880 ammonia and the mixture was stirred for an additional night, and then the mixture was diluted with EtOAc and washed with water and saturated brine. Organic substances evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent a gradient 95-5% water and 0.2%TFA in acetonitrile. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as a pale yellow solid. Yield: 59 mg

1H NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 9.99-9.86 (m, 2H), 9.69-9.56 (m, 1H), 8.85 (s, 1H), 8.53 (d, J=7,4 Hz, 1H), 8.24 (d, J=3.1 Hz, 1H), 8.00 (dd, J=3,1, 7.9 Hz, 1H), 7.95 (d, J=7,4 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.52-7.43 (m, 2H), 7.30 (t, J=7.5 Hz, 1H), 7.23-7.01 (m, 5H), 6.95-6.87 (m, 1H), 4.33-4.21 (m, 1H), 4.03-3.92 (m, 2H), 3.80-3.67 (m, 2H), 2.79-2.65 (m, 2H), 1.80 (s, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=692,2 (RASSC.=692,2884) (multimode+)

Example 43

2-tert-butyl-N-((1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)thiazole-4-carboxamide

Stage (a) 2,2-dimethylpropanoate

The sulfide of phosphorus(V) (1,330 ml, 12,51 mmol) was added to stir suspense is and Pihlajamaa (5 g, 49,43 mmol) in tert-butyl methyl ether (100 ml) and the reaction mixture was stirred over the weekend at K.T. Mixture was filtered through celite and evaporated in vacuum to obtain specified in the subtitle compound as a yellow resinous solid. Output: 9,27,

1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.16 (s, 1H), 1.32 (s, 9H).

MS: [M+H]+=118 (multimode+)

Stage (b) ethyl-2-tert-butylthiazole-4-carboxylate

Ethyl-3-bromo-2-oxopropanoic (6,20 ml, 49,40 mmol) is carefully added to a stirred solution of 2,2-dimethylpropanamide (5,79 g, 49,40 mmol) in ethanol (60 ml). The solution is then heated under reflux for 16 hours After cooling, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and evaporated in vacuum. In the purification by chromatography on silica gel (Biotage, 100 g) with elution with a mixture of EtOAc: ISO-hexane, 1:10, has been specified in the subtitle compound as a yellow oil. Output: 6,56,

1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 4.40 (q, J=7,1 Hz, 2H), 1.48 (s, N), 1.39 (t, J=6.3 Hz, 3H).

MS: [M+H]+=214 (multimode+)

Stage (C) 2-tert-butylthiazole-4-carboxylic acid

The lithium hydroxide (2.8 g, 120,25 mmol) was added to a stirred mixture of ethyl-2-tert-butylthiazole-4-carboxylate (6,56 g, 30,76 mmol) in THF (100 ml) and water (40 ml). After 16 hours was added HCl (62.5 ml, 125 mmol) and p is the target concentrated to approximately 40 ml The reaction mixture was distributed between EtOAc and brine. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuum to obtain specified in the subtitle compound as not quite white/yellow solid. Output: 5,41,

1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 1.46 (s, 9H).

MS: [M+H]+=186 (multimode+)

Stage (d) 2-tert-butyl-N-((1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)thiazole-4-carboxamide

To a solution of 2-tert-butylthiazole-4-carboxylic acid (0,074 g, 0.40 mmol) in acetonitrile (5 ml) was added DIPEA (was 0.138 ml, of 0.79 mmol) and HATU (0,151 g, 0.40 mmol). The mixture was left to mix with K.T. within 10 minutes, after which the solution was added N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (0,19 g, 0.40 mmol) in MeCN (5 ml) with 2 EQ. DIPEA (0,139 ml of 0.79 mmol) and the mixture was stirred at K.T. during the night. Added ammonia (1 ml) and after stirring for 1 h was added water (1 ml), then the crude reaction mixture was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent a gradient 95-5% water and 0.2%TFA in acetonitrile. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the connection header in VI is e white fluffy solid. The output 174 mg.

1H NMR (300 MHz, DMSO) δ 9.44 (s, 1H), 8.40 (d, J=7,3 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.13 (s, 1H), 8.03 (dd, J=7,9, 3.1 Hz, 1H), 7.51-7.45 (m, 2H), 7.23-7.03 (m, 6N), 6.90 (dd, J=8,4, 2.4 Hz, 1H), 4.20 (d, J=4,8 Hz, 2H), 4.00 (s, 1H), 3.90 (s, 1H), 2.50 (s, 6N), 1.71 (s, 8H), 1.39 (s, 9H).

MS: [M+H]+=646 (RASSC.=646) (multimode+)

Example 44

N-((1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)benzo[d]thiazol-2-carboxamide

To a solution of benzo[d]thiazole-2-carboxylic acid (0,071 g, 0.40 mmol) in acetonitrile (5 ml) was added DIPEA (was 0.138 ml, of 0.79 mmol) and HATU (0,151 g, 0.40 mmol). The mixture was left to mix with K.T. within 10 minutes, after which the solution was added N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (0,19 g, 0.40 mmol) in MeCN (5 ml) with 2 EQ. DIPEA (0,139 ml of 0.79 mmol) and the mixture was stirred at K.T. within 2 hours was Added 1 EQ. HATU (0,151 g, 0.40 mmol) and the reaction mixture was stirred for another 1 h was Added water (1 ml), then the crude reaction mixture was purified by preparative HPLC on a column (Waters X-Bridge, using as eluent a gradient 95-5% water 0.1% ammonia in acetonitrile. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compound as a yellow fluffy solid. Yield: 33 mg

1H NMR (300 MHz, DMSO) δ 9.41 (s, 1H), 8.1 (d, J=7.5 Hz, 1H), 8.33-8.21 (m, 3H), 8.11-8.04 (m, 2H), 7.61 (t, J=7.8 Hz, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.18 (t, J=8,8 Hz, 3H), 7.05 (d, J=8,3 Hz, 1H), 6.89 (s, 1H), 6.68 (dd, J=8,5, 2.3 Hz, 1H), 4.00 (s, 1H), 3.92 (s, 1H), 3.21 (s, 2H), 2.00 (s, 6H), 1.89-1.78 (m, 4H), 1.74-1.65 (m, 4H).

MS: [M+H]+=640,1 (RASSC.=640,2394) (multimode+)

Example 45

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-methylthiazole-2-carboxamide

A solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (200 mg, 0.34 mmol), ethyl-4-methylthiazole-2-carboxylate (57,7 mg, 0.34 mmol) and triethylamine (0,094 ml, 0.67 mmol) in ethanol (1 ml) was heated to 100°C in a sealed tube in a microwave reactor for 24 hours the Mixture was purified using preparative HPLC with reversed phase (eluent = MeCN/NH3(aq.)), the appropriate fractions were combined, evaporated to obtain a white solid, which was dried over night at 40°C under vacuum and received specified in the header connection. Yield: 23 mg

1H NMR (500 MHz, CD3OD) δ 8.04 (d, J=3.1 Hz, 1H), 8.00 (dd, J=8.0 Hz, 3.0 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.30 (s, 1H), 7.18-7.15 (m, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.06 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.97 (d, J=8,3 Hz, 1H), 6.81 (d,, J=2.5 Hz, 1H), 6.60 (dd, J=8,3 Hz, 2.5 Hz, 1H), 4.08-4.04 (m, 1H), 3.92-3.87 (m, 1H), 3.44-3.41 (m, 4H), 3.25 (s, 2H), 2.33 (s, 3H), 2.17 (s, 4H), 1.86-1.72 (m, 6H), 1.69-1.62 (m, 2H).

MS: [M+H]+=646,2 (RASSC.=646,2499) (multimode+)

Example 46

N-((1s,4s)-4-(2-(4'-((1,4-oxaz the pan-4-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)-nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide hydrochloride (1.8 g, 3,66 mmol) in acetonitrile (100 ml) was added 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (to 0.645 g, 3,66 mmol) and triethylamine (5,10 ml, 36,61 mmol). With the addition of triethylamine, the reaction mixture turned into a homogeneous solution. Then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (2,448 ml of 3.84 mmol)and the mixture was stirred at K.T. during the night. The mixture is evaporated to dryness and the residue was dissolved in EtOAc (750 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain specified in the subtitle compound as a foam. Output: 1.8V,

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.08-8.06 (m, 2H), 7.90 (d, J=7.2 Hz, 1H), 7.63 (dt, J=7,1, 1,6 Hz, 1H), 7.56-7.55 (m, 1H), 7.47 (d, J=9,2 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.25-7.16 (m, 3H), 6.69 (d, J=6,7 Hz, 1H), 4.27-4.15 (m, 2H), 2.61 (s, 3H), 1.99-1.80 (m, 6H), 1.73-1.67 (m, 2H).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

The palladium acetate (0,033 g, 0.15 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,120 g, 0.29 mmol) was added to acetonitrile (22,92 ml) under nitrogen. The resulting solution was stirred in ECENA 10 minutes To this solution was added potassium carbonate (1,217 g 8,80 mmol)dissolved in water (22,92 ml), then 4-formylphenylboronic acid (0,660 g, 4.40 mmol) and N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (1.8 g, with 2.93 mmol) and the mixture was heated at 80°C for 24 h the Mixture was poured into water and was extracted with in EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow foam. It was purified using column chromatography (eluent = EtOAc), to obtain specified in the subtitle compound as a white foam. Output: 1,5,

1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.39 (ddd, J=8,0, 3,3, 0.2 Hz, 1H), 8.10-8.04 (m, 3H), 7.86 (d, J=8,2 Hz, 1H), 7.73 (d, J=8,2 Hz, 2H), 7.48 (d, J=1.8 Hz, 1H), 7.36-7.17 (m, 5H), 6.68 (dd, J=6,9, 0.8 Hz, 1H), 4.31-4.24 (m, 1H), 4.19-4.12 (m, 1H), 2.59 (s, 3H), 2.01-1.85 (m, 6H), 1.75-1.67 (m, 2H).

Stage (C) N-((1s,4s)-4-(2-(4'-((1,4-oxazepan-4-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of hydrochloride homomorpholine (52,3 mg, 0.38 mmol) in DCM (3 ml) was added triethylamine (or 0.035 ml, 0.25 mmol). The mixture was left to mix with K.T. within 10 minutes, after which was added N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.25 mmol). After 40 minutes was added triacetoxyborohydride sodium (81 mg, 0.38 mmol) and the reaction mixture AC is stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain foam. It was purified using prep. HLPC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined, evaporated and the residue triturated with ether to obtain a solid substance. This solid was dried over night at 40°C under vacuum to obtain specified in the connection header. Yield: 93 mg

1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=7.7 Hz, 1H), 8.32 (dd, J=8,2, 3.1 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 8.03 (d, J=9,2 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.71-7.63 (m, 3H), 7.52 (t, J=7.8 Hz, 1H), 7.48-7.45 (m, 3H), 7.41 (t, J=1.9 Hz, 1H), 7.22-7.18 (m, 1H), 7.09 (d, J=6,9 Hz, 1H), 4.36-3.19 (m, 14H), 2.75 (s, 3H), 1.96-1.83 (m, 8H).

MS: [M+H]+=677,2 (RASSC.=677,3251) (multimode+)

Example 47

N-((1s,4s)-4-(2-(4'-((dimethylamino)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carbox-amide (150 mg, 0.25 mmol) in DCM (3 ml) was added dimethylamine, 2 M solution in MTBE (0,190 ml, 0.38 mmol). The mixture was left to mix with K.T. for 40 minutes, then added triacetoxyborohydride sodium (81 mg, 0.38 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO ) and evaporated to obtain foam. This foam is then purified using preparative HPLC with a reversed phase (eluent = TFA (aq.)/MeCN). The appropriate fractions were combined, evaporated and the residue triturated with ether to obtain specified in the connection header in the form of solids. Yield: 89 mg

1H NMR (400 MHz, CDCl3) δ 8.33 (dd, J=8,1, 3.2 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.68-7.64 (m, 2H), 7.64-7.60 (m, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.49-7.45 (m, 3H), 7,42 (t, J=1.9 Hz, 1H), 7.22-7.18 (m, 1H), 7.04 (d, J=6,9 Hz, 1H), 4.28 (s, 1H), 4.19 (s, 2H), 4.06-3.92 (m, 1H), 2.78 (s, 6H), 2.74 (s, 3H), 1.96-1.82 (m, 8H).

MS: [M+H]+=621,1 (RASSC.=621,2989) (multimode+)

Example 48

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.25 mmol) in DCM (3 ml) was added (2S,6R)-2,6-dimethylpiperazine (43,4 mg, 0.38 mmol). The mixture was left to mix with K.T. for 40 minutes, then added triacetoxyborohydride sodium (81 mg, 0.38 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain foam. This foam was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN). According to dtweedie fractions were combined, evaporated and the residue triturated with ether to obtain a solid substance. This solid was dried over night at 40°C To produce specified in the connection header. Output: 131 mg.

1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=7,4 Hz, 1H), 8.31 (dd, J=8,2, 3.1 Hz, 1H), 8.24 (s, 1H), 8.08-8.04 (m, 2H), 7.98 (d, J=7,4 Hz, 1H), 7.79-7.73 (m, 1H), 7.65 (d, J=8,2 Hz, 2H), 7.53-7.45 (m, 3H), 7.41 (t, J=1.8 Hz, 1H), 7.19-7.16 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 4.30-4.27 (m, 1H), 4.22-4.15 (m, 3H), 3.84-3.77 (m, 2H), 3.41 (d, J=10.5 Hz, 2H), 3.26 (d, J=12.3 Hz, 2H), 2.77 (s, 4H), 1.95-1.84 (m, 8H), 1.34 (d, J=6.4 Hz, 6H).

MS: [M+H]+=690,2 (RASSC.=690,3568) (multimode+)

Example 49

5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(1-methyl-1H-pyrazole-3-carboxamido)cyclohexyl)nicotinamide

HATU (0,141 g and 0.37 mmol) was added to a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (0,042 g, 0.34 mmol), N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide 2HCl (0.2 g, 0.34 mmol) and DIPEA (0,235 ml, 1.35 mmol) in DMF (5 ml) and the solution was stirred at K.T. within 20 hours the Reaction mixture was treated with a mixture of 7 M NH3/Meon (1 ml) and was stirred for 1 h and evaporated in vacuo, and the remaining DMF solution was purified by HPLC with reversed phase with a mixture of aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Output: 169 mg.

1H NMR (300 MHz, DMSO) δ 8.34 (m, 1H), 8.26 (m, 1H), 8.04 (m, 1 is), 7.77 (m, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.19-7.10 (m, 3H), 7.07 (m, 1H), 6.92 (m, 1H), 6.60 (m, 1H), 4.44-3.46 (m, 6H), 4.24 (s, 2H), 3.87 (s, 3H), 3.28-2.48 (m, 4H), 1.87-1.56 (m, 8H).

MS: APCI (+ve): 629 (M+1)

Example 50

N-((1s,4s)-4-(5-fluoro-2-(4'-(pyrrolidin-1-ylmethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.25 mmol) in DCM (3 ml) was added pyrrolidine (to 0.032 ml, 0.38 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (81 mg, 0.38 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain specified in the connection header in the form of foam. Yield: 97 mg

1H NMR (400 MHz, CDCl3) δ 13.08 (s, 1H), 8.33 (dd, J=8,2, 3.1 Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 8.00 (d, J=7,4 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.65-7.58 (m, 3H), 7.54-7.45 (m, 4H), 7.40 (t, J=1.9 Hz, 1H), 7.20 (ddd, J=7,9, 2,3, 1.0 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.30-3.95 (m, 4H), 3.72-3.65 (m, 2H), 2.91-2.83 (m, 2H), 2.73 (s, 3H), 2.19-2.11 (m, 2H), 2.08-1.99 (m, 2H), 1.95-1.82 (m, 8H).

MS: [M+H]+=647,1 (RASSC.=647,3146) (multimode+)

Example 51

N-((1s,4s)-4-(5-fluoro-2-(4'-(((2-hydroxyethyl)(methyl)amino)methyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]-pyridine-2-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.25 mmol) in DCM (3 ml) was added 2-(methylamino)ethanol (0,030 ml, 0.38 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (81 mg, 0.38 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain specified in the connection header in the form of foam. Yield: 36 mg

1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=7,4 Hz, 1H), 8.32 (dd, J=8,2, 3.1 Hz, 1H), 8.20 (s, 1H), 8.07-8.02 (m, 2H), 7.99 (d, J=7,4 Hz, 1H), 7.72-7.65 (m, 3H), 7.54-7.46 (m, 4H), 7.43 (d, J=1.8 Hz, 1H), 7.20 (d, J=8,1 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 4.31-4.15 (m, 6H), 3.97 (t, J=4.6 Hz, 2H), 2.86 (s, 3H), 2.75 (s, 3H), 1.96-1.84 (m, 8H).

MS: [M+H]+=651,1 (RASSC.=651,3095) (multimode+)

Example 52

N-((1s,4s)-4-(2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid

DIPEA (of 0.081 ml, 0.46 mmol) and HATU (0,176 g, 0.46 mmol) was added to 1H-benzo[d]imidazole-4-carboxylic acid (Apollo Scientific Limited) (0.075 g, 0.46 mmol) in acetonitrile (1 ml). The mixture was stirred for 10 min, then the solution was added DIPEA (of 0.081 ml, 0.46 mmol) and N-((1s,4s)-4-aminocyclohexane)-2-(2'-((dimethylamino)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline dihydrochloride (of 0.085 g, 0.15 in the mol) in acetonitrile (1 ml). After 6 hours, to the reaction mixture was added an additional amount of acid (30 mg), activated with HATU (60 mg) and DIPEA (0.05 ml) in acetonitrile (1,000 ml). The mixture was stirred overnight, then was added 880 ammonia (2 ml) and the reaction mixture was stirred for 4 h the Reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic substances evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using as eluent a gradient 95-5% water and 0.2%TFA in acetonitrile. The fractions containing the target compound evaporated to dryness to obtain specified in the title compound as a white foam. Yield: 61 mg

1H NMR (400 MHz, DMSO) δ 9.96-9.67 (m, 2H), 9.45-9.31 (m, 1H), 8.56-8.48 (m, 2H), 8.25 (d, J=3.0 Hz, 1H), 8.01 (dd, J=7,9, 3.0 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.25-7.19 (m, 1H), 7.16-7.06 (m, 3H), 7.02-7.00 (m, 1H), 6.89 (dd, J=8,4, 2.4 Hz, 1H), 4.22-4.13 (m, 2H), 4.07-3.95 (m, 2H), 1.86-1.70 (m, 8H). The remaining protons obscured the peaks of the solvent.

MS: [M+H]+=623,2 (RASSC.=623,2782) (multimode+)

Example 53

N-((1s,4s)-4-(2-(4'-((dimethylamino)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

The palladium acetate (0,00 g, 0.22 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,184 g, 0.45 mmol) under nitrogen were added to acetonitrile (35,0 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (sm 1,857 g, 13,44 mmol)dissolved in water (35,0 ml)and then 4-formylphenylboronic acid (1,007 g, 6,72 mmol) and N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (2.6 g, 4,48 mmol) and the mixture was heated at 80°C for 2 hours the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to obtain a light brown foam. It was purified using column chromatography (eluent = 80% EtOAc:hexane to pure EtOAc) to obtain specified in the subtitle compound as a white foam. Output 2,13,

1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.39 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 8.04 (d, J=6,9 Hz, 1H), 7.94-7.90 (m, 3H), 7.74 (d, J=8,2 Hz, 2H), 7.60-7.57 (m, 2H), 7.46 (t, J=1.3 Hz, 1H), 7.25-7.23 (m, 1H), 7.21-7.16 (m, 1 H), 4.30-4.22 (m, 1H), 4.10-4.03 (m, 1H), 2.60 (s, 3H), 1.99-1.78 (m, 6H), 1.73-1.59 (m, 2H).

MS: [M+H]+=559 (multimode+).

Stage (b) N-((1s,4s)-4-(2-(4'-((dimethylamino)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide triptorelin

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (150 mg, 0.27 mmol) in DCM (3 ml) was added dimethylamine, 2 M rest the p in MTBE (methyl tert-butyl ether, 0,201 ml, 0.40 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain a colorless glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 109 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.91 (s, 1H), 7.67-7.62 (m, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.53-7.47 (m, 3H), 7.39 (t, J=1.9 Hz, 1H), 7.23-7.19 (m, 2H), 4.29-4.21 (m, 1H), 4.20 (s, 2H), 4.13-4.04 (m, 1H), 2.80 (s, 6H), 2.64 (s, 3H), 1.98-1.75 (m, 6H), 1.73-1.57 (m, 2H).

MS: [M+H]+=588,3 (RASSC.=588,2444) (multimode+)

Example 54

N-((1s,4s)-4-(2-(4'-(((38,5P)for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (150 mg, 0.27 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (46,0 mg, 0.40 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4and viparita is getting yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 88 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 8.03 (d, J=6,9 Hz, 1H), 7.91 (s, 1H), 7.65-7.48 (m, 3H), 7.44 (d, J=8,2 Hz, 2H), 7.37 (s, 1H), 7.24-7.17 (m, 2H), 4.24 (br s, 1H), 4.14-3.97 (m, 3H), 3.67 (br s, 2H), 3.35-3.17 (m, 2H), 3.01 (t, J=12.0 Hz, 2H), 2.64 (s, 3H), 2.00-1.74 (m, 6H), 1.73-1.56 (m, 2H), 1.38-1.23 (m, 8H).

MS: [M+H]+=657,3 (RASSC.=657,3023) (multimode+)

Example 55

N-((1s,4s)-4-(2-(4'-((1,4-oxazepan-4-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)-nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (150 mg, 0.27 mmol) in DCM (3 ml) were added hydrochloride 1,4-oxazepan (55,4 mg, 0.40 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain a white foam. It was purified by HPLC to obtain specified in the connection header. Yield: 75 mg

1H NMR (400 MHz, DMSO) δ 8.35 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.08 (s, 1H), 8.06 (dd, J=8,1, 3.2 Hz, 1H), 7.77 (d, J=8,2 Hz, 2H), 7.64-7.51 (m, 6H), 7.26-7.22 (m, 1H), 4.41 (d, J=4,1 Hz, 2H), 4.01 (br s, 1H), 3.92-3.81 (m, 2H), 3.81-3.64 (m, 3H), 3.55-3.43 (m, 1H), 3.43-3.33 (m, 1H), 3.31-3.19 (m, 2H) 2.65 (s, 3H), 2.16-1.98 (m, 2H), 1.83-1.58 (m, 8H).

MS: [M+H]+=644,3 (RASSC.=644,2707) (multimode+)

Example 56

N-((1s,4s)-4-(5-fluoro-2-(2'-hydroxy-4'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

A solution of potassium carbonate (0,643 g and 4.65 mmol) in water (4.5 ml), 3-hydroxy-4-identilied (0,385 g, 1.55 mmol) and N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)-cyclohexyl)-2-methylthiazole-4-carboxamide (0.9 g, 1.55 mmol) were added sequentially to a stirred solution of palladium(II) acetate (0,035 g, 0.16 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (to 0.127 g, 0.31 mmol) in acetonitrile (6.0 ml) and heated at 70°C for 1 h the Mixture was cooled to K.T., was extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with a mixture of 50% EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a pale brown solid. Yield: 139 mg

1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.91 (s, 1H), 8.34 (d, J=7.7 Hz, 1H), 8.26 (d, J=3.2 Hz, 1H), 8.07 (s, 1H), 8.03 (m, 1H), 7.58 (d, J=8,3 Hz, 1H), 7.51-7.44 (m, 4H), 7.41-7.37 (m, 2H), 7.19 (m, 1H), 4.01 (m, 1H), 3.86 (m, 1H), 2.62 (s, 3H), 1.81-1.62 (m, 8H).

MS:APCI (+ve) 575 (M+1).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(2'-hydroxy-4'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamidotryptamine

N-((1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-hydroxybiphenyl-3-yloxy)-nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (65 mg, 0.11 mmol), morpholine (at 0.020 ml, 0.23 mmol) and acetic acid (0,013 ml, 0.23 mmol) was dissolved in DCM (5 ml) and was stirred for 10 minutes was Added triacetoxyborohydride sodium (47,9 mg, 0.23 mmol) and the mixture was stirred for another 1 h, the Reaction mixture was diluted with DCM (50 ml), washed with saturated NaHCO3(aq.) and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by HPLC with reversed phase with a mixture of MeCN/aq. TFA as eluent to obtain specified in the title compounds as white solids. Yield: 27 mg

1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 9.90 (s, 1H), 8.34 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.3 Hz, 1H), 8.08 (s, 1H), 8.03 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.15 (m, 1H), 7.03-6.95 (m, 2H), 4.34-4.22 (m, 2H), 4.05-3.82 (m, 4H), 3.69-3.56 (m, 2H), 3.35-3.04 (m, 4H), 2.66 (s, 3H), 1.80-1.62 (m, 8H).

MS: APCI (+ve): 646 (M+1).

Example 57

N-((1s,4s)-4-(5-fluoro-2-(2'-hydroxy-4'-(piperazine-1-ylmethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-hydroxybiphenyl-3-yloxy)-nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (65 mg, 0.11 mmol), PIP is Razin (of 48.7 mg, of 0.57 mmol) and acetic acid (to 0.032 ml, or 0.57 mmol) was dissolved in DCM (5 ml) and was stirred for 10 minutes was Added triacetoxyborohydride sodium (47,9 mg, 0.23 mmol) and the mixture was stirred for a further 1 h the Reaction mixture was diluted with DCM (50 ml), washed with saturated NaHCO3(aq.) and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by HPLC with reversed phase with a mixture of MeCN/aq. TFA as eluent to obtain specified in the title compounds as white solids. Yield: 22 mg

1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.34 (d, J=7.2 Hz, 1H), 8.25 (d, J=3.1 Hz, 1H), 8.08 (s, 1H), 8.03 (m, 1H), 7.59 (d, J=8,2 Hz, 1H), 7.46-7.38 (m, 2H), 7.34 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13 (m, 1H), 6.92 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.00 (m, 1H), 3.87 (m, 1H), 3.79-3.55 (m, 2H), 3.16 (m, 4H), 2.85-2.68 (m, 4H), 2.65 (s, 3H), 1.79-1.61 (m, 8H).

MS: APCI (+ve) 645 (M+1).

Example 58

N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

Stage (a) Ethyl-2-(pivaloyloxymethyl)thiazole-4-carboxylate

2-Amino-2-taxative (3.0 g, 17,12 mmol) and 3-bromo-2-oxopropanoic acid (3,14 g, 18,83 mmol) was dissolved in EUN (20 ml), was added 4Å molecular sieves and the reaction mixture was heated under reflux for 20 h, then was cooled to K.T., was filtered, washed with EtOH and evaporated in vacuum. The remaining semi-solid substances is about treated with a mixture of 50% EtOAc/DCM and the resulting light brown solid was filtered. The filtrate is evaporated in vacuum and the residue was purified by chromatography on silica with a mixture of 20% EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a pale yellow oil. Output: 2,47,

1H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 5.40 (s, 2H), 4.30 (q, J=7,1 Hz, 2H), 1.30 (t, J=7,3 Hz, 3H), 1.20 (s, 9H).

MS: APCI (+ve) 272 (M+1).

Stage (b) 2-(hydroxymethyl)thiazole-4-carboxylic acid

NaOH solution (1,769 g, 44,23 mmol) in water (20,0 ml) was added to a stirred solution of ethyl-2-(pivaloyloxymethyl)thiazole-4-carboxylate (2.4 g, cent to 8.85 mmol) in a mixture of THF (20 ml) and Meon (10.0 ml) and the reaction mixture was stirred for 72 h was Acidified With 2 M HCl (10 ml) and evaporated in vacuo to obtain crude 2-(hydroxymethyl)thiazole-4-carboxylic acid as a white solid. Was purified by chromatography with reversed phase with a mixture of MeCN/aq. TFA as eluent to obtain specified in the subtitle compound as a white solid. Output: 1,4,

1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 4.73 (s, 2H).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamidotryptamine

DCC (N,N-dicyclohexylcarbodiimide, 0,063 g, 0.30 mmol) was added to a solution of 2-(hydroxymethyl)thiazole-4-carboxylic acid (0,044 g, 0.28 mmol) and HOBt (0,048 g, 0.30 mmol) in DMF (3 ml) and the AC is stirred for 10 minutes Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (0.15 g, 0.25 mmol) and DIPEA (0,088 ml, 0.51 mmol) in DMF (2 ml) and the reaction mixture was stirred for 20 hours the Mixture is evaporated in vacuum and the remaining DMF solution was purified by HPLC with reversed phase with a mixture of aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 82 mg

1H NMR (400 MHz, DMSO) δ 10.18-9.91 (m, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.18 (s, 1H), 8.04 (m, 1H), 7.60 (d, J=8,2 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.19-7.08 (m, 4H), 6.92 (d, J=8,2 Hz, 1H), 4.74 (s, 2H), 4.38-3.47 (m, 9H), 3.23-3.02 (m, 2H), 2.78-2.58 (m, 2H), 1.81-1.57 (m, 8H).

MS: APCI (+ve) 662 (M-1).

Example 59

3'-(5-fluoro-3-((1s,4s)-4-(5-methylimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylic acid

Stage (a) methyl-3-(morpholinomethyl)-4-(tripterocalyx)benzoate

To a suspension of the hydrochloride of methyl-4-hydroxy-3-(morpholinomethyl)benzoate (4 g, 13,90 mmol) in DMF (25 ml) was added triethylamine (of 6.78 ml, 48,66 mmol). The mixture was bought beige color and the suspension changed shape, but was not transparent and was turned into a homogeneous solution. To this suspension is cooled to 5°C. then was added 1,1,1-Cryptor-N-phenyl-N-(trifloromethyl)methanesulfonamide (of 10.93 g, 30,58 mmol who). The ice bath was removed and the mixture was stirred at K.T. during the night. The mixture was poured into water (400 ml) and podslushivaet using saturated NaHCO3(aq.). Organic matter was extracted into ether (×3), combined, washed with brine, dried (MgSO4) and evaporated to obtain white solids. The crude product was purified using column chromatography (eluent = 20% EtOAc in hexane), to obtain specified in the subtitle compound as a white solid. Output: 3,9,

1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=2.1 Hz, 1H), 8.05 (dd, J=8,6, 2.2 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 3.95 (s, 3H), 3.70 (t, J=4.6 Hz, 4H), 3.58 (s, 2H), 2.46 (t, J=4.6 Hz, 4H).

Stage (b) methyl-3'-(3-((1s,4s)-4-(tert-butoxycarbonyl-amino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylate

In a test tube for microwave reactor was loaded acetonitrile (2 ml), then tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (1 g, of 1.80 mmol), methyl-3-(morpholinomethyl)-4-(tripterocalyx)benzoate (0,690 g of 1.80 mmol), potassium carbonate (0,746 g, 5.40 mmol), water (2 ml), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,074 g, 0.18 mmol) and finally palladium acetate (0,020 g, 0.09 mmol). The mixture was heated in a microwave reactor at 80°C for 1 h the Mixture was diluted with EtOAc and then washed with NaHCO3(aq.), brine, with the sewed (MgSO 4) and evaporated to obtain an oil. It was purified using column chromatography (eluent = mixture 1:1 hexane:EtOAc), to obtain specified in the subtitle compound as oil. Yield: 650 mg

MS: [M+H]+=663 (multimode+).

Stage (C) methyl-3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylate the dihydrochloride

To a solution of methyl-3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylate (,6 g of 0.91 mmol) in DCM (5 ml) was added hydrogen chloride, 4.0 M solution in dioxane (3,39 ml of 13.58 mmol). The mixture was stirred at K.T. within 3 days. The mixture was concentrated in vacuo and the residue triturated with ether. The ether was removed under vacuum and the result has been mentioned in the subtitle compound as a pale yellow solid. Yield: 0.52 g

MS: [M+H]+=563 (multimode+).

Stage (d) 3'-(5-fluoro-3-((1s,4s)-4-(5-methylimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylic acid

To a suspension of the hydrochloride of methyl-3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)-2-(morpholinomethyl)biphenyl-4-carboxylate (150 mg, 0.25 mmol) and 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (to 44.1 mg, 0.25 mmol) in acetonitrile (4 ml) was added triethylamine (0,349 ml of 2.50 mmol). A mixture of p is remedial when K.T. until then, until it became homogeneous. To this solution is then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (0,167 ml, 0.26 mmol). The mixture was stirred at room temperature for one hour. To this mixture was then added lithium hydroxide (0,024 ml of 2.50 mmol), water (1 ml) and methanol (1 ml). The mixture was placed in a test tube for microwave reactor and heated up to 80°C for 30 minutes the Mixture was purified using prep. HPLC with reversed phase (eluent = a mixture of TFA (aq.)/MeCN), the appropriate fractions were combined, evaporated and the residue triturated with ether to obtain a white solid, which was dried overnight under vacuum to obtain specified in the connection header. Yield: 105 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.14 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 2H), 7.67-7.56 (m, 3H), 7.49 (d, J=8,2 Hz, 1H), 7.33 (ddd, J=7,8, 2,1, 0.3 Hz, 1H), 7.27-7.23 (m, 2H), 7.11 (d, J=6,9 Hz, 1H), 4.48 (s, 2H), 4.12 (s, 1H), 4.06 (s, 1H), 3.78-3.63 (m, 4H), 3.13-2.90 (m, 4H), 2.72 (s, 3H), 1.96-1.79 (m, 8H).

MS: [M+H]+=707,2 (RASSC.=707,2993) (multimode+).

Example 60

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (150 mg, 0.27 mmol) in DCM (3 ml) was added 1-methyl-1,4-diazepan (0,050 ml, 0.40 mmol). With the ect was left to mix with K.T. within 40 min, then was added triacetoxyborohydride sodium (85 mg, 0.40 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain a colorless glass. It was purified by HPLC to obtain specified in the connection header. Yield: 20 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,1, 3.2 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 8.03 (d, J=7,4 Hz, 1H), 7.91 (s, 1H), 7.65-7.44 (m, 6H), 7.40-7.34 (m, 1H), 7.20 (d, J=7.9 Hz, 2H), 4.24 (br s, 1H), 4.18-4.03 (m, 3H), 3.83-3.20 (m, 8H), 2.87 (s, 3H), 2.64 (s, 3H), 2.48 (br s, 2H), 1.98-1.75 (m, 6H), 1.73-1.57 (m, 2H).

MS: [M+H]+=657,3 (RASSC.=657,3023) (multimode+).

Example 61

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide hydrochloride

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)-nicotinamide)cyclohexylcarbamate (5.29 g, 9,52 mmol) in DCM (35 ml) was added 4.0 M hydrogen chloride in dioxane (23,81 ml, 95,25 mmol). The mixture was stirred at K.T. within 24 hours the Mixture is evaporated to dryness to obtain specified in the subtitle compound as a white solid. Output: 4,56,

MS: [M+H]+=456 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-what advanace)nicotinamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide hydrochloride (1.5 g, of 3.05 mmol) in acetonitrile (100 ml) was added 1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (1,069 g, 7,63 mmol) and triethylamine (4,25 ml, 30,50 mmol). Then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (TR) (of 5.83 ml, to 9.15 mmol) and the mixture was stirred at K.T. within 2 hours the Mixture is evaporated to dryness and the residue was dissolved in DCM (150 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain foam. The product was purified using column chromatography (eluent = pure EtOAc), to obtain specified in the subtitle compound as a white foam. Yield: 1.04 g

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 7.87 (d, J=6,7 Hz, 1H), 7.64 (dt, J=7,5, 1.5 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.22-7.14 (m, 2H), 6.69 (d, J=7.7 Hz, 1H), 6.53 (s, 1H), 4.26-4.17 (m, 1H), 4.12-4.03 (m, 1H), 3.78 (s, 3H), 2.28 (s, 3H), 1.95-1.73 (m, 6H), 1.67-1.58 (m, 2H).

MS: [M+H]+=578 (multimode+).

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide

1,1'-Bis(diphenylphosphino)ferrocene (0,050 g, 0.09 mmol) and DCM complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0,074 g, 0.09 mmol) was stirred under nitrogen in dry dimethylsulfoxide (5 ml) for 10 minutes was Added potassium acetate (0,530 g, 5.40 mmol), N-((1s,4s)-4-(1,5-di is ethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3 iodinate)-nicotinamide (1.04 g, of 1.80 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,608 g is 2.40 mmol) and the reaction mixture was heated at 80°C during the night. The reaction mixture was cooled and was diluted with water (100 ml). The suspension was stirred at K.T. for 30 minutes, then the precipitate was filtered. The residue was dissolved in DCM, dried (MgSO4) and the solvent was removed to obtain a brown oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as an orange foam. Output: 0,81,

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,3, 3.2 Hz, 1H), 8.10-8.04 (m, 2H), 7.74 (dd, J=6,4, 1.0 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.29 (ddd,J=8,1, 2,5, 1.1 Hz, 1H), 6.65 (d, J=7,4 Hz, 1H),6.51 (s, 1H), 4.26-4.17 (m, 1H), 4.11-4.03 (m, 1H), 3.75 (s, 3H), 2.27 (s, 3H), 1.94-1.73 (m, 6H), 1.67-1.56 (m, 2H), 1.32 (s, 12H).

MS: [M+H]+=578 (multimode+).

Stage (d) 4-bromo-2-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)phenol

To a solution of 5-bromo-2-hydroxybenzaldehyde (1 g, equal to 4.97 mmol) in DCM (50 ml) was added (2R,6S)-2,6-dimethylpiperazine (0,852 g, 7,46 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (1,582 g, 7,46 mmol). The reaction mixture was stirred at K.T. within 24 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain a white foam. It was purified using the Biotage (eluent = 2.5% of 7 M ammonia in a mixture of methane is/DCM) to obtain specified in the subtitle compound as a white solid. Output: 1,32,

1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J=8,7, 2.3 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 3.64 (s, 2H), 3.00-2.90 (m, 2H), 2.87-2.80 (m, 2H), 1.74 (t, J=10,9 Hz, 2H), 1.05 (d, J=6,4 Hz, 6N).

MS: [M+H]+=300 (multimode+).

Stage (e) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)-methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating

In a test tube for microwave reactor was loaded acetonitrile (2 ml), then N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide (100 mg, 0,17 mmol), 4-bromo-2-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)phenol (51,8 mg, 0,17 mmol), potassium carbonate (71,8 mg, 0.52 mmol), water (2 ml), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7 mg, 0.02 mmol) and finally palladium acetate (2 mg, 8,66 Microm). The mixture was heated in a microwave reactor at 80°C for 1 h the Mixture was diluted with EtOAc and then washed with NaHCO3(aq.), brine, dried (MgSO4) and evaporated to a yellow oil. It was purified by HPLC to obtain specified in the title compounds as white solids. Output: 7,5 mg

1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=7,4 Hz, 1H), 8.13 (d, J=3.1 Hz, 1H), 8.08 (dd, J=7,9, or 2.9 Hz, 1H), 7.49-7.41 (m, 5H), 7.37-7.34 (m, 1H), 7.12 (d, J=7,6 Hz, 1H), 6.86 (d, J=8,8 Hz, 1H), 6.42 (s, 1H), 4.16-4.10 (m, 1H), 3.98-3.91 (m, 1H), 3.86 (s, 2H), 3.72 (s, 3H), 3.51-3.40 (m, 3H), 2.34-2.25 (m, 6H), 1.92-1.77 (m, 6H), 1.74-1.63 (m, 2H), 1.29 (d, J=6.6 Hz, 8H).

MS: [M+H]+=670,3 (RASSC.=670,3517) (multimode+).

Example 62

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-formylphenyl-3-yloxy)-nicotinamide

The palladium acetate (a 4.86 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17,78 mg, 0.04 mmol) under nitrogen were added to acetonitrile (3,38 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (180 mg, of 1.30 mmol)dissolved in water (3,38 ml), then 4-formylphenylboronic acid (97 mg, of 0.65 mmol) and N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (250 mg, 0.43 mmol) and the mixture was heated at 80°C for 2 h, the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. It was purified using column chromatography (eluent = pure EtOAc), to obtain specified in the subtitle compound as a white foam. Output: 187 mg.

1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.39 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 8.04 (d, J=6,9 Hz, 1H), 7.92-7.88 (m, 2H), 7.76-7.72 (m, 2H), 7.62-7.55 (m, 2H), 7.47-7.45 (m, 1H), 7.25-7.20 (m, 1H), 6.67 (d, J=7,4 Hz, 1H), 6.51 (s, 1H), 4.30-4.27 (m, 1H), 4.10-4.01 (m, 1H), 3.66 (s, 3H), 2.26 (s, H), 1.98-1.76 (m, 6H), 1.70-1.56 (m, 2H).

MS: [M+H]+=556 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-formylphenyl-3-yloxy)-nicotinamide (150 mg, 0.27 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (46.2 mg, 0.40 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (86 mg, 0.40 mmol). The reaction mixture was stirred at K.T. during the night. The mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 107 mg

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 8.00 (d, J=6,9 Hz, 1H), 7.63 (d, J=8,2 Hz, 2H), 7.59-7.43 (m, 4H), 7.39-7.35 (m, 1H), 7.22-7.17 (m, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.49 (s, 1H), 4.25-4.17 (m, 1H), 4.11 (s, 1H), 4.09-4.01 (m, 1H), 3.76-3.66 (m, 4H), 3.31 (d, J=10,8 Hz, 2H), 3.15 (t, J=12.0 Hz, 2H), 2.26 (s, 3H), 1.95-1.74 (m, 6H), 1.69-1.57 (m, 2H), 1.33 (d, J=6,4 Hz, 6N).

MS: [M+H]+=654,4 (RASSC.=654,3568) (multimode+).

Example 63 N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(methoxymethyl)thiazole-4-carboxamide

Stage (a) 2-(methoxymethyl)thiazo the-4-carboxylic acid

Sodium hydride (0,151 g of 3.77 mmol) was added to a solution of 2-(hydroxymethyl)thiazole-4-carboxylic acid (0.2 g, of 1.26 mmol) in DMF (2 ml) and was stirred for 20 minutes was Added methyliodide (0,236 ml of 3.77 mmol) and the reaction mixture was stirred for another 2 hours was Added water (2 ml), then NaOH (0,251 g, 6,28 mmol) and was stirred for 20 hours the Reaction mixture was heated at 60°C for 5 h, then was cooled to K.T., acidified using 2 M HCl and purified by HPLC with reversed phase with a mixture of MeCN/aq. TFA as eluent to obtain specified in the subtitle compound as a white solid. Yield: 31 mg

MS: APCI (+ve) 174 (M+1).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(methoxymethyl)thiazole-4-carboxamide

DCC (0,042 g, 0.20 mmol) was added to a solution of 2-(methoxymethyl)thiazole-4-carboxylic acid (0,029 g, 0,17 mmol) and HOBt (0,032 g, 0.20 mmol) in DMF (2 ml) and was stirred for 10 minutes and Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (0.1 g, 0,17 mmol) and DIPEA (0,059 ml, 0.34 mmol) in DMF (1 ml) and the reaction mixture was stirred for 20 hours the Mixture is evaporated in vacuum and the remaining DMF solution was purified by HPLC with reversed phase with a mixture of aq. TFA/MeCN as eluent to obtain specified in the title compounds as white is on solids. Yield: 17 mg

1H NMR (400 MHz, DMSO) δ 8.33 (d, J=7,3 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.25 (s, 1H), 8.04 (m, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.26-6.85 (m, 6H), 4.70 (s, 2H), 4.38-4.17 (m, 1H), 3.99 (m, 1H), 3.87 (m, 1H), 3.82-3.03 (m, 7H), 3.41 (s, 3H), 2.81-2.48 (m, 2H), 1.81-1.60 (m, 8H).

MS: APCI (+ve) 676 (M+1).

Example 84

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (150 mg, 0.25 mmol) in DCM (3 ml) was added 1-methyl-1,4-diazepan (0,047 ml, 0.38 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (81 mg, 0.38 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain foam. This foam was purified using prep. HPLC with reversed phase (eluent = a mixture of TFA (aq.)/MeCN). The appropriate fractions were combined, evaporated and the residue triturated with ether to obtain a solid substance. This compound is then purified by prep. HPLC with reversed phase (eluent = mixture of NH3(aq.)/MeCN). The appropriate fractions were combined and the residue triturated with ether to obtain a solid substance. This solid was dried over night at 40°C is obtaining specified in the connection header. Yield: 31 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.05 (m, 3H), 7.56-7.50 (m, 4H), 7.41-7.32 (m, 5H), 7.22-7.14 (m, 2H), 6.67 (d, J=6,9 Hz, 1H), 4.28-4.21 (m, 1H), 4.20-4.14 (m, 1H), 2.75-2.69 (m, 6H), 2.66-2.63 (m, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 1.98-1.64 (m, 12H).

MS: [M+H]+=690,3 (RASSC.=690,3568) (multimode+).

Example 65

N-((1s,4s)-4-(2-(3'-(((SP,58)for 3,5-dimethylpiperazine-1-yl)methyl)-5'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

The palladium acetate (a 3.87 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14,14 mg, 0.03 mmol) under nitrogen were added to acetonitrile (4 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (143 mg, of 1.03 mmol)dissolved in water (4 ml), then N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (200 mg, 0.34 mmol) and 3-bromo-5-hydroxybenzaldehyde (or 69.3 mg, 0.34 mmol) and the mixture was heated at 80°C for 2 hours the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to obtain a brown oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified under the head connection in the form of a white foam. Yield: 102 mg

MS: [M+H]+=575 (multimode+).

Stage (b) N-((1s,4s)-4-(2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-5'-hydroxybiphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (104 mg, 0.18 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (31,0 mg, 0.27 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (of 57.5 mg, 0.27 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the connection header. Yield: 29 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7,3 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.06 (dd, J=8,0, 3.1 Hz, 1H), 7.96 (s, 1H), 7.80-7.75 (m, 1H), 7.51-7.42 (m, 2H), 7.37-7.35 (m, 1H), 7.18-7.15 (m, 1H), 7.03 (s, 1H), 6.94 (t, J=2.0 Hz, 1H), 6.76 (s, 1H), 4.16-4.10 (m, 1H), 3.98-3.91 (m, 1H), 3.61 (s, 2H), 3.42-3.32 (m, 2H), 3.12-3.07 (m, 3H), 2.62 (s, 3H), 2.12 (t, J=11.8 Hz, 2H), 1.91-1.78 (m, 6H), 1.76-1.64 (m, 2H), 1.25 (d, J=6,7 Hz, 6H).

MS: [M+H]+=673,3 (RASSC.=673,2972) (multimode+).

Example 66

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-5'-hydroxybiphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-p is razol-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamide

The palladium acetate (3,89 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14,22 mg, 0.03 mmol) under nitrogen were added to acetonitrile (4 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (144 mg, 1.04 mmol)dissolved in water (4 ml), then N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)phenoxy)nicotinamide (200 mg, 0.35 mmol) and 3-bromo-5-hydroxybenzaldehyde (to 69.6 mg, 0.35 mmol) and the mixture was heated at 80°C for 2 hours the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to obtain a light brown foam. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as a white foam. Yield: 144 mg

MS: [M+H]+=572 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-5'-hydroxybiphenyl-3-yloxy)-5-fornicating

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamide (159 mg, 0.28 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (47,6 mg, 0.42 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxy the sodium hydride (88 mg, 0.42 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 65 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.51-7.42 (m, 3H), 7.38-7.36 (m, 1H), 7.16 (dt, J=7,5, 1.9 Hz, 1H), 7.05 (s, 1H), 6.97 (t, J=1.8 Hz, 1H), 6.78 (s, 1H), 6.40 (s, 1H), 4.17-4.07 (m, 1H), 3.97-3.88 (m, 1H), 3.71 (s, 3H), 3.70-3.67 (m, 2H), 3.47-3.35 (m, 2H), 3.16 (dd, J=12,9, 2,2 Hz, 2H), 2.26 (s, 3H), 2.22 (s, 1H), 2.19 (s, 1H), 1.91-1.76 (m, 6H), 1.74-1.62 (m, 2H,), 1.27 (d, J=6,7 Hz, 6N).

MS: [M+H]+=670,4 (RASSC.=670,3517) (multimode+).

Example 67

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Pd-118 (0,117 g, 0.18 mmol) was stirred in acetonitrile (15 ml) for 15 min, then was added potassium carbonate (0,747 g, 5.40 mmol), 4-formylphenylboronic acid (0,270 g of 1.80 mmol) and tert-butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexylcarbamate (1 g, of 1.80 mmol). The reaction mixture was heated at 80°C for 8 h, then left to stand overnight. The acetonitrile is evaporated and the aqueous residue is time to relax is whether EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic extracts were washed with water and saturated brine. Organic matter was dried over sodium sulfate and filtered. The filtrate is evaporated and the oil obtained was dissolved in DCM. The crude product was purified via Biotage (silica, 50 g), elwira 50%EtOAc in isohexane. Pure fractions evaporated to dryness to obtain specified in the subtitle compound in the form of not-quite-white solid. Output: 0,78 g

MS: [M-H]+=532 (multimode+).

Stage (b) tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0,78 g of 1.46 mmol) in DCM (5 ml) was added (2S,6R)-2,6-dimethylpiperazine (0,250 g, 2,19 mmol). The mixture was left to mix with K.T. within 2 hours Then added triacetoxyborohydride sodium (0,465 g, 2,19 mmol). After stirring for 1 h the reaction was complete. The mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to obtain specified in the subtitle compound as a pale foam. Output: 0,88,

1H NMR (300 MHz, CDCl3) δ 8.37 (dd, J=3.1 and 7.8 Hz, 1H), 8.08-8.03 (m, 2H), 7.56-7.53 (m, 4H), 7.42-7.35 (m, 3H), 7.15-7.10 (m, 1H), 4.38-4.31 (m, 1H), 4.22-4.14 (m, 1H), 3.65-3.57 (m, 1H), 3.54 (s, 2H), 3.00-2.93 (m, 2H), 2.79 (d, J=16,3 Hz, 2H), 1.85-1.61 (m, 11N), 1.41 (s, N), 1.04 (d, J=6,4 Hz, 6N).

MS: [M+H]+=632 (multimode+).

Stage (C) N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating hydrochloride

To a solution of tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (0.88 g, of 1.39 mmol) in DCM (3 ml) was added 4 M HCl (in dioxane) (3,48 ml, 13,93 mmol). After a minute began precipitation of solid matter in the sludge. Was added methanol (3 ml) in order to make the solution homogeneous. The reaction mixture was stirred at K.T. during the night. The solution was concentrated in vacuo, then triturated with ether. The pale solid was filtered to obtain specified in the subtitle compound. Output: 0,71,

MS: [M-H]+=532 (multimode+).

Stage (d) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fioricetonline hydrochloride (0.1 g, 0,19 mmol) in acetonitrile (1 ml) was added 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,041 g 0,19 mmol) and triethylamine (0,262 ml, 1.88 mmol). With the addition of triethylamine, the reaction mixture turned into a homogeneous solution. Then added cyclic ang is grid 1-papapostolou acid, 1.57 M solution in THF (TR) (0,126 ml, 0.20 mmol)and the mixture was stirred at K.T. within 10 minutes the Mixture was evaporated to dryness and the residue was dissolved in EtOAc and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain an oil. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 69 mg

1H NMR (400 MHz, DMSO) δ 8.82-8.80 (m, 1H), 8.37-8.35 (m, 2H), 8.26 (d, J=3.1 Hz, 1H), 8.06 (dd, J=3.1 and 7.8 Hz, 1H), 7.74 (d,J=7.9 Hz, 1H), 7.68-7.61 (m, 4H), 7.54-7.45 (m, 4H), 7.40 (d, J=7.9 Hz, 2H), 7.23-7.20 (m, 1H), 3.40-3.32 (m, 2H), 3.15-3.08 (m, 2H), 2.52-2.47 (m, 3H), 2.33-2.32 (m, 2H), 1.79-1.69 (m, 9H), 1.18 (d, J=6,7 Hz, 6H).

MS: [M+H]+=694,3 (RASSC.=694,3317) (multimode+).

Example 68

N-((1s,4s)-4-(2-(34((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (100 mg, 0,17 mmol), 5-bromo-2-hydroxybenzaldehyde (34,6 mg, 0,17 mmol) and sodium carbonate (148 mg, 0.52 mmol who) under nitrogen were added to THF (2,000 ml) and degassed water (1 ml). Then added tetrakis(triphenylphosphine)palladium(0) (4 mg, of 3.45 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as a white solid. Yield: 95 mg

MS: [M+H]+=575 (multimode+).

Stage (b) N-((1s,4s)-4-(2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (88,2 mg, 0.15 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (26,3 mg, 0.23 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (48,8 mg, 0.23 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Output: a 27.4 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d,J=7.2 Hz, 1H), 811 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.95 (s, 1H), 7.81-7.75 (m, 1H), 7.51-7.40 (m, 4H), 7.37-7.34 (m, 1H), 7.13-7.10 (m, 1H), 6.88 (d, J=8,2 Hz, 1H), 4.17-4.09 (m, 1H), 4.02 (s, 2H), 3.99-3.92 (m, 1H), 3.58-3.47 (m, 2H), 3.40-3.32 (m, 2H), 2.62 (s, 3H), 2.53 (t, J=12,4 Hz, 2H), 1.93-1.78 (m, 6H), 1.77-1.64 (m, 2H), 1.30 (d, J=6,7 Hz, 6N).

MS: [M+H]+=673,3 (RASSC.=673,2972) (multimode+).

Example 69

N-((1s,4s)-4-(2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-2'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (100 mg, 0,17 mmol), 3-bromo-2-hydroxybenzaldehyde (34,6 mg, 0,17 mmol) and sodium carbonate (148 mg, 0.52 mmol) under nitrogen were added to THF (2 ml) and degassed water (1 ml). Then added tetrakis(tricresylphosphate)palladium(0) (4 mg, of 3.45 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as a white solid. Output: 0,74,

MS: [M+H]+=575 (a mule is Titova+).

Stage (b) N-((1s,4s)-4-(2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-hydroxybiphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-2'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (86,2 mg, 0.15 mmol) in dichloromethane (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (25,7 mg, 0.23 mmol). The mixture was left to mix with K.T. for 40 minutes, then added triacetoxyborohydride sodium (47,7 mg, 0.23 mmol). The reaction mixture was stirred at K.T. within 2 hours. The mixture was diluted with dichloromethane and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Output: 14,7 mg

1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=7,1 Hz, 1H), 8.13 (d, J=3.1 Hz, 1H), 8.08 (dd, J=7,9, 3.1 Hz, 1H), 7.96 (s, 1H), 7.46-7.38 (m, 4H), 7.27 (dd, J=7,7, 1.5 Hz, 1H), 7.14 (dt, J=7,9, 2.0 Hz, 1H), 7.06 (dd, J=7,4, and 1.4 Hz, 1H), 6.86 (t, J=9,3 Hz, 1H), 4.18-4.17 (m, 1H), 3.99-3.91 (m, 1H), 3.79 (s, 2H), 3.47-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.14-3.08 (m, 2H), 2.54 (s, 3H), 2.12 (t, J=12.3 Hz, 2H), 1.94-1.77 (m, 6H), 1.73-1.60 (m, 2H), 1.23 (d, J=6,7 Hz, 6N).

MS: [M+H]+=673,2 (RASSC.=673,2972) (multimode+).

Example 70

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

DCC(0.035 g, 0,17 mmol) was added to a solution of 2-(hydroxymethyl)thiazole-4-carboxylic acid (0,027 g, 0,17 mmol) and HOBt (0,026 g, 0,17 mmol) in DMF (1 ml) and was stirred for 10 minutes and Then was added a solution of the crude N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethyl-piperazine-1-yl)methyl)berenil-3-yloxy)-5-fioricetonline (0.08 g, 0.14 mmol) and DIPEA (0,098 ml of 0.56 mmol) in DMF (1 ml) and the reaction mixture was stirred for 20 hours the Solution was concentrated in vacuo, then the residue was added a mixture of water/methanol/DMSO. The crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%TFA in methanol as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compounds as white solids. Yield: 28 mg

1H NMR (400 MHz, DMSO) δ 8.33 (d, J=6,9 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.18 (s, 1H), 8.05 (dd, J=7,3, 3.1 Hz, 1H), 7.64 (d, J=8,2 Hz, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.52-7.48 (m, 3H), 7.37 (d, J=7.9 Hz, 2H), 7.21-7.18 (m, 1H), 4.70 (s, 2H), 3.36-3.27 (m, 2H), 3.05-2.97 (m, 2H), 2.53-2.47 (m, 6H), 2.15-2.03 (m, 2H), 1.80-1.63 (m, 8H), 1.17 (d, J=8,9 Hz, 6N).

MS: [M+H]+=673,2 (RASSC.=673,2) (multimode+).

Example 71

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)pyrazolo[1,5-a]-pyridine-2-carboxamide

HATU (0,069 g, 0.18 mmol) was added in one portion under nitrogen at 25°C for N-((1s,4s)-4-amino shall illogical)-2-(4'-(((3S,5R) - for 3,5-dimethyl-piperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating (0.08 g, 0.15 mmol), pyrazolo[1,5-a]pyridine-2-carboxylic acid (0,024 g, 0.15 mmol) and DIPEA (0,079 ml, 0.45 mmol) in acetonitrile (1 ml). The resulting solution was stirred at 25°C for 10 min. the Reaction mixture was concentrated and diluted with EtOAc, washed sequentially with saturated NaHCO3, saturated brine and water. The organic layer was dried over MgSO4, filtered and evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 70 mg

1H NMR (400 MHz, DMSO) δ 8.61 (d, J=11.5 Hz, 1H), 8.35 (d, J=6,9 Hz, 1H), 8.26 (d, J=2,8 Hz, 1H), 8.07 (dd, J=3,1, 7,3 Hz, 1H), 7.78-7.65 (m, 4H), 7.53-7.50 (m, 3H), 7.36 (d, J=7.7 Hz, 2H), 7.30 (t, J=7.7 Hz, 1H), 7.23-7.21 (m, 1H), 7.02 (t, J=6,9 Hz, 1H), 6.98 (s, 1H), 3.38-3.28 (m, 2H), 3.10-3.04 (m, 2H), 2.56-2.44 (m, 4H), 2.23 - 2.14 (m, 2H), 1.84-1.67 (m, 9H), 1.17 (d, J=10.4 Hz, 6N).

MS: [M+H]+=676,3 (RASSC.=676,3411) (multimode+).

Example 72

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide

Acetate palla the Oia to 3.89 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14,22 mg, 0.03 mmol) under nitrogen were added to acetonitrile (3,38 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (144 mg, 1.04 mmol)dissolved in water (3,38 ml), and then 3-formylphenylboronic acid (51.9 mg, 0.35 mmol) and N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (200 mg, 0.35 mmol) and the mixture was heated at 80°C for 2 hours The mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to obtain a brown oil. It was purified using column chromatography (eluent = pure EtOAc), with light brown foam. Yield: 123 mg

MS: [M+H]+=556 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)-methyl) - biphenyl-3-yloxy)-5-fornicating

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide (121 mg, 0.22 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (37,3 mg, 0.33 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (69,2 mg, 0.33 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO (aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 21 mg

1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.51-7.49 (m, 2H), 7.44-7.34 (m, 3H), 7.21-7.15 (m, 1H), 6.40 (s, 1H), 4.15-4.07 (m, 1H), 3.98-3.09 (m, 1H), 3.85 (s, 2H), 3.70 (s, 3H), 3.51-3.39 (m, 2H), 3.22 (dd, J=12,9, 2,2 Hz, 2H), 2.36 (t, J=12,2 Hz, 2H), 2.25 (s, 3H), 1.89-1.75 (m, 6H), 1.74-1.62 (m, 2H), 1.27 (d, J=6,7 Hz, 6N).

MS: [M+H]+=654,3 (RASSC.=654,3568) (multimode+).

Example 73

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(pyrrolidin-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (1.2 g, 2,07 mmol), 4-(3-hydroxypropyl)-phenylboronic acid (0,372 g 2,07 mmol), potassium carbonate (0,857 g of 6.20 mmol) and Pd-118 (is 0.135 g, 0.21 mmol) was stirred in DMF (15 ml). The resulting mixture was stirred and heated at 70°C during the night. The reaction mixture was poured into water and the organic substances were extracted into EtOAc (×2). The EtOAc extracts were combined, dried (MgSO4) and evaporated to obtain an oil. The residue was purified using column chromatography (eluent = EtOAc). Suitable the fractions were combined and evaporated to obtain specified in the subtitle compound as a foam. Output: 0,65,

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.12-8.08 (m, 2H), 7.90 (s, 1H), 7.55-7.47 (m, 4H), 7.38-7.36 (m, 1H), 7.25-7.20 (m, 3H), 7.16-7.13 (m, 1H), 4.28-4.22 (m, 1H), 4.10-4.06 (m, 1H), 3.73-3.67 (m, 2H), 2.74 (t, J=7.7 Hz, 2H), 2.60 (s, 3H), 1.96-1.79 (m, 8H), 1.69-1.61 (m, 2H).

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0.65 g, 1.10 mmol) and pyridine (0,107 ml of 1.32 mmol) in DCM (7 ml) was added methanesulfonamide (0,112 ml, 1.44 mmol) and the reaction mixture was stirred at K.T. during the night. Then to the reaction mixture was added pyridine (0,107 ml of 1.32 mmol) and methanesulfonamide (0,111 ml, 1.44 mmol) and was stirred for another 3 h at K.T. Reaction mixture is evaporated to obtain a residue, which was distributed between EtOAc and 2 M HCl (aq.). The EtOAc layer was then washed with another aliquot of 2 M HCl (aq.), 2× feast upon. NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain a brown oil. His triturated with ether overnight to obtain specified in the subtitle compound as a white solid. Output: 0,6,

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.07 (m, 2H), 7.90 (s, 1H), 7.56-7.49 (m, 4H), 7.37 (d, J=2.1 Hz, 1H), 7.24-7.19 (m, 3H), 7.15 (dt, J=7,4, and 2.1 Hz, 1H), 4.27-4.22 (m, 3H), 4.12-4.04 (m, 1H), 3.01 (s, 3H), 2.78 (t, J=7,6 Hz, 2H), 2.61 (, 3H), 2.15-2.05 (m, 2H), 1.96-1.80 (m, 6H), 1.69-1.63 (m, 2H).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(pyrrolidin-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

In a test tube for microwave reactor was loaded 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (120 mg, 0.18 mmol), pyrrolidine (0,045 ml, 0.54 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 5 minutes. The mixture was purified using HPLC with reversed phase (eluent = a mixture of TFA (aq.)/MeCN), the appropriate fractions were combined, evaporated and the residue triturated with ether to obtain a white solid, which was dried overnight at 40°C. under vacuum to obtain specified in the connection header. Yield: 86 mg

1H NMR (400 MHz, CDCl3) δ 13.09 (s, 1H), 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.09-8.07 (m, 2H), 7.90 (s, 1H), 7.56-7.48 (m, 4H), 7.36 (t, J=1.9 Hz, 1H), 7.21-7.18 (m, 3H), 7.16 (dtd, J=7,5, 1,8,0,2 Hz, 1H), 4.28-4.22 (m, 1H), 4.11-4.05 (m, 1H), 3.87-3.81 (m, 2H), 3.08-3.01 (m, 2H), 2.76-2.70 (m, 4H), 2.61 (s, 3H), 2.18-2.10 (m, 4H), 2.07-2.01 (m, 2H), 1.95-1.79 (m, 6H), 1.67-1.62 (m, 2H).

MS: [M+H]+=642,2 (RASSC.=642,2914) (multimode+)

Example 74

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

In a test tube for microwave reactor was loaded 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexyl bemail)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (120 mg, 0.18 mmol), tert-butyl-1-piperidinecarboxylate (101 mg, 0.54 mmol) and acetonitrile (1 ml). The mixture was heated up to 80°C for 30 minutes the Mixture was evaporated to dryness and the residue suspended in DCM (2 ml) and TFA (2 ml). After 20 min the reaction mixture was evaporated to dryness. The residue was dissolved in acetonitrile and purified using prep. chromatography with reversed phase (eluent = a mixture of TFA (aq.)/MeCN). The appropriate fractions were combined, evaporated and the residue triturated with ether to obtain a white solid, which was dried overnight at 40°C. under vacuum to obtain specified in the connection header. Yield: 85 mg

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,1, 3.2 Hz, 1H), 8.09-8.06 (m, 2H), 7.89 (s, 1H), 7.55-7.47 (m, 4H), 7.35-7.34 (m, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.19-7.14 (m, 3H), 4.25-4.20 (m, 1H), 4.08-4.01 (m, 1H), 3.60-3.54 (m, 4H), 3.47-3.42 (m, 4H), 3.02-2.97 (m, 2H), 2.70 (t, J=7,3 Hz, 2H), 2.60 (s, 3H), 2.09-2.01 (m, 2H), 1.93-1.77 (m, 6H), 1.68-1.58 (m, 2H).

MS: [M+H]+=657,2 (RASSC.=657,3023) (multimode+).

Example 75

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

In a test tube for microwave reactor was loaded 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (110 mg, 0.16 mmol), (2R,6S)-2,6-dimethylpiperazine (56,5 mg, 0.49 mmol) and acetonitrile (1 ml). The mixture was heated up to 80°C for 3 minutes The mixture was purified using HPLC with reversed phase (eluent = a mixture of TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain the residue, which is triturated with ether to obtain white solids. This solid was dried over night at 40°C under vacuum to obtain specified in the connection header. Yield: 99 mg

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.07 (m, 2H), 7.91 (s, 1H), 7.56-7.48 (m, 4H), 7.36 (s, 1H), 7.25-7.15 (m, 4H), 4.24 (s, 1H), 4.11-4.04 (m, 1H), 3.85-3.78 (m, 2H), 3.46 (d, J=10.0 Hz, 2H), 3.27 (t, J=12.0 Hz, 2H), 3.08-3.02 (m, 2H), 2.75-2.69 (m, 2H), 2.62 (s, 3H), 2.14-2.07 (m, 2H), 1.95-1.79 (m, 6H), 1.69-1.60 (m, 2H), 1.36 (d, J=5,1 Hz, 6N).

MS: [M+H]+=685,3 (RASSC.=685,3336) (multimode+).

Example 76

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-utiltity-4-carboxamid

Stage (a) Ethyl-2-utiltity-4-carboxylate

Ethyl-3-bromo-2-oxopropanoic (4,10 ml, 32,67 mmol) was added dropwise over 10 min to a stirred solution proportioned (3 g, 33,65 mmol) in ethanol (40 ml), cooled in an ice bath. After 16 h, the reaction mixture was evaporated in vacuum. In the purification by chromatography on silica gel with elution with a mixture of EtOAc:ISO-hexane, 1:3 received specified in the subtitle compound as a yellow oil. Output: 2,78,

1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 4.46-4.33 (m, 6H), 3.11 (q, J=7 Hz, 4H).

Stage (b) 2-utiltity-4-carboxylic acid

The lithium hydroxide (1,405 g, 58,68 mmol) in water (of 13.75 ml) was treated with ultrasound for 10 min, then was added to a stirred mixture of ethyl-2-utiltity-4-carboxylate (2,78 g, 15,01 mmol) in THF (55 ml). The reaction mixture was stirred at K.T. during the night. The solution was diluted with water and was extracted with EtOAc (×3). The organic extracts were discarded. The aqueous phase was acidified with 2 M HCl and was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuum to obtain specified in the subtitle compound as a brown oil, which solidify upon standing with obtaining waxy solids. Output: 1,02,

1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 5.65-5.55 (m, 1H), 3.11 (q, J=7.5 Hz, 2H), 1.43 (t, J=7,6 Hz, 3H).

Stage (C) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-utiltity-4-carboxamid

HATU (to 0.060 g, 0.16 mmol) at 25°C. under nitrogen was added in one portion to N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating (0.08 g, 0.15 mmol), 2-utiltity-4-carboxylic acid (0,021 g, 0.13 mmol) and DIPEA (0,069 ml, 0.40 mmol) in acetonitrile (1 ml). The resulting solution was stirred at 25°C for 10 min. the Reaction mixture conc who was narrowly, and was diluted with EtOAc, and washed sequentially with saturated NaHCO3, saturated brine and water. The organic layer was dried over MgSO4, filtered and evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compound as a white fluffy solid. Yield: 59 mg

1H NMR (400 MHz, DMSO) δ 8.36 (d, J=7,4 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.11 (s, 1H), 8.05 (dd, J=7,8, 3.1 Hz, 2H), 7.67 (d, J=8,2 Hz, 2H), 7.57-7.49 (m, 4H), 7.44 (d, J=7.9 Hz, 2H), 7.24-7.19 (m, 1H), 3.43-3.39 (m, 2H), 3.17-3.15 (m, 2H), 2.98 (q, J=7.5 Hz, 2H), 2.52-2.49 (m, 4H), 2.34-2.31 (m, 2H), 1.77-1.67 (m, 8H), 1.29 (t, J=7,6 Hz, 3H), 1.20 (d, J=6,4 Hz, 6N).

MS: [M+H]+=671,2 (RASSC.=671,3179) (multimode+).

Example 77

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxy-3'-((4-isopropylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide (450 mg, 0.78 mmol), 5-bromo-2-hydroxybenzaldehyde (157 mg, 0,78 IMO the ü) and sodium carbonate (669 mg, 2.34 mmol) under nitrogen were added to THF (6,00 ml) and degassed water (3 ml). Then added tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.02 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound in the form of not-quite-white solid. Output: 275 mg.

MS: [M+H]+=572 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxy-3'-((4-isopropyl-piperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide (140 mg, 0.24 mmol) in DCM (3 ml) was added 1-isopropylpiperazine (0,053 ml of 0.37 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (78 mg, and 0.37 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white is on solids. Output: 110 mg.

1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=3.1 Hz, 1H), 8.07 (dd, J=7,9, 3.1 Hz, 1H), 7.52-7.38 (m, 5H), 7.13-7.09 (m, 1H), 6.91 (d, J=9,2 Hz, 1H), 6.38 (s, 1H), 4.16 (s, 2H), 4.14-4.09 (m, 1H), 3.94-3.86 (m, 1H), 3.70 (s, 3H), 3.57-3.32 (m, 8H), 2.25 (s, 3H), 1.92-1.72 (m, 6H), 1.72-1.59 (m, 2H), 1.33 (d, J=6,4 Hz, 6N).

MS: [M+H]+=684,3 (RASSC.=684,3673) (multimode+).

Example 78

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-hydroxybiphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-2'-hydroxybiphenyl-3-yloxy)nicotinamide

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide (150 mg, 0.26 mmol), 3-bromo-2-hydroxybenzaldehyde (52,2 mg, 0.26 mmol) and sodium carbonate (223 mg, 0.78 mmol) under nitrogen were added to THF (2,000 ml) and degassed water (1 ml). Then added tetrakis(triphenylphosphine)palladium(0) (6 mg, 5,20 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as a white solid in the society. Output: 108,4 mg.

MS: [M+H]+=572 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-hydroxybiphenyl-3-yloxy)-5-fornicating

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-formyl-2'-hydroxybiphenyl-3-yloxy)nicotinamide (150 mg, 0.26 mmol) in DCM (3 ml) was added (2R,6S)-2,6-dimethylpiperazine (45 mg, 0,39 mmol). The mixture was left to mix with K.T. for 40 min, then was added triacetoxyborohydride sodium (83 mg, 0,39 mmol). The reaction mixture was stirred at K.T. within 2 hours the Mixture was diluted with DCM and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and evaporated to a yellow glass. It was purified by HPLC to obtain specified in the title compounds as white solids. Output: 95,5 mg.

1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=3.1 Hz, 1H), 8.08 (dd, J=7,9, 3.1 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.30 (dd, J=7,7, 1.5 Hz, 1H), 7.21-7.14 (m, 2H), 6.92 (t, J=7,6 Hz, 1H), 6.48-6.35 (m, 1H), 4.15-4.08 (m, 1H), 4.04 (s, 2H), 3.97-3.87 (m, 1H), 3.64 (s, 3H), 3.52-3.42 (m, 2H), 3.37-3.30 (m, 2H), 2.52 (t, J=12,4 Hz, 2H), 2.24 (s, 3H), 1.94-1.74 (m, 6H), 1.72-1.59 (m, 2H), 1.27 (d, J=6.4 Hz, 6H).

MS: [M+H]+=670,3 (RASSC.=670,3517) (multimode+).

Example 79

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-(pyrrolidin-1-yl)propyl)biphenyl-3-yloxy)nicotinamide

Stage (a) N-((1s,4s)-4-(15-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide

The palladium acetate is 0.019 g, 0.09 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0,071 g, 0,17 mmol) under nitrogen were added to acetonitrile (10 ml). The resulting solution was stirred for 10 minutes To this solution was added potassium carbonate (0,718 g, 5,20 mmol)dissolved in water (10,00 ml)and then 4-(3-hydroxypropyl)phenylboronic acid (0.312 g, of 1.73 mmol) and N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (1 g, at 1.73 mmol) and the mixture was heated at 80°C for 2 h the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to obtain a light yellow foam. It was purified using column chromatography (eluent = 3% methanol/DCM)to obtain specified in the subtitle compound as a white foam. Output: 0,61,

1H NMR (400 MHz, CD3OD) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.05 (m, 2H), 7.55-7.47 (m, 4H), 7.37-7.35 (m, 1H), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 1H), 6.67 (d, J=7.7 Hz, 1H), 6.50 (s, 1H), 4.27-4.19 (m, 1H), 4.12-4.01 (m, 1H), 3.70 (t, J=6.3 Hz, 2H), 3.66 (s, 3H), 2.74 (t, J=7.8 Hz, 2H), 2.25 (s, 3H) 1.95-1.75 (m, 6H), 1.67-1.54 (m, 4H).

MS: [M+H]+=586 (multimode+).

Stage (b) 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propylaminosulfonyl

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide (0,61 g, 1,04 m is ol) and pyridine (0,295 ml, 3.65 mmol) in DCM (7 ml) was added methanesulfonamide (0,284 ml, 3.65 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture is evaporated to obtain a residue, which was distributed between EtOAc and 2 M HCl (aq.). The EtOAc layer was then washed with another aliquot of 2 M HCl (aq.), 2× feast upon. NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain a light yellow oil. His triturated with ether overnight to obtain specified in the subtitle compound as a white solid. Output: 665 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7,6 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.07 (dd, J=7,9, 3.1 Hz, 1H), 7.54-7.47 (m, 4H), 7.23 (d, J=8,2 Hz, 2H), 7.15-7.11 (m, 1H), 6.41 (s, 1H), 4.22 (t, J=6.3 Hz, 2H), 4.16-4.08 (m, 1H), 3.97-3.90 (m, 1H), 3.69 (s, 3H), 3.03 (s, 3H), 2.75 (t, J=7,6 Hz, 2H), 2.25 (s, 3H) 2.08-2.00 (m, 2H), 1.90-1.76 (m, 6H), 1.73-1.62 (m, 2H).

MS: [M+H]+=664 (multimode+).

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-(pyrrolidin-1-yl)propyl)-biphenyl-3-yloxy)nicotinamide

In a test tube for microwave reactor was loaded 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (150 mg, 0.23 mmol), pyrrolidine (0,057 ml of 0.68 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 5 minutes and the mixture was purified by HPLC to obtain specified in the title compound as a white solid washes the VA. Output: 99,5 mg.

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=3.1 Hz, 1H), 8.05 (dd, J=8,1, 3.2 Hz, 1H), 7.55-7.51 (m, 2H), 7.48-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.26 (d, J=8,2 Hz, 2H), 7.17-7.11 (m, 1H), 6.51-6.36 (m, 1H), 4.15-4.06 (m, 1H), 3.98-3.87 (m, 1H), 3.70 (s, 3H), 3.67-3.58 (m, 2H), 3.21-3.13 (m, 2H), 3.07-2.98 (m, 2H), 2.72 (t, J=7,6 Hz, 2H), 2.17-1.92 (m, 6H) 1.90-1.75 (m, 6H), 1.73-1.62 (m, 2H).

MS: [M+H]+=639,3 (RASSC.=639,3459) (multimode+).

Example 80

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)sikorksy)-5-fluoro-2-(4'-(3-(4-methylpiperazin-1-yl)propyl)biphenyl-3-yloxy)-nicotinamide

In a test tube for microwave reactor was loaded 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (150 mg, 0.23 mmol), 1-methylpiperazine (0.075 ml, of 0.68 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 20 minutes and the mixture was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 76 mg

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.51 (d, J=8,2, 2H), 7.46 (d, J=4,9, 2H), 7.40 (s, 1H), 7.24 (d, J=8,2 Hz, 2H), 7.16-7.10 (m, 1 H), 6.48-6.39 (m, 1H), 4.13-4.06 (m, 1H), 3.97-3.89 (m, 1H), 3.70 (s, 3H), 3.53-3.36 (m, 8H), 3.10-3.03 (m, 2H), 2.89 (s, 3H), 2.71 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.07-1.98 (m, 2H), 1.89-1.73 (m, 6H), 1.73-1.61 (m, 2H).

MS: [M+H]+=668,3 (RASSC.=668,3724) (multimode+).

Example 81

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)bifani the-3-yloxy)-5-fornicating

In a test tube for microwave reactor was loaded 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (145 mg, 0.22 mmol), (2R,6S)-2,6-dimethylpiperazine (74,8 mg, 0.66 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 30 minutes and the mixture was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 86 mg

1H NMR (400 MHz, CDCl3) δ 8.11-8.07 (m, 1H), 8.07-8.02 (m, 1H), 7.51 (d, J=6,9 Hz, 2H), 7.46 (d, J=3.8 Hz, 2H), 7.39 (s, 1H), 7.24 (d, J=7.2 Hz, 2H), 7.16-7.09 (m, 1H), 6.43 (s, 1H), 4.15-4.04 (m, 1H), 3.98-3.86 (m, 1H), 3.73-3.56 (m, 6H), 3.04 (t, J=7,6 Hz, 2H), 2.82 (t, J=12,8 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H), 2.24 (s, 3H), 2.09-1.99 (m, 2H), 1.90-1.72 (m, 6H), 1.72-1.61 (m, 2H), 1.35 (d, J=6.2 Hz, 6H).

MS: [M+H]+=682,3 (RASSC.=682,3881) (multimode+).

Example 82

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide (450 mg, 0.78 mmol), 2-(4-bromophenyl)ethanol (0,109 ml, 0.78 mmol) and sodium carbonate (669 mg, 2.34 mmol) under nitrogen were added to THF (6,00 ml)and degassed water (3 ml). Then was added tetrakis-(triphenylphosphine)palladium(0) (18 mg, 0.02 mmol) and the reaction mixture was heated under reflux for 2 hours the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = 3% methanol/DCM) to give after evaporation specified in the subtitle compound as a white foam. Yield: 310 mg

1H NMR (400 MHz, CD3OD) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.3 Hz, 1H), 8.06 (s, 1H), 7.56-7.48 (m, 3H), 7.38-7.35 (m, 1H), 7.29 (s, 1H), 7.15 (dt, J=7,4, and 2.1 Hz, 1H), 6.67 (d, J=7,4 Hz, 1H), 6.51 (d, J=0.8 Hz, 1H), 4.27-4.19 (m, 1H), 3.93-3.86 (m, 1H), 3.67 (s, 3H), 2.90 (t, J=6.5 Hz, 2H), 2.25 (s, 3H) 1.95-1.75 (m, 6H), 1.67-1.59 (m, 2H).

MS: [M+H]+=572 (multimode+).

Stage (b) 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)-nicotinamide (0,315 g, 0.55 mmol) and pyridine (0,134 ml of 1.65 mmol) in DCM (7 ml) was added methanesulfonamide (0,129 ml of 1.65 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture is evaporated to obtain a residue, which was distributed between EtOAc and 2 M HCl (aq.). The EtOAc layer was then washed with another aliquot of 2 M HCl (aq.), 2× feast upon. NaHCO3(aq.), what assalam, dried (MgSO4) and evaporated to a yellow oil. His triturated with ether to obtain specified in the subtitle compound as a white solid. Yield: 310 mg

MS: [M+H]+=650 (multimode+).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating

In a test tube for microwave reactor was loaded 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (150 mg, 0.23 mmol), (2R,6S)-2,6-dimethylpiperazine (79 mg, 0.69 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 30 minutes and the mixture was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 72 mg

1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=2,8 Hz, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.46 (d, J=4,6 Hz, 2H), 7.41 (s, 1H), 7.29 (d, J=8,2 Hz, 2H), 7.15-7.10 (m, 1H), 6.42 (s, 1H), 4.13-4.05 (m, 1H), 3.96-3.87 (m, 1H), 3.67 (s, 3H), 3.34-3.19 (m, 4H), 3.07-3.00 (m, 2H), 2.88 (t, J=12.3 Hz, 2H), 2.24 (s, 3H), 1.90-1.73 (m, 6H), 1.72-1.60 (m, 2H), 1.38 (d, J=6,4 Hz, 6N).

MS: [M+H]+=668,3 (RASSC.=668,3724) (multimode+).

Example 83

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-(4-isopropylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-nicotinamide

In a test tube for microwave reactor was loaded 2-(3'-(-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (150 mg, 0.23 mmol), 1-isopropylpiperazine (0,099 ml, 0.69 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 30 minutes and the reaction mixture was purified by HPLC to obtain specified in the title compounds as white solids. Output: 110 mg.

1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.54 (d, J=8,2 Hz, 2H), 7.47 (d, J=4.9 Hz, 2H), 7.42-7.39 (m, 1H), 7.30 (d, J=8,2 Hz, 2H), 7.18-7.12 (m, 1H), 6.42 (s, 1H), 4.14-4.06 (m, 1H), 3.97-3.90 (m, 1H), 3.71 (s, 3H), 3.59-3.31 (m, 9H), 3.22-3.15 (m, 2H), 3.03-2.96 (m, 2H), 2.25 (s, 3H), 1.91-1.74 (m, 6H), 1.73-1.61 (m, 2H), 1.35 (d, J=6,7 Hz, 6N).

MS: [M+H]+=682,3 (RASSC.=682,3881) (multimode+).

Example 84

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (1 g, of 1.80 mmol), 5-bromo-2-hydroxybenzaldehyde (0,362 g of 1.80 mmol) and sodium carbonate (0,572 g, 5.40 mmol) under nitrogen were added to THF (6 ml) and degassed water (3 ml). Then added tetrakis(triphenylphosphine)palladium(0) (0,042 g, 0.04 mmol) and the reaction mixture was heated under reflux for 28 h and then left to cool down over the weekend. Added the additional amount of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)-cyclohexylcarbamate (0.3 g), sodium carbonate (0.1 g) and tetrakis-(triphenylphosphine)palladium(0) (0.01 g) and stirred at 80°C for another 3 hours the Mixture was poured into water and was extracted into EtOAc (×2). The extracts were combined, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (silica, 50 g), elwira 100%DCM to remove impurities and then with 20%DCM in the ether for elution of the product. Containing the product fractions were combined and concentrated to obtain specified in the subtitle compound in the form of not-quite-white solid. Output: 1,0,

MS: [M-H]-=548 (multimode+).

Stage (b) tert-butyl(1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

Tert-butyl(1s,4s)-4-(5-fluoro-2-(3'-formyl-4'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1.2 g, to 2.18 mmol) and (2S,6R)-2,6-dimethylpiperazine (1,247 g, 10,92 mmol) was stirred at K.T. in DCM (10 ml). Was added acetic acid (of 0.625 ml, 10,92 mmol) and the reaction mixture was stirred for 30 minutes Then added triacetoxyborohydride sodium (2,314 g, 10,92 mmol) and the reaction mixture was left to mixed under nitrogen overnight. The mixture was diluted with DCM and washed with saturated solution of NaHCO3(aq.) (×2), dried (MgSO4) and evaporated to obtain a pale foam. Held clear what the cartridge SCX, elwira 100%methanol to remove impurities, and then rinsing 20%ammonia in methanol for elution of the product. Containing the product fractions were combined and concentrated in vacuum to obtain specified in the subtitle compound as a white solid. Output: 0,38,

MS: [M+H]+=648 (multimode+).

Stage (C) N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating hydrochloride

To tert-butyl(1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (0.35 g, 0.54 mmol) in DCM (1 ml) was added HCl (4 mol in dioxane) (1,351 ml, 5.40 mmol). After 1 min started to form a flocculent precipitate, therefore, was added methanol (0.5 ml)to make the solution homogeneous. The reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was concentrated in vacuo and triturated with ether to obtain specified in the subtitle compound as a white solid. Output: 0,35,

MS: [M+H]+=548 (multimode+).

Stage (d) N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline of hydrochl the reed (0.08 g, 0.15 mmol) in acetonitrile (1 ml) was added 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,047 g, 0.22 mmol) and DIPEA (0,077 ml, 0.44 mmol). Then added HATU (0.167 g, 0.44 mmol) and the mixture was stirred at K.T. within 1 h was Added water (0.5 ml) and conc. HCl (1 ml) and the crude product was purified by preparative HPLC on a column of Phenomenex, using the gradient 95-50% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying during the night with obtaining specified in the title compound as a fluffy white solid. Yield: 25 mg

1H NMR (400 MHz, DMSO) δ 8.98-8.86 (m, 1H), 8.81-8.79 (m, 1H), 8.38-8.34 (m, 2H), 8.26 (d, J=4,6 Hz, 1H), 8.07 (dd, J=6,6, and 6.6 Hz, 1H), 7.80 (d, J=4.9 Hz, 1H), 7.74-7.43 (m, 5H), 7.26-7.20 (m, 2H), 4.13-3.88 (m, 4H), 3.67 (s, 2H), 2.52-2.47 (m, 7H), 1.81-1.66 (m, 8H), 1.16 (d, J=18.2 Hz, 6N).

MS: [M+H]+=717,3 (RASSC.=710,3266) (multimode+).

Example 85

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fluoro-nicotinamide (0.08 g, 0.13 mmol) in acetonitrile (1 ml) was added 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (0,034 g 0,19 mmol) and DIPEA (0,068 ml to 0.39 mmol). Then added HATU (0,147 g 0,39 mmol) and the mixture premesis what does K.T. within 1 h was Added 880 ammonia (2 ml) and the reaction mixture was stirred for 5 days. Was added water (0.5 ml) and the crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compound as a white fluffy solid. Yield: 40 mg

1H NMR (400 MHz, DMSO) δ 8.39-8.37 (m, 2H), 8.25 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.95-7.93 (m, 1H), 7.61 (s, 1H), 7.54-7.42 (m, 5H), 7.38 (s, 1H), 7.16-7.11 (m, 2H), 6.99-6.94 (m, 3H), 3.50-3.43 (m, 2H), 3.36-3.33 (m, 2H), 2.66 (s, 3H), 2.50-2.49 (m, 6H), 1.81-1.71 (m, 8H), 1.20 (d, J=6,7 Hz, 6N).

MS: [M+H]+=706,3 (RASSC.=706,3517) (multimode+).

Example 86

N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexyl)-2-methylthiazole-4-carboxamide (1.2 g, 2,07 mmol), 4-(2-hydroxyethyl)phenylboronic acid (0,446 g, 2,69 mmol) and sodium carbonate (0,260 ml of 6.20 mmol) in THF (10 ml) and water (5,00 ml) was added tetrakis(triphenylphosphine)palladium(0) (0,048 g, 0.04 mmol). The mixture was heated up to 80°C during the night. Added extra is niteline amount of 4-(2-hydroxyethyl)phenylboronic acid (0,446 g, 2,69 mmol) and the reaction mixture was heated for a further 24 h the Mixture was evaporated and the residue was distributed between water and EtOAc. The aqueous layer was again extracted with EtOAc and the extracts were combined. The mixture was purified using chromatography normal phase (eluent = EtOAc), the appropriate fractions were combined and evaporated to obtain foam. Her triturated with ether overnight to obtain finely dispersed solid, which was isolated by filtration to obtain specified in the subtitle compound. Output: 0,9,

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.11-8.07 (m, 2H), 7.90 (s, 1H), 7.55-7.49 (m, 4H), 7.37 (t, J=1.8 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.15 (dt, J=7,4, and 2.1 Hz, 1H), 4.27-4.22 (m, 1H), 4.12-4.04 (m, 1H), 3.92-3.87 (m, 2H), 2.90 (t, J=6.5 Hz, 2H), 2.61 (s, 3H), 1.96-1.79 (m, 6H), 1.69-1.62 (m, 2H).

MS: [M+H]+=575 (multimode+).

Stage (b) 2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0.8 g, of 1.39 mmol) and pyridine (0,225 ml, 2,78 mmol) in DCM (10 ml) was added methanesulfonamide (0,226 ml of 2.92 mmol) and the reaction mixture was stirred at K.T. during the night. Added more methanesulfonanilide (0,226 ml of 2.92 mmol) and pyridine (0,225 ml, 2,78 mmol) and the reaction mixture was left to mix for e is e 24 PM After this time the reaction had reached completion. The mixture was diluted with DCM (50 ml) and washed 2×2 M HCl (aq.), NaHCO3(aq.), dried (MgSO4) and evaporated to obtain an oil. His triturated with ether to obtain specified in the subtitle compound as a solid substance. Output: 0,81,

1H NMR (300 MHz, CDCl3) δ 8.38 (dd, J=8,3, 3.1 Hz, 1H), 8.10-8.06 (m, 2H), 7.90 (s, 1H), 7.57-7.49 (m, 4H), 7.38 (d, J=1.7 Hz, 1H), 7.30-7.25 (m, 2H), 7.23-7.14 (m, 2H), 4.44 (t, J=6,8 Hz, 2H), 4.28-4.21 (m, 1H), 4.13-4.03 (m, 1H), 3.09 (t, J=6,8 Hz, 2H), 2.91 (s, 3H), 2.61 (s, 3H), 1.98-1.78 (m, 6H), 1.71-1.62 (m, 2H).

Stage (C) N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

To a suspension of 2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (120 mg, 0.18 mmol) in acetonitrile (1 ml) was added (2R,6S)-2,6-dimethylpiperazine (63,0 mg, 0.55 mmol). The mixture was heated up to 80°C in a microwave reactor for 30 minutes. The mixture was purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined, evaporated to obtain the residue, which is triturated with ether to obtain solid, which was isolated by filtration and dried overnight under vacuum at 40°C To produce specified in the connection header. Yield: 102 mg

1H NMR (400 MHz, CDCl3) δ 8.37-833 (m, 1H), 8.13 (d, J=7,4 Hz, 1H), 8.09 (q, J=1.6 Hz, 1H), 7.94 (s, 1H), 7.57-7.49 (m, 4H), 7.39-7.35 (m, 2H), 7.27 (d, J=8,2 Hz, 2H), 7.17 (dd, J=7,7, 1.8 Hz, 1H), 4.25-4.21 (m, 1H), 4.10-4.06 (m, 1H), 3.70-3.63 (m, 2H), 3.48-3.38 (m, 2H), 3.25-2.95 (m, 6H), 2.63 (s, 3H), 1.97-1.88 (m, 4H), 1.87-1.79 (m, 2H), 1.71-1.63 (m, 2H), 1.39 (dd, J=6,7, 1.8 Hz, 6N).

MS: [M+H]+=671,3 (RASSC.=671,3179) (multimode+).

Example 87

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

In a test tube for microwave reactor was loaded 2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (100 mg, 0.15 mmol), 1-methyl-1,4-diazepan (0,057 ml, 0.46 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 1 h and the reaction mixture was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 18 mg

1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=7.2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.57 (d, J=8,2 Hz, 2H), 7,50-7.46 (m, 2H), 7.43-7.40 (m, 1H), 7.31 (d, J=8,2 Hz, 2H), 7.19-7.13 (m, 1H), 4.17-4.09 (m, 1H), 4.01-3.93 (m, 1H), 3.71 (s, 3H), 3.57-3.43 (m, 4H), 3.42-3.34 (m, 2H), 3.09-3.00 (m, 2H), 2.95 (s, 3H), 2.33-2.23 (m, 2H), 2.61 (s, 3H), 1.92-1.78 (m,6H), 1.77-1.65 (m, 2H).

MS: [M+H]+=671,3 (RASSC.=671,3179) (multimode+).

Example 88

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4-methylthiazole-2-carboxamide

In the atmosphere of nitrogen and at K.T. to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (0.07 g, 0.13 mmol) in dry DCE (1 ml) was slowly added trimethylaluminum (0,192 ml, 0.38 mmol) (2 M in heptane). After stirring at K.T. within 15 min (Attention! Allocated gaseous methane) was added ethyl-4-methylthiazole-2-carboxylate (of 0.022 g, 0.13 mmol). The mixture was then stirred in a microwave reactor (CEM Discover) at 80°C for 1 h the Reaction is then carefully extinguished by adding aqueous HCl (1 M, 10 ml)and then diluted with DCM (20 ml). The organic phase is then dried over MgSO4and then concentrated to obtain the crude amide. This crude amide pererestorani in methanol and purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compounds as white solids. Yield: 10 mg

1H NMR (500 MHz, DMSO) δ 8.31 (d, J=7,1 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.07-8.03 (m, 2H), 7.59 (s, 2H), 7.49-7.44 (m, 2H), 7.37 (s, 1H), 7.14 (d, J=a 13.9 Hz, 1H), 4.01-3.98 (m, 1H), 3.88-3.84 (m, 1H), 3.37 (s, 2H,), 2.66-2.62 (m, 2H), 2.50-2.50 (m, 7H), 2.41 (s, 3H), 2.38-2.35 (m, 1H), 1.83-1.79 (m, 4H), 1.69-1.66 (m, 4H), 1.18 (d, J=6.4 Hz, 6H).

MS: [M+H]+=673,2 (RASSC.=673,2972) (multimode+).

Example 89

N-((s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-methylpyridine

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornication-amide (147 mg, 0.25 mmol) in acetonitrile (4 ml) was added 6-methilpiralidone acid (to 34.5 mg, 0.25 mmol) and triethylamine (0,351 ml, 2,52 mmol). After addition of triethylamine, the reaction mixture turned into a homogeneous solution. Then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (has 0.168 ml, 0.26 mmol)and the mixture was stirred at K.T. within 2 hours the Mixture is evaporated to dryness and the residue was dissolved in DCM (15 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain foam. It was purified by preparative HPLC to obtain specified in the connection header. Yield: 43 mg

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.86-7.76 (m, 2H), 7.58-7.48 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.34 (m, 2H), 7.15-7.10 (m, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.19 (s, 2H), 4.17-4.11 (m, 1H), 4.03-3.94 (m, 1H), 3.67-3.56 (m, 2H), 3.51 (d, J=12,8 Hz, 2H), 2.78 (t, J=12.3 Hz, 2H), 2.47 (s, 3H), 1.91-1.82 (m, 6H), 1.79-1.68 (m, 2H), 1.33 (d, J=6,4 Hz, 6N).

MS: [M+H]+=667 (RASSC.=667,3408) (multimode+).

Example 90

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-isopropylthiazole-4-carboxamid

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine the n-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.26 mmol) in acetonitrile (4 ml) was added 2-isopropylthiazole-4-carboxylic acid (to 44.0 mg, 0.26 mmol) and triethylamine (0,358 ml, 2.57 mmol). By the addition of triethylamine, the reaction mixture turned into a homogeneous solution. Then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (0,172 ml, 0.27 mmol)and the mixture was stirred at K.T. within 2 hours the Mixture is evaporated to dryness and the residue was dissolved in DCM (15 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain foam. It was purified by preparative HPLC to obtain specified in the connection header. Yield: 15 mg

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7,4 Hz, 1H), 8.12-7.97 (m, 3H), 7.52-7.40 (m, 4H), 7.36 (s, 1H), 7.14-7.09 (m, 1H), 6.89 (d, J=8,2 Hz, 1H), 4.17-4.10 (m, 1H), 4.03 (s, 2H), 4.00-3.92 (m, 1H), 3.56-3.47 (m, 2H), 3.37 (d, J=13.1 Hz, 2H), 2.56 (t, J=12.3 Hz, 2H), 1.91-1.78 (m, 6H), 1.78-1.65 (m, 2H), 1.38-1.25 (m, 12H).

MS: [M+H]+=701,2 (RASSC.=701,3285) (multimode+).

Example 91

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)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 (28.4 mg, 0,17 mmol) in acetonitrile (5 ml) was added DIPEA (0,057 ml, 0.34 mmol) and HATU (of 65.1 mg, 0,17 mmol). The mixture was left to mix with K.T. for 10 min, then was added RA is solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (100 mg, 0,17 mmol) in acetonitrile (5 ml) with DIPEA (0,057 ml, 0.34 mmol) and the mixture was stirred at K.T. within 30 minutes. The reaction mixture was diluted in EtOAc (10 ml), washed with water, brine, dried (MgSO4) and evaporated to obtain foam. It was purified by preparative HPLC to obtain specified in the title compounds as white solids. Yield: 31 mg

1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=6,9 Hz, 1H), 8.11-8.06 (m, 2H), 7.75 (s, 1H), 7.57-7.42 (m, 4H), 7.38 (s, 1H), 7.15-7.08 (m, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.16-4.07 (m, 5H), 3.98-3.89 (m, 1H), 3.62-3.52 (m, 2H), 3.44 (d, J=to 12.8 Hz, 2H), 2.95 (t, J=6.2 Hz, 2H), 2.67 (t, J=12,6 Hz, 2H), 2.10-1.64 (m, 12H), 1.32 (d, J=6,7 Hz, 6H).

MS: [M+H]+=696,4 (RASSC.=696,3673) (multimode+).

Example 92

2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxy-biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexyl)nicotinamide

To a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (33,2 mg, 0,17 mmol) in acetonitrile (5 ml) was added DIPEA (0,057 ml, 0.34 mmol) and HATU (of 65.1 mg, 0,17 mmol). The mixture was left to mix with K.T. for 10 min, then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (100 mg, 0,17 mmol) in acetonitrile (5 ml) with DIPEA (0,057 ml, 0.34 mmol) and the mixture was stirred at K.T. within 30 minutes. The reaction mixture was diluted in EtOAc (25 ml), PR is mawali water, brine, dried (MgSO4) and evaporated to a yellow oil. It was purified by preparative HPLC to obtain specified in the title compounds as white solids. Yield: 55 mg

1H NMR (400 MHz, CD3OD) δ 8.14-8.04 (m, 2H), 7.58-7.47 (m, 4H), 7.38 (s, 1H), 7.15-7.11 (m, 1H), 7.06 (s, 1H), 6.92 (d, J=8,2 Hz, 1H), 4.18 (s, 2H), 4.17-4.11 (m, 1H), 3.98-3.90 (m, 4H), 3.66-3.56 (m, 2H), 3.52 (d, J=13.3 Hz, 2H), 2.79 (t, J=12,6 Hz, 2H), 1.96-1.76 (m, 6H), 1.75-1.63 (m, 2H), 1.33 (d, J=6,4 Hz, 6N).

MS: [M+H]+=724,3 (RASSC.=724,3234) (multimode+).

Example 93

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

The palladium(II) acetate (5,49 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (0,020 g, 0.05 mmol) was stirred in acetonitrile (1.5 ml) for 15 min, then the solution was added potassium carbonate (0,203 g of 1.47 mmol) in water (3,00 ml)and then 4-(3-hydroxypropyl)phenylboronic acid (0,106 g, 0.59 mmol) and a solution of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide (0,300 g, 0.49 mmol) in acetonitrile (2,000 ml). The reaction mixture was heated at 70°C for 18 h, then kept at K.T. within 3 days. The reaction mixture R is bavlyali EtOAc and washed with water and saturated brine. Organic matter was dried over sodium sulfate, filtered and evaporated to obtain the crude product. It was purified by flash chromatography on silica (Combi-Flash Companion, column Biotage SNAP 100 g), gradient elution 0 to 10% EtOAc in isohexane. Pure fractions evaporated to dryness to obtain specified in the subtitle compound as a pale yellow foam. Output: 0,219,

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.12-8.04 (m, 3H), 7.56-7.46 (m, 4H), 7.41-7.36 (m, 2H), 7.33 (d, J=7.9 Hz, 1H), 7.23-7.12 (m, 4H), 6.67 (d, J=6,8 Hz, 1H), 4.30-4.12 (m, 2H), 3.68 (dd, J=11,7, 6.3 Hz, 2H), 2.74-2.67 (m, 2H), 2.60 (s, 3H), 1.99-1.82 (m, 8H), 1.76-1.67 (m, 2H).

MS: [M+H]+=622,2 (RASSC.=622,2829) (multimode+).

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(5-methylimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl

Methanesulfonanilide (0,048 ml of 0.62 mmol) and pyridine (0,050 ml of 0.62 mmol) was added to a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide (0,192 g, 0.31 mmol) in DCM (5 ml). The reaction mixture was stirred at K.T. overnight, then diluted with DCM and washed with water and saturated brine. Organic matter was dried over sodium sulfate, filtered and evaporated to obtain the crude specified in the subtitle compound as a pale yellow oil, which is e used in the next stage without further purification. Output: 0,25,

[M+H]+=700 (multimode+).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

A mixture of 3-(3'-(5-fluoro-3-((1s,4s)-4-(5-methylimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylenecarbonate (to 0.108 g, 0.15 mmol) and tert-butyl piperazine-1-carboxylate (0,086 g, 0.46 mmol) in acetonitrile (1.2 ml) was heated to 80°C. in a microwave reactor for 30 minutes was Added an additional amount of amine (60 mg) and the reaction mixture was placed in the same conditions for another 2 hours Volatile impurities evaporated and the residue was dissolved in DCM (0.5 ml). Was added TFA (0.5 ml, of 6.49 mmol) and the reaction mixture was stirred over night. Volatile impurities are evaporated and the crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 101 mg

1H NMR (400 MHz, CD3OD) δ 8.49-8.36 (m, 2H), 8.13-8.05 (m, 2H), 7.73-7.56 (m, 2H), 7.54-7.44 (m, 4H), 7.42-7.39 (m, 1H), 7.23 (d, J=8,2 Hz, 2H), 7.18-7.11 (m, 2H), 4.19-4.01 (m, 2H), 3.50-2.89 (m, 10H), 2.74-2.64 (m, 5H), 2.06-1.72 (m, 10H).

MS: [M+H]+=690,3 (RASSC.=690,3568) (multimode+).

Example 94

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)IU the Il)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid

To a solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (100 mg, 0,17 mmol) in dry DMF (5 ml) at CPT nitrogen was added DIPEA (0,057 ml, 0.34 mmol). The solution was stirred to homogeneity. To this solution under nitrogen was added dropwise a solution of 1H-benzo[d]imidazole-4-carboxylic acid (27.8 mg, 0,17 mmol) and 1,1'-carbonyldiimidazole (27.8 mg, 0,17 mmol) in dry DMF (5 ml) and left to mix at 40°C for 1 h, the Reaction mixture was allowed to mix at 50°C during the night. The mixture is evaporated to dryness and the residue was dissolved in chloroform (15 ml) and washed with saturated NaHCO3(aq.), water, dried (MgSO4) and evaporated to a yellow oil. This oil was purified by preparative HPLC to obtain specified in the connection header. Output: 36,5 mg.

1H NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 8.49 (d, J=6,9 Hz, 1H), 8.12-8.07 (m, 2H), 7.91 (d, J=7.7 Hz, 1H), 7.84 (d, J=8,2 Hz, 1H), 7.52-7.41 (m, 6H), 7.38 (s, 1 H), 7.16-7.10 (m, 1H), 6.87 (d,J=8.5 Hz, 1H), 4.21-4.09 (m, 2H,), 4.07 (s, 2H), 3.62-3.49 (m, 2H), 3.41 (d, J=12,8 Hz, 2H), 2.65 (t, J=12,4 Hz, 2H), 1.99-1.74 (m, 8H), 1.30 (d, J=6,7 Hz, 6H).

MS: [M+H]+=692,3 (RASSC.=692,336) (multimode+).

Example 95

2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxy-biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(2-hydroxy-5-methylbenzamide)-cyclohexyl)nicotinamide

To a solution of 2-HYDR the xylose-5-methylbenzoic acid (29,4 mg, 0,19 mmol) in THF (1 ml) was added HOBt (29,6 mg, 0,19 mmol) and EDCl (30.9 mg, 0.16 mmol), the mixture was stirred for 10 min at K.T. This mixture then was added to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornication-amide (100 mg, 0.16 mmol) and triethylamine (0,090 ml, 0.64 mmol) in THF (1 ml) and N-methyl-2-pyrrolidinone (1 ml). The reaction mixture was stirred at K.T. during the night. Prepared additional aliquot of 0.5 EQ. phenol, EDCl and HOBt and then added to the reaction mixture. The mixture is evaporated to dryness and the residue was dissolved in DCM (15 ml) and washed with saturated NaHCO3(aq.), water, dried (MgSO4) and evaporated to a yellow oil. It was purified by preparative HPLC to obtain specified in the connection header. Output: 33,5 mg.

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7,0 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.07 (dd, J=7,9, 3.1 Hz, 1H), 7.54-7.52 (m, 1H), 7.51-7.40 (m, 4H), 7.36-7.34 (m, 1H), 7.16-7.08 (m, 2H), 6.88 (d, J=8,2 Hz, 1H), 6.74 (d, J=8,2 Hz, 1H), 4.16-4.09 (m, 1H), 4.04 (s, 2H), 4.01-3.93 (m, 1H), 3.58-3.48 (m, 2H), 3.39 (d, J=11.3 Hz, 2H), 2.59 (t, J=12,4 Hz, 2H), 2.22 (s, 3H), 1.90-1.80 (m, 6H), 1.79-1.67 (m, 2H), 1.30 (d, J=6.4 Hz, 6H).

MS: [M+H]+=682,3 (RASSC.=682,3404) (multimode+).

Example 96

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-form the Il-3'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (700 mg, of 1.26 mmol) in THF (11,900 ml) was added 4-bromo-2-hydroxybenzaldehyde (500 mg, 2.49 mmol), sodium carbonate (0,158 ml of 3.78 mmol) and water (5,95 ml). Then added tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.03 mmol) and the mixture was heated up to 80°C for 24 h the Reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated to obtain the crude material. It was purified using column chromatography, obtaining specified in the subtitle compound as a foam. Output: 0,5 g

1H NMR (400 MHz, CDCl3) 6 11.11 (s, 1H), 9.94 (s, 1H), 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.64 (d, J=8,2 Hz, 1H), 7.61-7.56 (m, 2H), 7.42 (t, J=1.4 Hz, 1H), 7.28-7.19 (m, 3H), 4.42-4.34 (m, 1H), 4.21-4.15 (m, 1H), 3.65-3.59 (m, 1H), 1.88-1.67 (m, 6H), 1.54-1.46 (m, 2H), 1.41 (s, 9H).

MS: [M-H]-=548 (multimode-).

Stage (b) tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-3'-hydroxybiphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (500 mg, of 0.91 mmol) in DCM (10 ml) was added CIS-2,6-dimethylpiperazine (156 mg, of 1.36 mmol). The mixture was stirred at K.T. for 20 min, then was added triacetoxyborohydride sodium (289 mg, of 1.36 mmol). The mixture was stirred at K.T. within but is I. The reaction mixture is evaporated and the residue was dissolved in EtOAc. The EtOAc layer was washed with water, brine, dried (MgSO4) and evaporated to obtain a solid substance. It was purified by column chromatography (eluent = 5% 7 N. NH3in a mixture of methanol/DCM) to obtain specified in the subtitle compound as a foam. Yield: 430 mg

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 8.04 (d, J=7,4 Hz, 1H), 7.54-7.50 (m, 2H), 7.36-7.34 (m, 1H), 7.13-7.10 (m, 1H), 7.06-7.00 (m, 3H), 4.39-4.33 (m, 1H), 4.20-4.14 (m, 1H), 3.73 (s, 2H), 3.63-3.58 (m, 1H), 3.02-2.94 (m, 2H), 2.91-2.87 (m, 2H), 1.86-1.67 (m, 8H), 1.50-1.44 (m, 2H), 1.41 (s, 9H), 1.07 (d, J=6,4 Hz, 6N).

MS: [M+H]+=648 (multimode+).

Stage (C) N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating hydrochloride

To a solution of tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (0.4 g, of 0.62 mmol) in DCM (6 ml) was added hydrogen chloride, 4.0 M solution in dioxane (1,544 ml of 6.17 mmol). The mixture was stirred at K.T. during the night. The mixture is evaporated to dryness and the residue triturated with ether to obtain solid, which was isolated by filtration to obtain specified in the subtitle compound as a white solid. Output: 478 mg

MS: [M+H]+=548 (multimode+).

Stage (d) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)3'-hydroxybiphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To a solution of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (40,2 mg, 0.23 mmol) in acetonitrile (3 ml) was added DIPEA (0,040 ml, 0.23 mmol). To this mixture was then added HATU (87 mg, 0.23 mmol). The mixture was stirred at K.T. for 10 min, after which it was added to a solution of the hydrochloride of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.23 mmol) and DIPEA (0,040 ml, 0.23 mmol) in acetonitrile (3 ml). The mixture was stirred at K.T. during the night. To the mixture was then added 1 ml water and 1 ml of acetic acid and the mixture is then purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain a residue. His triturated with ether to obtain specified in the connection header in the form of a solid, which was isolated by filtration and dried overnight under vacuum at 40°C. Yield: 103 mg

1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J=8,2, 3.1 Hz, 1H), 8.25 (s, 1H), 8.11-8.05 (m, 2H), 7.75 (d, J=9,2 Hz, 1H), 7.60-7.56 (m, 1H), 7.52-7.45 (m, 2H), 7.37 (t, J=3,7 Hz, 1 H), 7.27 (d, J=8,2 Hz, 1 H), 7.17-7.11 (m, 3H), 6.98 (d,, J=6,9 Hz, 1H), 4.24-4.17 (m, 4H), 3.74-3.67 (m, 2H), 3.41-3.33 (m, 2H), 3.23-3.15 (m, 2H), 2.72 (s, 3H), 1.96-1.78 (m, 8H), 1.36 (d, J=6,7 Hz, 6N).

MS: [M+H]+=706,3 (RASSC.=706,3517) (multimode+).

Example 97

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-pyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (30,8 mg, 0,19 mmol) in acetonitrile (3 ml) was added DIPEA (of 0.066 ml, 0.38 mmol). To this mixture was then added HATU (72,3 mg, 0,19 mmol). The mixture was stirred at K.T. for 10 min, after which it was added to a solution of the hydrochloride of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (125 mg, 0,19 mmol) and DIPEA (of 0.066 ml, 0.38 mmol) in acetonitrile (3 ml). The mixture was stirred at K.T. during the night. Then to the mixture was added 1 ml water and 1 ml of acetic acid, after which it was purified using preparative HPLC with a reversed phase (eluent = TFA (aq.)/MeCN). The appropriate fractions were combined and evaporated to obtain a residue. His triturated with ether to obtain specified in the connection header in the form of a solid, which was isolated by filtration and dried overnight under vacuum at 40°C. Yield: 96 mg

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7,4 Hz, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.51-7.43 (m, 2H), 7.40-7.37 (m, 1H), 7.25-7.17 (m, 3H), 7.10-7.07 (m, 2H), 6.97-6.93 (m, 2H), 4.17-4.11 (m, 1H), 4.07 (s, 1H), 4.04-3.99 (m, 1H), 3.58-3.51 (m, 2H), 3.45-3.40 (m, 2H), 2.64 (t, J=12,6 Hz, 2H), 1.92-1.70 (m, 8H), 1.31 (d, J=6,4 Hz, 6N).

MS: [M+H]+=692,2 (RASSC.=692,336) (multimode+).

Example 98

N-((1s,4s)-4-(2-(4'-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of 2-methylthiazole-4-carboxylic acid (to 27.2 mg, 0,19 mmol) in acetonitrile (3,00 ml) was added DIPEA (of 0.066 ml, 0.38 mmol). To this mixture was then added HATU (72,3 mg, 0,19 mmol). The mixture was stirred at K.T. for 10 min, after which it was added to a solution of the hydrochloride of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fioricetonline (125 mg, 0,19 mmol) and DIPEA (of 0.066 ml, 0.38 mmol) in acetonitrile (3 ml). The mixture was stirred at K.T. during the night. To the reaction mixture were added 1 ml 7 N. NH3in methanol and then left to mix for 2 hours To the mixture was then added 1 ml water and 1 ml of acetic acid and then purified using prep. HPLC with reversed phase (eluent = TFA (aq.)/MeCN), the appropriate fractions were combined and evaporated to obtain a residue. His triturated with ether to obtain specified in the connection header in the form of a solid, which was isolated by filtration and dried overnight under vacuum at 40°C. Yield: 84 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7.2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.51-7.43 (m, 2H), 7.37 (t, J=1.8 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.18 (dt, J=7,9, 1.8 Hz, 1H), 7.11-7.08 (m, 2H), 4.14-4.11 (m, 1H), 4.09 (s, 2H), 4.00-3.94 (m, 1H), 3.58-3.51 (m, 2H), 3.43 (d, J=13.3 Hz, 2H), 2.67-2.60 (m, 5H), 1.88-1.67 (m, 8H), 1.32 (d, J=6,7 Hz, 6N).

MS: [M+H]+=673,2 (RASSC.=673,2972) (multimodem the I+).

Example 99

N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)cinoxacin-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexyl)cinoxacin-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (2,56 g, to 5.21 mmol) in acetonitrile (100 ml) was added cinoxacin-2-carboxylic acid (0,907 g, to 5.21 mmol) and triethylamine (7,26 ml, 52,06 mmol). With the addition of triethylamine, the reaction mixture turned into a homogeneous solution. Then added cyclic anhydride 1-papapostolou acid, 1.57 M solution in THF (3,48 ml vs. 5.47 mmol)and the mixture was stirred at K.T. within 2 hours the Mixture is evaporated to dryness and the residue was dissolved in DCM (150 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain specified in the subtitle compound as a light brown foam. Output: is 3.08,

1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.37 (dd, J=8,1, 3.2 Hz, 1H), 8.22-8.18 (m, 1H),8.11-8.07 (m, 2H), 7.95 (d, J=6,9 Hz, 1H), 7.91-7.85 (m, 3H), 7.64-7.59 (m, 1H), 7.59-7.56 (m, 1H), 7.20-7.14 (m, 2H), 4.33-4.24 (m, 1H), 4.24-4.13 (m, 1H), 2.07-1.82 (m, 6N), 1.80-1.67 (m, 2H).

MS: [M+H]+=612 (multimode+).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide

1,1'-Bis(diphenylphosphino)ferrocene (0,046 g, 0.08 mmol who) and DCM complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0,067 g, 0.08 mmol) was stirred in dry dimethylsulfoxide (10 ml) under nitrogen for 10 minutes was Added potassium acetate (0,482 g, 4,91 mmol), N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide (1 g, of 1.64 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,552 g of 2.18 mmol) and the reaction the mixture was heated at 80°C during the night. The reaction mixture was cooled and was diluted with water (100 ml). The suspension was stirred at K.T. for 30 minutes, then the precipitate was filtered. The residue was dissolved in DCM, dried (MgSO4) and the solvent was removed to obtain a brown oil. The crude substance was purified using the Biotage (eluent = pure EtOAc) to give after evaporation specified in the subtitle compound as a brown oil. Output: 0,492,

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide (485 mg, of 0.79 mmol), 2-(4-bromophenyl)ethanol (0,111 ml of 0.79 mmol) and sodium carbonate (681 mg, of 2.38 mmol) under nitrogen were added to THF (6 ml) and degassed water (3 ml). Then added tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.02 mmol) and the reaction mixture was heated under reflux for 2 hours the Mixture was poured into water and was extracted into EtOAc (×2). Extracts joint is issued, washed with brine, dried (MgSO4) and evaporated to a yellow oil. This crude substance was purified using the Biotage (eluent = 3% methanol/DCM) to give after evaporation specified in the subtitle compound as a white foam. Output: 223 mg.

1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.39 (dd, J=8,2, 3.3 Hz, 1H), 8.23-8.19 (m, 1H), 8.16-8.13 (m, 1H), 8.10 (d, J=3.1 Hz, 1H), 7.96 (dd, J=8,2, 1.5 Hz, 1H), 7.89-7.76 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.42-7.34 (m, 4H), 7.17-7.11 (m, 3H), 4.36-4.27 (m, 1H), 4.14-4.05 (m, 1H), 3.88 (t, J=6.3 Hz, 2H), 2.83 (t, J=6.3 Hz, 2H), 2.09-1.85 (m, 8H).

MS: [M+H]+=606 (multimode+).

Stage (d) 2-(3'-(5-fluoro-3-((1s,4s)-4-(cinoxacin-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide (0,265 g, 0.44 mmol) and pyridine (0,124 ml, 1.53 mmol) in DCM (10 ml) was added methanesulfonamide (0,119 ml, 1.53 mmol) and the reaction mixture was stirred at K.T. within 48 hours the Reaction mixture is evaporated to obtain a residue, which was distributed between EtOAc and 2 M HCl (aq.). The EtOAc layer was then washed with another aliquot of 2 M HCl (aq.), 2 × feast upon. NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain a light yellow oil. His triturated with ether to obtain specified in the subtitle compound in the form of not-quite-white solid. Output: 248 mg.

1H NMR (400 MHz, CD3OD) δ 9.41 (s, 1H), 8.15-8.07 (m, 3H), 8.02-7.99 (m, 1H), 7.95-7.84 (m, 2H), 7.50-7.42 (m, 5H), 7.21-7.17 (m, 3H), 4.35 (t, J=6,8 Hz, 2H), 4.22-4.15 (m, 1H), 4.08-4.00 (m, 1H), 2.93 (s, 3H), 2.01-1.73 (m, 10H).

MS: [M+H]+=684 (multimode+).

Stage (e) N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-cinoxacin-2-carboxamide

In a test tube for microwave reactor was loaded 2-(3'-(5-fluoro-3-((1s,4s)-4-(cinoxacin-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (100 mg, 0.15 mmol), (2R,6S)-2,6-dimethylpiperazine (50,1 mg, 0.44 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 30 minutes. The reaction mixture was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 52 mg

1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 8.51 (d, J=6,9 Hz, 1H), 8.29 (d, J=7,4 Hz, 1H), 8.15-8.05 (m, 3H), 8.01 (d, J=8.5 Hz, 1H), 7.95-7.83 (m, 2H), 7.51-7.39 (m, 5H), 7.19-7.11 (m, 3H), 4.23-4.14 (m, 1H), 4.07-3.98 (m, 1H), 3.67-3.55 (m, 4H), 3.15-3.07 (m, 2H), 2.96-2.88 (m, 2H), 2.75 (t, J=12.9 Hz, 2H), 2.02-1.71 (m, 8H), 1.37 (d, J=6,4 Hz, 6N).

MS: [M+H]+=702,5 (RASSC.=702,3568) (multimode+).

Example 100

N-((1s,4s)-4-(5-fluoro-2-(3'-(piperazine-1-ylmethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

The palladium(II) acetate (7,32 the g 0.03 mmol) was added to a suspension of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (0,027 g, 0.07 mmol) in acetonitrile (6 ml). The mixture was stirred at K.T. under nitrogen for 1 h solution was Added potassium carbonate (0,270 g, a 1.96 mmol) in water (3,00 ml), then a mixture of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)-nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (0.400 g, of 0.65 mmol) and 3-formylphenylboronic acid (0,147 g, 0.98 mmol). The mixture was heated at 80°C. overnight, then concentrated, diluted with EtOAc and water and filtered to remove palladium residues. The layers were separated and the organic layer was washed with water and saturated brine. Organic matter was dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica (Combi-Flash Companion, Biotage SNAP 50 g), gradient elution 0 to 5% methanol in EtOAc. Pure fractions evaporated to dryness to obtain specified in the subtitle compound as painted in cream color foam. Output: 0,341,

MS: [M+H]+=592 (multimode+).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

tert-Butylpiperazine-1-carboxylate (0,071 g, 0.38 m mol) was added to a solution of N-((1s,4s)-4-(5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carbox the amide (0,113 g, 0,19 mmol) in DCM (2 ml). After 40 min was added triacetoxyborohydride sodium (0,061 g, 0.29 mmol) and the mixture was stirred over night. Was added methanol (1 ml), then the mixture was distributed between EtOAc and water. The organic layer was washed with saturated brine and dried over sodium sulfate, then concentrated. Added DCM (1 ml), then was slowly added TFA (1 ml, 12,98 mmol). The mixture was stirred for 4 h, then concentrated and the crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water with 0.1%TFA in methanol as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 120 mg

1H NMR (400 MHz, CD3OD) δ 8.48-8.44 (m, 2H), 8.11-8.07 (m, 2H), 7.75-7.70 (m, 1H), 7.63-7.60 (m, 2H), 7.56 (d, J=8,3 Hz, 1H), 7.50 (d, J=5.3 Hz, 2H), 7.45-7.44 (m, 1H), 7.39-7.32 (m, 2H), 7.21-7.17 (m, 2H), 4.17-4.11 (m,1H),4.07-4.02 (m, 1H), 3.90-3.85 (m, 2H), 2.97-2.91 (m, 4H), 2.73-2.72 (m, 3H), 1.97-1.75 (m, 8H).

MS: [M+H]+=662,5 (RASSC.=662,3255) (multimode+).

Example 101

N-((1s,4s)-4-(2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

EDCl (0,046 g, 0.24 mmol) was added to a solution of 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxylic acid (0,040 g, 0.24 mmol) and HOBt (0.037 g, 0.24 mmol) in DMF (2 ml) and p is remedial within 15 minutes Solution was added N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3R,5S) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fluoro-nicotinamide (0.12 g, 0.22 mmol) and triethylamine (0,061 ml, 0.44 mmol) in DMF (2 ml) and the reaction mixture was stirred for another 20 h was Added to a mixture of 7 M NH3/Meon (1 ml) and was stirred for 2 hours was Acidified with 2 M HCl and purified by HPLC with reversed phase with a mixture of aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Output: 143 mg.

1H NMR (400 MHz, DMSO) δ 8.33 (d, J=7.2 Hz, 1H), 8.25 (d, J=3,4 Hz, 1H), 8.05 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.48 (m, 2H), 7.40 (m, 1H), 7.27 (d, J=8,1 Hz, 1H), 7.14 (m, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.34 (s, 1H), 4.18 (m, 2H), 4.01 (m, 4H), 3.84 (m, 2H), 3.62-3.45 (m, 5H), 2.89-2.76 (m, 2H), 2.74 (t, J=7,1 Hz, 2H), 1.96 (m, 2H), 1.81-1.60 (m, 8H), 1.24 (d, J=6,6 Hz, 6N).

MS: APCI (+ve): 696 (M+1).

Example 102

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (0.5 g, 0.87 mmol), 3-(2-hydroxyethyl)phenylboronic acid (0,144 g, 0.87 mmol) and sodium carbonate (0,109 ml, 2,60 mmol) in THF (4 ml) and water (2 ml) was added tetrakis(Triveni the phosphine)palladium(0) (0,020 g, 0.02 mmol). The mixture was heated up to 80°C during the night. The reaction mixture was cooled, diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to obtain a residue. The crude substance was purified using column chromatography (eluent = 5% MeOH/DCM)to obtain specified in the subtitle compound as a white foam. Yield: 320 mg

1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=3.1 Hz, 1H), 8.07 (dd, J=7,9, 3.1 Hz, 1H), 7.50-7.47 (m, 2H), 7.45-7.43 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.29 (t, J=7,6 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.16-7.13 (m, 1H), 6.40 (s, 1H), 4.14-4.10 (m, 1H), 3.96-3.92 (m, 1H), 3.75 (t, J=6.9 Hz, 2H), 3.68 (s, 3H), 2.83 (t, J=6.9 Hz, 2H), 2.25 (s, 3H), 1.90-1.78 (m, 6H), 1.72-1.64 (m, 2H).

MS: [M+H]+=572 (multimode+).

Stage (b) 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)ethylmethanesulfonate

To a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide (0.32 g, 0,56 mmol) in DCM (5 ml) was added pyridine (0,091 ml, 1.12 mmol) and then methanesulfonanilide (0,091 ml, 1.18 mmol). The mixture was stirred at K.T. within 18 hours the Mixture was diluted with DCM and washed with 2 M HCl (aq.), the feast upon. NaHCO3(aq.), brine, dried (MgSO4) and evaporated to obtain specified in the subtitle compound as a white foam. Output: 312 mg.

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.08-8.04 (m, 2H), 7.57-7.46 (m, 3H), 7.44-7.3 (m, 1H), 7.39-7.34 (m, 2H), 7.23 (d, J=7.7 Hz, 1H), 7.17 (dt, J=7,6, 1.9 Hz, 1H), 6.67 (d, J=7,4 Hz, 1H), 6.50 (s, 1H), 4.44 (t, J=6.9 Hz, 2H), 4.26-4.20 (m, 1H), 4.10-4.04 (m, 1H), 3.67 (s, 3H), 3.10 (t, J=6,9 Hz, 2H), 2.88 (s, 3H), 2.25 (s, 3H), 1.94-1.78 (m, 6H), 1.67-1.58 (m, 2H).

MS: [M-H]-=647,6 (multimode-).

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

In the vial for microwave reactor was loaded 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)ethylmethanesulfonate (100 mg, 0.15 mmol), tert-butyl piperazine-1-carboxylate (86 mg, 0.46 mmol) and acetonitrile (1 ml). The mixture was heated at 80°C for 45 minutes the Mixture was evaporated and dissolved in DCM (2 ml) and then was added TFA (2 ml). The mixture is evaporated and the residue was dissolved in methanol and purified using preparative HPLC with a reversed phase (eluent = a mixture of TFA (aq.)/MeCN), the appropriate fractions were combined, evaporated to obtain a residue, which was dissolved in minimum amount of DCM and then besieged using isohexane. The solvents were removed in vacuum to obtain specified in the title compound which was dried overnight at 40°C under vacuum. Yield: 73 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=6,9 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.51-7.45 (m, 4H), 7.43 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.25-7.21 (m, 1H), 7.19-7.15 (m, 1H), 6.41 (s, 1H), 4.16-4.09 (m, 1H), 3.97-3.90 (m, 1H), 3.69 (s, 3H), 3.45-3.40 (m, 4), 3.30-3.24 (m, 4H), 3.17-3.10 (m, 2H), 3.02-2.95 (m, 2H), 2.25 (s, 3H), 1.88-1.78 (m, 6H), 1.74-1.64 (m, 2H).

MS: [M+H]+=640 (RASSC.=640) (multimode+).

Example 103

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating

In the vial for microwave reactor was loaded 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-fluoro-pyridine-2-yloxy)biphenyl-3-yl)ethylmethanesulfonate (100 mg, 0.15 mmol), (2S,6R)-2,6-dimethylpiperazine (52,7 mg, 0.46 mmol) and acetonitrile (1 ml). The mixture was heated up to 80°C for 20 minutes the Mixture was purified using prep. HPLC with reversed phase (eluent = a mixture of TFA/MeCN), the appropriate fractions were combined, evaporated and the residue triturated with ether to obtain specified in the connection header in the form bezvestnogo solid, which was dried over night at 40°C under vacuum. Yield: 78 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=8,2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.51-7.46 (m, 4H), 7.43-7.42 (m, 1H), 7.36-7.31 (m, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.19-7.15 (m, 1H), 6.40 (s, 1H), 4.15-4.08 (m, 1H), 3.91 (s, 1H), 3.69 (s, 3H), 3.58-3.53 (m, 4H), 3.14-3.07 (m, 2H), 3.01-2.94 (m, 2H), 2.64 (t, J=12.9 Hz, 2H), 2.25 (s, 3H), 1.87-1.77 (m, 6H), 1.73-1.64 (m, 2H), 1.35 (d, J=6,4 Hz,6N).

MS: [M+H]+=668,3 (RASSC.=668,3724) (multimode+).

Example 104

N-((1S,4S)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6,7,8-tetrahydro-it is dazo[1,2-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine-2-carboxamide

Stir a mixture of 4-(3-hydroxypropyl)phenylboronic acid (345 mg, at 1.91 mmol), N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)-nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyridine-2-carboxamide (825 mg, 1.37 mmol) and sodium carbonate (435 mg, 4,10 mmol) in THF (16 ml) and water (8 ml) was degirolami for 5 min, and treated with tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) and was heated under reflux overnight. The solution was diluted with water and was extracted with EtOAc (2×). The extracts were washed with brine, dried (Na2SO4) and evaporated. The residue was purified on a cartridge 25 g of silica using a gradient of acetone in isohexane as eluent, to obtain specified in the subtitle compound as a white foam. Output: 351 mg

1H NMR (300 MHz, CDCl3) δ 8.40-8.35 (m, 1H), 8.09-8.04 (m, 2H), 7.70-7.59 (m, 2H), 7.54-7.49 (m, 4H), 7.39-7.35 (m, 2H), 7.26-7.24 (m, 1H), 7.17-7.12 (m, 1H), 6.95-6.90 (m, 1H), 4.27-4.17 (m, 1H), 4.13-4.03 (m, 1H), 3.98-3.94 (m, 1H), 3.76-3.66 (m, 3H), 2.81-2.71 (m, 4H), 2.02-1.78 (m, 12H), 1.70-1.61 (m, 2H).

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)-biphenyl-4-yl)propylaminosulfonyl

Mix a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)-beef the Nile-3-yloxy)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (351 mg, of 0.57 mmol), pyridine (0,139 ml, 1,72 mmol) and DMAP (dimethylaminopyridine, 7.01 mg, 0.06 mmol) in DCM (20 ml) was treated with methanesulfonamide (0,134 ml, 1,72 mmol) and was stirred over night. The mixture was treated with an additional amount of DMAP (7,01 mg, 0.06 mmol), then pyridine (0,139 ml, 1,72 mmol), and then methanesulfonanilide (0,134 ml, 1,72 mmol) and was stirred for 3 hours the Mixture was treated with an additional amount of DMAP (7,01 mg, 0.06 mmol), then pyridine (0,139 ml, 1,72 mmol), and then methanesulfonanilide (0,134 ml, 1,72 mmol) and was stirred and heated under reflux for 2 hours the Mixture was diluted with DCM, washed sequentially with 0.1 M aqueous solution of potassium hydrosulfate, then 1 M aqueous a sodium bicarbonate solution and then brine, dried (Na2SO4) and evaporated. The residue was stirred under ether for 3 h and filtered. The solid was washed with ether and dried to obtain specified in the subtitle compound as a yellow powder. Output: 283 mg.

1H NMR (300 MHz, CDCl3) δ 8.59-8.51 (m, 1H), 8.26 (dd, J=8,3, 3.1 Hz, 1H), 8.08-8.03 (m, 2H), 7.68 (d, J=8,1 Hz, 1H), 7.59 (d, J=8,3 Hz, 2H), 7.52-7.44 (m, 3H), 7.25-7.22 (m, 1H), 6.94-6.91 (m, 1H), 4.26-4.09 (m, 6H), 3.20 (t, J=6.2 Hz, 2H), 2.99 (s, 3H), 2.78 (t, J=7.5 Hz, 3H), 2.16-1.80 (m, 14H).

Stage (C) N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

peremeshivanii a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)-pyridine-2-yloxy)biphenyl-4-yl)propylenecarbonate (282 mg, 0.38 mmol) and (28,6K)-2,6-dimethylpiperazine (217 mg, 1,90 mmol) in acetonitrile (3 ml) was heated at 80°C in a microwave reactor for 20 minutes the Solution was concentrated to small volume and purified by preparative HPLC with a reversed phase column (Gemini-NX C18 5 micron 110A 30×100 mm Axia, using a gradient of methanol in 0.1%aqueous TFA at 30 ml/min as eluent, to obtain specified in the title compound as a white powder. Yield: 240 mg

1H NMR (400 MHz, DMSO) δ 8.38 (d, J=6,7 Hz, 1H), 8.25 (d, J=3.1 Hz, 1H), 8.22-8.15 (m, 1H), 8.02 (dd, J=7,9, 3.1 Hz, 1H), 7.97-7.93 (m, 1H), 7.60 (d, J=8,2 Hz, 2H), 7.53-7.50 (m, 2H), 7.44-7.43 (m, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.19-7.16 (m, 1H), 4.08-4.05 (m, 2H), 3.97-3.84 (m, 2H), 3.53-3.39 (m, 4H), 2.87 (t, J=6.2 Hz, 2H), 2.68-2.63 (m, 2H), 2.54-2.46 (m, 5H), 1.95-1.70 (m, 14H), 1.22 (d, J=6,4 Hz, 6N).

MS: [M+H]+=708,5 (RASSC.=708,4037) (multimode+).

Example 105

N-((1s,4s)-4-(2-(4'-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyridine-2-carboxamide

The palladium(II) acetate (3,72 mg, 0.02 mmol) was added to a suspension of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (0,014 g, 0.03 mmol) in acetonitrile (2,210 ml). The mixture was stirred at K.T. under nitrogen for 1 h solution was Added potassium carbonate (0,137 is, 0,99 mmol) in water (1,105 ml), then a mixture of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyridine-2-carboxamide (0.2 g, 0.33 mmol) and 4-formylphenylboronic acid (0.075 g, 0.50 mmol). The mixture was heated at 80°C during the night. The solution was concentrated, diluted with EtOAc and water. The layers were separated, and the organic layer was washed with water and saturated brine. Organic matter was dried (MgSO4), filtered and concentrated. The obtained solid was purified on silica (Biotage 50 g), elwira 7%methanol in EtOAc. The fractions containing the product were combined and concentrated to obtain specified in the subtitle compound as a pale brown foam. Output: 0,11,

MS: [M-H]-=580 (multimode+).

Stage (b) N-((1s,4s)-4-(2-(4'-(((2-(dimethylamino)ethyl)(methyl)amino)-methyl) - biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide (0.11 g, 0,19 mmol) and N1,N1,N2-trimethylated-1,2-diamine (0,024 ml to 0.19 mmol) was stirred in methanol (2 ml) at K.T. was Added acetic acid (0,016 ml, 0.28 mmol) and the reaction mixture was stirred for 30 minutes Then added triacetoxyborohydride sodium (0,200 g, 0.95 mmol) and the reaction mixture was allowed to mix under azo what Ohm for 3 hours The mixture was diluted with EtOAc and washed with saturated solution of NaHCO3(aq.) (×2), dried (MgSO4) and evaporated to obtain yellow solid (0.12 g). This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compounds as white solids. Yield: 36 mg

1H NMR (400 MHz, DMSO) δ 8.21 (d, J=4.0 Hz, 1H), 8.12 (d, J=12,8 Hz, 1H), 8.00-7.96 (m, 1H), 7.70 (s, 1H), 7.64 (d, J=9,2 Hz, 2H), 7.61-7.57 (m, 1H), 7.50-7.44 (m, 6H), 7.21-7.16 (m, 1H), 4.02 (t, J=5.8 Hz, 4H), 3.84 (s, 3H), 3.32-3.28 (m, 4H), 2.95 (t, J=6,1 Hz, 2H), 2.81-2.76 (m, 3H), 2.64 (s, 1H), 2.37 (s, 3H), 1.97-1.84 (m, 5H), 1.79-1.67 (m, 8H).

MS: [M+H]+=668,5 (RASSC.=668,3724) (multimode+).

Example 106

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-methoxybiphenyl-3-yloxy)-5-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-formyl-2'-methoxybiphenyl-3-yloxy)-nicotinamide

A solution of potassium carbonate (0,215 g, 1.56 mmol) in water (5 ml), N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodine-phenoxy)nicotinamide (0.3 g, 0.52 mmol) and 3-formyl-2-methoxyphenylalanine acid (0,112 g of 0.62 mmol) were added sequentially to paramesh is by the solution of palladium acetate(And) (0,012 g, 0.05 mmol) and S-Phos (0,042 g, 0.10 mmol) in acetonitrile (7 ml) and heated at 70°C for 1 h the Mixture was cooled to K.T., was extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with a mixture of 40% EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a brown foam. Yield: 290 mg

1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.38 (m, 1H), 8.08 (m, 2H), 7.84 (m, 2H), 7.63 (m, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.49 (m, 2H), 7.24 (m, 1H), 6.66 (d, J=8,3 Hz, 1H), 6.51 (s, 1H), 4.24 (m, 1H), 4.04 (m, 1H), 3.69 (s, 3H), 3.55 (s, 3H), 2.27 (s, 3H), 1.98-1.81 (m, 8H).

MS: APCI (+ve): 586 (M+1).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)-methyl)-2'-methoxybiphenyl-3-yloxy)-5-fornicating

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-2'-methoxybiphenyl-3-yloxy)nicotinamide (0.28 g, 0.48 mmol) and (2S,6R)-2,6-dimethylpiperazine (0,109 g, 0.96 mmol) was stirred in DCM (50 ml) for 30 minutes was Added acetic acid (by 0.055 ml, 0.96 mmol) and Meon (10 ml), then triacetoxyborohydride sodium (0,203 g, 0.96 mmol) and the reaction mixture was stirred for another 20 hours the Reaction was suppressed using 2 M HCl (30 ml), was extracted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on dioxi the e silicon with a mixture of 5% MeOH/DCM as eluent to obtain specified in the title compounds as white solids. Output: 234 mg.

1H NMR (400 MHz, DMSO) δ 9.81-9.54 (m, 1H), 9.03-8.77 (m, 1H), 8.34 (d, J=7,4 Hz, 1H), 8.24 (d, J=3.3 Hz, 1H), 8.01 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.46 (d, J=8,1 Hz, 1H), 7.38 (m, 3H), 7.20 (m, 3H), 6.36 (s, 1H), 4.04 (s, 2H), 3.97 (m, 1H), 3.80 (m, 1H), 3.70 (s, 3H), 3.59-3.30 (m, 4H), 3.33 (s, 3H), 2.65 (m, 2H), 2.23 (s, 3H), 1.77-1.57 (m, 8H), 1.21 (d, J=6,5 Hz, 6N).

MS: APCI (+ve):684 (M+1).

Example 107

2-(2'-chloro-3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fornicating

Stage (a) 2-(2'-chloro-3'-formylphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fornicating

A solution of potassium carbonate (0,215 g, 1.56 mmol) in water (5 ml), 3-bromo-2-chlorobenzaldehyde (0,137 g of 0.62 mmol) and N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)phenoxy)nicotinamide (0.3 g, 0.52 mmol) were added sequentially to a stirred solution of palladium acetate(II) (a 0.012 g, 0.05 mmol) and S-Phos (0,043 g, 0.10 mmol) in acetonitrile (7 ml) and heated at 70°C for 2 hours the Mixture was cooled to K.T., was extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with a mixture of 40% EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a brown foam. Yield: 170 mg

Stage (b) 2-(2'-chlorine is -3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fornicating

2-(2'-Chloro-3'-formylphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fornicating (0.17 g, 0.29 mmol) and (2S,6R)-2,6-dimethylpiperazine (of 0.066 g of 0.58 mmol) was stirred in DCM (50 ml) for 30 minutes was Added acetic acid (0,033 ml of 0.58 mmol) and Meon (10 ml), then triacetoxyborohydride sodium (0,122 g of 0.58 mmol) and the reaction mixture was stirred for another 20 hours the Reaction was suppressed using 2 M HCl (30 ml), was extracted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica with a mixture of 5% MeOH/DCM as eluent to obtain specified in the title compounds as white solids. Yield: 145 mg

1H NMR (400 MHz, DMSO) δ 9.07-8.93 (m, 1H), 8.34-8.18 (m, 1H), 8.30 (d, J=7,4 Hz, 1H), 8.25 (d, J=3.2 Hz, 1H), 8.00 (m, 1H), 7.49 (m, 2H), 7.37 (t, J=7,6 Hz, 1H), 7.31 (m, 1H), 7.19 (m, 3H), 6.37 (s, 1H), 3.95 (m, 1H), 3.87-3.58 (m, 2H), 3.70 (s, 2H), 3.54 (s, 2H), 3.31 (m, 2H), 2.99 (m, 2H), 2.23 (s, 3H), 2.16 (m, 2H), 1.75-1.56 (m, 8H), 1.16 (d, J=6.5 Hz, 6H).

MS: APCI (+ve): 688 (M+1).

Example 108

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(3'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Tetrakis(triphenylphosphine)palladium(0) (0,033 g, 0.03 mmol) was added to a mixture of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-idfe is hydroxy)nicotinamide)-cyclohexylcarbamate (0.8 g, 1.44 mmol), 3-(3-hydroxypropyl)phenylboronic acid (0,285 g, was 1.58 mmol) and sodium carbonate (0,458 g, 4,32 mmol) in water (5,00 ml) and THF (10 ml). The mixture was heated at 70°C for 17 hours, the Reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was dried over sodium sulfate, filtered and evaporated to obtain the crude product. This crude product was purified by flash chromatography on silica (Biotage, 100 g), elwira a mixture of 1:1 isohexane/EtOAc. Pure fractions were combined and evaporated to dryness to obtain specified in the subtitle compound as a white solid. Yield: 0.55 g

MS: [M+H]+=564 (multimode+).

Stage (b) 3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propylaminosulfonyl

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(3'-(3-hydroxypropyl)-biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.5 g, 0.89 mmol) and pyridine (0,143 ml, 1.77 mmol) in DCM (5 ml) was added methanesulfonamide (0,145 ml of 1.86 mmol) and the reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain specified in the subtitle compound in the form of not-quite-white foam. Output: 0,56,

MS: [M-H]-=640 (mode is Wai+).

Stage (C) benzyl-4-(3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)piperazine-1-carboxylate

To a solution of 3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propylenecarbonate (0,278 g, 0.43 mmol) in acetonitrile (2.5 ml) was added benzyl-piperazine-1-carboxylate (0,167 ml, 0.87 mmol). The mixture was heated up to 80°C in a microwave reactor for 45 minutes. The solution was diluted with ethyl acetate and washed with water. Organic matter was separated (×3), dried (MgSO4) and concentrated to a yellow oil. This oil pererestorani in DCM, then purified on silica (Biotage, 25 g), elwira 100% EtOAc. Organic substances were combined and concentrated to obtain specified in the subtitle compound as a white foam. Output: 0,26,

MS: [M+H]+=766 (multimode+).

Stage (d) benzyl-4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)piperazine-1-carboxylate hydrochloride

To benzyl-4-(3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)-piperazine-1-carboxylate (0.26 g, 0.34 mmol) in DCM (2 ml) was added HCl (4 mol in dioxane) (1.5 ml, 6,00 mmol). The reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was concentrated in vacuum and raster and with ether to obtain specified in the subtitle compound as a white solid in the form of HCl salts of mono. Output: 0,17,

MS: [M+H]+=666 (multimode+).

Stage (e) benzyl-4-(3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)piperazine-1-carboxylate

To a solution of benzyl-4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)piperazine-1-carboxylate (0.17 g, 0.26 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.036 g, 0.26 mmol) in acetonitrile (2 ml) was added triethylamine (0,356 ml, 2.55 mmol). The original suspension was left for 10 min to turn it into the solution. Then added 1.57 M EMM in THF (0,171 ml, 0.27 mmol) and the mixture was stirred for 2 h the Solution was diluted with water and was extracted with EtOAc. Organic substances were combined, dried (MgSO4) and concentrated in vacuum to obtain specified in the subtitle compound as a white fluffy foam. Output: 0,18,

MS: [M+H]+=788 (multimode+).

Stage (f) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-5-fluoro-2-(3'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)-nicotinamide

Benzyl-4-(3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl)-piperazine-1-carboxylate (0.15 g, 0,19 mmol) in HCl (aqueous 5 M) (a 10.74 ml, 53,69 mmol) was heated at 80°C for 1 h the Crude concentrated product was purified by preparative HPLC on column (Waters X-Bidge, using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compounds as white solids. Output: 161 mg.

1H NMR (400 MHz, DMSO) δ 8.21 (d, J=3,4 Hz, 1H), 8.10 (d, J=11.7 Hz, 1H), 7.99 (dd, J=5,4, a 5.4 Hz, 1H), 7.49-7.42 (m, 5H), 7.33 (t, J=7,3 Hz, 1H), 7.21-7.16 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.35 (s, 1H), 4.04-3.98 (m, 1H), 3.89-3.82 (m, 1H), 3.69 (s, 3H), 2.72-2.63 (m, 6H), 2.53-2.46 (m, 6H), 2.25 (s, 3H), 1.84-1.66 (m, 10H).

MS: [M+H]+=654 (RASSC.=654) (multimode+).

Example 109

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(pyrrolidin-1-yl)piperidine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo-[1,2-a]pyridine-2-carboxamide

4-(Pyrrolidin-1-yl)piperidine (0,044 g, 0.29 mmol) was added to a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide (of 0.085 g, 0.14 mmol) in DCM (2 ml). After 40 min was added triacetoxyborohydride sodium (0,046 g, 0.22 mmol) and the mixture was stirred over night. Was added methanol (1 ml), then the mixture was distributed between EtOAc and water. The organic layer was washed with saturated brine and concentrated, and then the crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-5% water 0,%TFA in methanol as eluent. The fractions containing the target compound in perivale to dryness to obtain specified in the title compound as a white foam. Yield: 107 mg

1H NMR (400 MHz, CD3OD) δ 8.54-8.43 (m, 2H), 8.10 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.77-7.68 (m, 3H), 7.66-7.60 (m, 1H), 7.56-7.51 (m, 4H), 7.47-7.45 (m, 1H), 7.24-7.14 (m, 2H), 4.35 (s, 2H), 4.16-4.03 (m, 2H), 3.68-3.59 (m, 3H), 3.44-3.37 (m, 1H), 3.17-3.04 (m, 4H), 2.73 (d, J=2,8 Hz, 3H), 2.44-2.36 (m, 2H), 2.18-1.74 (m, 14H). The remaining protons obscured by solvent.

MS: [M+H]+=730 (RASSC.=730) (multimode+).

About

N-((1s,4s)-4-(2-(4'-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxamide hydrochloride

Stage (a) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid

A solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (1 g, of 6.17 mmol) in methanol (100 ml) was first made when UA bar (350 kPa) over 5% rhodium on carbon (100 mg) overnight. The mixture was filtered through celite and the gasket was washed with methanol. The filtrates evaporated to obtain specified in the subtitle compound as a cream powder. Output: 0,953,

1H NMR (300 MHz, DMSO) δ 6.41 (s, 1H), 4.10 (t, J=6.2 Hz, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.01-1.94 (m, 2H), 1.83-1.74 (m, 2H).

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Mix a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide hydrochloride (2 g, 4.07 mmol), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (0,67 g, 4.07 mmol) and DIPEA (3.55 ml, 20,34 mmol) in DMF (20 ml) was treated with HATU (1,624 g, 4,27 mmol) and was stirred over night. The mixture is evaporated with the removal of much of the DMF and the residue was transferred into DCM, washed with water (3×), dried (Na2SO4) and evaporated. The residue was purified on a cartridge 50 g of silicon dioxide, elwira gradient of methanol in DCM, with a yellow glass. A few milligrams of this yellow glass rubbed with a drop of acetonitrile to obtain a solid substance. This substance was dissolved in a small amount of warm acetonitrile and contributed seed solids. The solution is then evaporated without heating on a rotary evaporator at 50 mbar (5 kPa) to produce specified in the subtitle compound as a cream powder. The output of 2.27,

1H NMR (400 MHz, DMSO) δ 8.29-8.26 (m, 2H), 8.03 (dd, J=7,9, 3.1 Hz, 1H), 7.60-7.57 (m, 2H), 7.24-7.20 (m, 3H), 6.34 (s, 1H), 4.08 (t, J=6.2 Hz, 2H), 3.99-3.93 (m, 1H), 3.87-3.81 (m, 1H), 2.75 (t, J=6,8 Hz, 2H), 2.00-1.94 (m, 2H), 1.81-1.62 (m, 10H). The singlet at 2,689, maybe tetramethylrhodamine of HATU.

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine-2-carboxamide

Stir the solution diacetoxynaphthalene (15 mg, 0.07 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (54 mg, 0.13 mmol) in acetonitrile (2.5 ml) was treated sequentially with a solution of potassium carbonate (275 mg, 1,99 mmol) in water (2 ml) then N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine-2-carboxamide (400 mg, 0.66 mmol)and then 4-formylphenylboronic acid (139 mg, of 0.93 mmol) and heated at 70°C for 6 hours the Mixture was diluted with EtOAc, washed with water and then brine, dried (MgSO4) and evaporated. The residue was purified on a cartridge 50 g of silica using EtOAc as eluent, to obtain specified in the subtitle compound as a brown glass. Output: 349 mg

1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.32 (d, J=7,4 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.91 (dd, J=15,5, 8,3 Hz, 4H), 7.66-7.64 (m, 2H), 7.57 (t, J=8,2 Hz, 1H), 7.30-7.27 (m, 1H), 7.24 (d, J=7.9 Hz, 1H), 6.33 (s, 1H), 4.00 (mult., hidden EtOAc), 3.86-3.79 (m, 1H), 2.74 (t, J=6.3 Hz, 2H), 1.97-1.91 (m, 2H), 1.79-1.62 (m, 10H) to +0.65 mole.% EtOAc.

Stage (d) N-((1s,4s)-4-(2-(4'-(((2-(dimethylamino)ethyl)(methyl)-amino)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide hydrochloride

Mix a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 0,17 mmol) and N1,N1,N2-trimethylated-1,2-diamine (17,57 mg, 0,17 mmol) in DCM (10 ml) was treated with acetic acid (9,84 μl, 0,17 mmol), and then triacetoxyborohydride sodium (54,7 mg, 0.26 mmol) and was stirred over night. The mixture was washed with 1 M aqueous solution of sodium bicarbonate, and then brine, dried (Na2SO4) and evaporated. The residue was purified on a cartridge 25 g of silicon dioxide, using hail the UNT 0.7 M methanolic ammonia solution in DCM as eluent, obtaining a faded oil. This glass was transferred into a small amount of DCM was treated with a few drops of 4 M hydrogen chloride in dioxane and evaporated. The residue is triturated with obtaining specified in the connection header in the form of a cream powder. Yield: 81 mg

1H NMR (400 MHz, DMSO) δ 11.40 (br s, 1H), 11.06 (br s, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.23 (d, J=3.1 Hz, 1H), 8.02 (dd, J=7,9, 3.1 Hz, 1H), 7.72 (dd, J=14,9, 8.5 Hz, 4H), 7.57-7.49 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 6.31 (s, 1H), 4.57-4.54 (m, 1H), 4.29-4.25 (m, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.98-3.93 (m, 1H), 3.83-3.79 (m, 1H), 3.69-3.62 (m, 4H), 2.81 (s, 6H), 2.71 (t, J=6.3 Hz, 2H), 2.66 (s, 3H), 1.96-1.90 (m, 2H), 1.77-1.60 (m, 10H). Also shows the presence of 0.5 mole.% dioxane.

MS: [M+H]+=668 (RASSC.=668) (multimode+).

Example 111

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylisoxazol-3-carboxamide

HATU (0.104 g g, 0.27 mmol) was added to a solution of 5-methylisoxazol-3-carboxylic acid (0.035 g, 0.27 mmol), N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornication-amide (0.15 g, 0.25 mmol) and DIPEA (0,173 ml of 0.99 mmol) in DMF (5 ml) and the solution was stirred at K.T. within 20 hours the Mixture was purified by HPLC with reversed phase with a mixture of aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 47 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7.9 Hz, 1H), .11 (d, J=3,4 Hz, 1H), 8.07 (m, 1H), 7.61 (d, J=8,2 Hz, 2H), 7.49 (d, J=5.3 Hz, 2H), 7.42 (m, 3H), 7.16 (m, 1H), 6.38 (s, 1H), 4.13 (m, 1H), 3.94 (m, 1H), 3.79 (s, 2H), 3.43 (m, 2H), 3.17 (m, 2H), 2.44 (s, 3H), 2.25 (m, 4H), 1.92-1.66 (m, 8H), 1.28 (d, J=6,9 Hz, 6N).

MS: APCI (+ve): 641 (M+1).

Example 112

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(4-(pyrrolidin-1-yl)piperidine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)-biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Tetrakis(triphenylphosphine)palladium(0) (0,062 g, 0.05 mmol) was added to a mixture of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (1,500 g, 2,70 mmol), 2-(4-bromophenyl)ethanol (0,416 ml of 2.97 mmol) and sodium carbonate (0,859 g, 8,10 mmol) in water (10,00 ml) and THF (20 ml). The mixture was heated at 70°C for 17 h, then the reaction mixture was diluted with EtOAc and washed with water and saturated brine. Organic matter was dried over sodium sulfate, filtered and evaporated to obtain the crude product. This crude product was purified by flash chromatography on silica (Combi-Flash Companion, Biotage SNAP 100 g) with gradient elution from 20 to 100% EtOAc in isohexane. Pure fractions evaporated to dryness to obtain specified in the subtitle compound as a colourless resin. Output: 1,036,

MS: [M-H]-=548 (multimode+).

Stage (b) N-(1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide hydrochloride

To tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexylcarbamate (1.1 g, 2.00 mmol) in DCM (10 ml) was added HCl (4 mol in dioxane) (10 ml, 40,00 mmol). The reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was concentrated in vacuo and triturated with ether to obtain specified in the subtitle compound as not quite white solid substance in the form of the mono-HCl salt. Output: 0,8,

MS: [M+H]+=450 (multimode+).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(2-hydroxyethyl)-biphenyl-3-yloxy)nicotinamide (0.3 g, 0.67 mmol) and 2-methylthiazole-4-carboxylic acid (0,105 g, 0.73 mmol) in acetonitrile (2 ml) was added triethylamine (0,930 ml, to 6.67 mmol). The original suspension was left for 10 min to turn it into the solution. Then added cyclic anhydride 1-papapostolou acid, 1.57 M in THF (T3P) (0,446 ml, 0.70 mmol) and the mixture was stirred for 30 minutes the Solution was diluted with water and was extracted with EtOAc. Organic substances were combined, dried (MgSO4) and concentrated in vacuum to obtain specified in the subtitle compound as a white fluffy foam. Output: 0,33,

MS: [M+H]+=575 (multimode+).

Stage (d) 2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)PI is one-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0.33 g, or 0.57 mmol) and pyridine (0,093 ml, 1.15 mmol) in DCM (3 ml) was added methanesulfonamide (0,094 ml of 1.21 mmol) and the reaction mixture was stirred at K.T. within 2 hours the Reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain oil. This oil was dissolved in DCM, then added isohexane until then, until it formed a solid substance. The suspension was concentrated in vacuum to obtain specified in the subtitle compound in the form of not-quite-white foam. Output: 0,38,

MS: [M+H]+=653 (multimode+).

Stage (e) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(4-(pyrrolidin-1-yl)piperidine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of 2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)-cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethylmethanesulfonate (0,19 g, 0.29 mmol) in acetonitrile (2 ml) was added 4-(pyrrolidin-1-yl)piperidine (0,112 g, 0.73 mmol). The mixture was heated up to 80°C in a microwave reactor for 30 minutes was Added an additional amount of 4-(pyrrolidin-1-yl)piperidine (0,112 g, 0.73 mmol) and the reaction mixture was stirred for another hour at 80°C. the Crude product was purified group is a rotary preparative HPLC on a column (Waters X-Bridge, using the gradient 95-5% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound were subjected to freeze-drying to obtain specified in the title compounds as white solids. Yield: 86 mg

1H NMR (300 MHz, DMSO) δ 10.29-10.21 (m, 1H), 10.03-9.96 (m, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.26 (d, J=3,4 Hz, 1H), 8.08-8.03 (m, 2H), 7.64 (d, J=8,4 Hz, 2H), 7.59-7.47 (m, 3H), 7.34 (s, 1H), 7.31 (s, 1H), 7.22-7.17 (m, 1H), 4.05-3.97 (m, 1H), 3.91-3.83 (m, 1H), 3.78-3.68 (m, 2H), 3.13-2.95 (m, 3H), 2.67 (s, 3H), 2.53-2.48 (m, 9H), 2.37-2.30 (m, 2H), 2.07-1.83 (m, 5H), 1.78-1.65 (m, 8H).

MS: [M+H]+=711 (RASSC.=711) (multimode+).

Example 113

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxamide

Mix a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 0,17 mmol) and (2R,6S)-2,6-dimethylpiperazine (of 29.4 mg, 0.26 mmol) in DCM (10 ml) was treated with acetic acid (9,84 μl, 0,17 mmol), and then triacetoxyborohydride sodium (54,7 mg, 0.26 mmol) and stirred throughout the night. The mixture was treated with an additional amount of (2R,6S)-2,6-dimethylpiperazine (15 mg) and triacetoxyborohydride sodium (22 mg) and was stirred for 6 hours the Mixture was washed with 1 M aqueous solution of sodium bicarbonate, then brine, dried (Na2SO4and the flash steam is Vali. The residue was purified by preparative HPLC with a reversed phase column (Gemini-NX C18 5 micron 110A 30×100 mm Axia, using a gradient of methanol in 0.1%aqueous TFA at 30 ml/min as eluent, to obtain specified in the title compound as a white powder. Yield: 94 mg

1H NMR (400 MHz, DMSO) δ 8.97-8.88 (m, 1H), 8.32 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.23-8.14 (m, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.66 (d, J=7.9 Hz, 2H), 7.54-7.51 (m, 2H), 7.48-7.46 (m, 1H), 7.39 (d, J=7.9 Hz, 2H), 7.26-7.19 (m, 2H), 6.34 (s, 1H), 4.04 (t, J=6.2 Hz, 2H), 4.00-3.96 (m, 1H), 3.86-3.82 (m, 1H), 3.72-3.68 (m, 1H), 3.35-3.31 (m, 2H), 3.05-3.01 (m, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.54-2.52 (m, 2H hidden DMSO), 2.16-2.07 (m, 1H), 1.99-1.93 (m, 2H), 1.80-1.61 (m, 10H), 1.17 (d, J=6,7 Hz, 6N).

MS: [M+H]+=680 (RASSC.=680) (multimode+).

Example 114

N-((1s,4s)-4-(5-fluoro-2-(4'-(piperazine-1-ylmethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Mix a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)-nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 0,17 mmol) and tert-butyl piperazine-1-carboxylate (48,0 mg, 0.26 mmol) in DCM (10 ml) was treated with acetic acid (9,84 μl, 0,17 mmol), and then triacetoxyborohydride sodium (54,7 mg, 0.26 mmol) and was stirred overnight. The mixture was treated with an additional quantity of tert-butyl piperazine-1-carboxylate (24 mg, 0.26 mmol) and triacetoxyborohydride sodium (22 mg) and peremeshivayu for 6 hours The mixture was washed with 1 M aqueous solution of sodium bicarbonate, and then brine, dried (Na2SO4) and evaporated. The residue was transferred into DCM (20 ml) and was treated with TFA (10 ml, 129,80 mmol) and was stirred for 1 h the Mixture was evaporated and the residue was purified by preparative HPLC with a reversed phase column (Gemini-NX C18 5 micron 110A 30×100 mm Axia, using a gradient of methanol in 0.1%aqueous TFA at 30 ml/min as eluent, to obtain specified in the title compound as a white powder. Yield: 88 mg

1H NMR (400 MHz, DMSO) δ 8.80-8.66 (m, 2H), 8.33 (d, J=7.2 Hz, 1H), 8.26 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.55-7.50 (m, 3H), 7.44 (d, J=7.7 Hz, 2H), 7.26-7.20 (m, 2H), 6.34 (s, 1H), 4.04 (t, J=6.2 Hz, 2H), 4.01-3.95 (m, 2H), 3.89-3.81 (m, 2H), 3.25-3.14 (m, 4H), 2.91-2.81 (m, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.54-2.52 (m, 2H), 1.99-1.93 (m, 2H), 1.80-1.61 (m, 10H).

MS: [M+H]+=652,2 (RASSC.=652,3411) (multimode+).

Example 115

6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-((3-morpholinopropan)methyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

A solution of palladium(II) acetate (0,013 g, 0.06 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0,047 g, 0.11 mmol) in acetonitrile (9,45 ml) was stirred at K.T. under nitrogen for 15 minutes was Added potassium carbonate (0,470 g, 3,40 mmol) in water (4.72 in the l), and then 4-formylphenylboronic acid (0,255 g, 1.70 mmol) and 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide (0.7 g, 1.13 mmol). The reaction mixture was heated up to 80°C for 1 h, the Reaction mixture was diluted with EtOAc and washed with water. Organic matter was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. This crude product was purified by flash chromatography on silica, using a column Isco Companion, 100 g silica, gradient elution from 3 to 7% methanol in dichloromethane. Pure fractions evaporated to dryness to obtain specified in the subtitle compound as a yellow solid. Output: 0,500,

1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.40 (dd, J=8,3, 3,9 Hz, 1H), 8.10 (s, 1H), 8.09-8.02 (m, 3H), 7.90 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.47-7.46 (m, 1H), 7.44-7.40 (m, 1H), 7.25-7.12 (m, 3H), 4.30-4.23 (m, 1H), 2.00-1.81 (m, 6H), 1.76-1.65 (m, 2H).

MS: [M+H]+=596,2 (multimode+).

Stage (b) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-((3-morpholinopropan-amino)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

To a stirred solution of 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-formylphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide (0,200 g, 0.34 mmol) in DCM (5 ml) was added acetic acid (0,038 ml, 0.67 mmol). The reaction mixture was stirred at K.T. is for 15 minutes Added triacetoxyborohydride sodium (0,142 g, 0.67 mmol) and the reaction mixture was stirred at K.T. within 3 days. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. Organic matter was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. This crude product was purified by preparative HPLC on a column of Phenomenex Gemini, using the gradient 95-15% water and 0.2%TFA in acetonitrile as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 35 mg

1H NMR (400 MHz, CD3OD) δ 8.61-8.58 (m, 1H), 8.47 (d, J=7.5 Hz, 1H), 8.30 (s, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,5, and 3.8 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.60-7.55 (m, 1H), 7.52-7.49 (m, 3H), 7.45-7.43 (m, 2H), 7.23-7.19 (m, 1H), 4.24 (s, 2H), 4.15-4.08 (m, 1H), 4.08-4.00 (m, 1H), 3.98-3.77 (m, 2H), 3.32-3.29 (m, 2H), 3.23 (t, J=8,4 Hz, 4H), 3.15 (t, J=8,4 Hz, 4H), 2.22-2.12 (m, 2H), 1.90-1.71 (m, 8H).

MS: [M+H]+=724,2 (multimode+).

Example 116

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(isopropylamino)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

In a test tube for microwave reactor was loaded 3-(3'-(5-fluoro-3-((1s,4s)-4-(5-methylimidazo[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (0.2 g, 0.29 mmol), propane-2-amine (0,122 ml, 143 mmol) and acetonitrile (1.5 ml). The reaction mixture was heated in a microwave reactor at 80°C for 2 hours It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 96 mg

1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.46 (d, J=7.8 Hz, 1H), 8.12-8.04 (m, 2H), 7.75 (dd, J=8,8, 7,3 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.53 (d, J=8,2 Hz, 2H), 7.47 (d, J=5,1 Hz, 2H), 7.42 (s, 1H), 7.27-7.12 (m, 5H), 4.18-4.09 (m, 1H), 4.09-4.01 (m, 1H), 3.38-3.26 (m, 5H), 2.99 (t, J=8,1 Hz, 2H), 2.72-2.67 (m, 1H), 2.03-1.74 (m, 10H), 1.29 (d, J=6,7 Hz, 6N).

MS: [M+H]+=663 (RASSC.=663) (multimode+).

Example 117

6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

To a stirred solution of 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide (0,304 g, 0.49 mmol) in THF (3,81 ml) was added 4-(2-hydroxyethyl)phenylboronic acid (0.09 g, 0.54 mmol) and sodium carbonate (of) 0.157 g, 1.48 mmol) in water (1,903 ml). The reaction mixture was stirred at K.T. under nitrogen for 15 minutes was Added tetrakis(triphenylphosphine)palladium(0) (0,011 g, 9,86 mmol) and the reaction mixture was heated to 70°C during the night. The reaction mixture was diluted with EtOAc and washed with water. Organic matter was dried over sulfate MAGN what I was filtered and evaporated to obtain the crude product. This crude product was purified by flash chromatography on silica, using a column Isco Companion, 50 g silica, gradient elution from 3 to 7% methanol in DCM. Pure fractions evaporated to dryness to obtain specified in the subtitle compound as a yellow foam. Output: 0,295,

1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J=7,7, 3.0 Hz, 1H), 8.10-8.05 (m, 3H), 7.54-7.50 (m, 3H), 7.46-7.41 (m, 2H), 7.38-7.37 (m, 1H), 7.25-7.19 (m, 2H), 7.17-7.12 (m, 2H), 4.29-4.19 (m, 1H), 4.18-4.09 (m, 1H), 3.88 (t, J=6,1 Hz, 2H), 2.88 (t, J=6,1 Hz, 2H), 1.99-1.79(m,6H), 1.74-1.64 (m, 2H).

MS: [M+H]+=612,2 (multimode+).

Stage (b) 2-(3'-(5-fluoro-3-((1s,4s)-4-(6-torymidae[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)-ethylmethanesulfonate

To a stirred solution of 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]-pyridine-2-carboxamide (0,295 g, 0.48 mmol) in DCM (6,74 ml) was added pyridine (0,078 ml, 0.96 mmol) and methanesulfonamide (0.075 ml, 0.96 mmol). The reaction mixture was stirred at K.T. under nitrogen overnight. The reaction mixture was diluted with DCM and washed with 2 M hydrochloric acid. Organic matter was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. This crude resin was washed with diethyl ether to obtain a solid substance, of which the second was collected by filtration and dried in air to obtain specified in the subtitle compound as a yellow solid. Output: 0,200,

1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=8,2, 3.5 Hz, 1H), 8.21 (s, 1H), 8.19-8.16 (m, 1H), 8.08 (s, 1H), 8.06 (d, J=2,9 Hz, 1H), 7.62-7.42 (m, 7H), 7.28 (s, 1H), 7.22 (d, J=8,2 Hz, 2H), 4.44 (t, J=6,8 Hz, 2H), 4.27-4.19 (m, 1H), 3.07 (t, J=6.5 Hz, 2H), 2.87 (s, 3H), 2.04-1.50 (m, 8H).

MS: [M+H]+=690,2 (multimode+).

Stage (C) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]-pyridine-2-carboxamide

In the vial for microwave reactor was added 2-(3'-(5-fluoro-3-((1s,4s)-4-(6-torymidae[1,2-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate (0,200 g, 0.29 mmol) and tert-butyl piperazine-1-carboxylate (0,270 g, 1,45 mmol) in acetonitrile (2 ml). The reaction mixture was heated to 100°C. by microwave irradiation for 4 h, the Reaction mixture was evaporated to dryness and pererestorani in DCM (2 ml) was added TFA (0,894 ml, 11,60 mmol). The reaction mixture was stirred at K.T. within 1 h, and then concentrated to obtain the crude product. This crude product was purified by preparative HPLC on a column (Waters X-Bridge, using the gradient 80-0% water and 0.2%TFA in methanol as eluent. The fractions containing the target compound evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 100 mg

1H NMR (400 MHz, CD3OD) δ at 8.62 (t, J=3.8 Hz, 1H), 8.31 (s, 1H), 8.12-8.10 (m, 1H), 8.09-8.05 (m, 1H, 7.61-7.52 (m, 3H), 7.50-7.44 (m, 3H), 7.42-7.40 (m, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.18-7.15 (m, 1H), 4.16-4.08 (m, 1H), 4.06-4.00 (m, 1H), 3.52-3.48 (m, 4H), 3.43-3.38 (m, 4H), 3.27-3.24 (m, 2H), 3.05-2.98 (m, 2H), 1.92-1.70 (m, 8H).

MS: (M+H)+=680,2.

Example 118

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Stir the solution diacetoxynaphthalene (7 mg, 0.03 mmol) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (27 mg, 0.07 mmol) in acetonitrile (2.5 ml) was treated sequentially with a solution of potassium carbonate (137 mg, 0,99 mmol) in water (2 ml), then N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyridine-2-carboxamido (200 mg, 0.33 mmol), then 4-(3-hydroxypropyl)-phenylboronic acid (84 mg, 0.46 mmol) and heated at 70°C for 6 hours the Mixture was diluted with EtOAc, washed with water and saturated brine, dried (MgSO4) and evaporated. The residue was purified on a cartridge Biotage Snap 25 g, elwira gradient from 50 to 100% acetone in isohexane, obtaining specified in the subtitle compound as a white foam. Yield: 170 mg

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.08 (d, J=3.1 Hz, 2H), 7.55-7.49 (m, 4H), 7.37-7.35 (m, 1H), 7.25-7.23 (m, 4H), 7.14 (dt, J=4,7, 2.4 G is, 1H), 6.71-6.69 (m, 1H), 6.47 (s, 1H), 4.26-4.20 (m, 1H), 4.11-4.05 (m, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.74-3.68 (m, 2H), 2.79-2.73 (m, 4H), 2.02-1.95 (m, 2H), 1.94-1.80 (m, 10H), 1.66-1.60 (m, 2H).

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl

Mix a solution of N-((1s,4s)-4-(fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (170 mg, 0.28 mmol) and pyridine (0,067 ml, 0.83 mmol) in DCM (10 ml) was treated with methanesulfonamide (0,065 ml, 0.83 mmol) and was stirred over the weekend. The solution was diluted with DCM and washed with 2 M HCl and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle of the connection.

1H NMR (400 MHz, CDCl3) δ 8.33 (dd, J=8,7, 2,9 Hz, 1H), 8.07 (s, 1H), 8.06 (d, J=3.6 Hz, 1H), 7.66-7.59 (m, 1H), 7.57-7.48 (m, 5H), 7.43-7.41 (m, 1H), 7.24 (d, J=7,3 Hz, 2H), 6.67 (s, 1H), 4.29-4.14 (m, 2H), 3.00 (s, 3H), 2.87 (t, J=6,7 Hz, 2H), 2.78 (t, J=8,1 Hz, 2H), 2.17-2.03 (m, 4H), 1.95-1.70 (m, 10H).

MS: [M+H]+=690,2 (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

In the vial for microwave processing was added 3-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-cyclohexylcarbonyl)-pyridine-2-yloxy)biphenyl-4-yl)-profile insolvent (0.09 g, 0.13 mmol) and piperazine (0,225 g, 2,61 mmol) in acetonitrile (1 ml). The reaction mixture was heated to 100°C. by microwave for 30 minutes the Reaction mixture was concentrated to obtain the crude product, which was purified preparative HPLC column Phenomenex Gemini using 95-15%gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Output: 0,043,

1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=2.4 Hz, 1H), 8.07 (dd, J=9,2, 2.4 Hz, 1H), 7.52-7.46 (m, 5H), 7.39 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.16-7.12 (m, 1H), 6.38 (s, 1H), 4.14-4.09 (m, 1H), 4.01 (t, J=6,1 Hz, 2H), 3.98-3.91 (m, 1H), 2.92-2.64 (m, 9H), 2.03-1.95 (m, 2H), 1.93-1.63 (m, 10H).

MS: [M+H]+=680,3 (multimode+)

Example 119

N-((1s,4s)-4-(2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) 4-hydroxy-N-methoxy-N-methyl-3-(morpholinomethyl)benzamid

EDCl (4.44 g, 23,18 mmol) was added in portions to a solution of 4-hydroxy-3-(morpholinomethyl)benzoic acid (5 g, 21,07 mmol), N,O-dimethylhydroxylamine (2.67 g, 27,40 mmol), DIPEA (of 4.05 ml, 23,18 mmol) and HOBt (3.55 g, 23,18 mmol) in DMF (25 ml), keeping the temperature below 10°C. the Mixture was stirred for 48 h, diluted with EtOAc (200 ml), washed with saturated NaHCO3(200 ml), water (2×100 ml) and brine, dried (Na2SO ), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with EtOAc as eluent to obtain specified in the subtitle compound as a colourless oil. Output: 3,20 g

1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8,8 Hz, 1H), 7.47 (s, 1H), 6.81 (d, J=8,8 Hz, 1H), 3.82-3.71 (m, 4H), 3.75 (s, 2H), 3.57 (s, 3H), 3.34 (s, 3H), 2.67-2.50 (m, 4H).

MS: APCI (+ve): 281 (M+1)

Stage (b) 4-hydroxy-3-(morpholinomethyl)benzaldehyde

Bis(cyclopentadienyl)zirconium chloride hydride (4,29 g, 16,27 mmol) was added in portions over 10 min to a solution of 4-hydroxy-N-methoxy-N-methyl-3-(morpholinomethyl)benzamide (3.8 g, 13.56 mmol) in THF (50 ml)in an atmosphere of N2maintaining the temperature below 20°C. was Stirred for 2 h, extinguished saturated potassium sodium tartrate, was extracted with EtOAc (3×100 ml), washed with saturated potassium sodium tartrate and brine, dried (Na2SO4), filtered and evaporated in vacuum. Was purified by flash chromatography with EtOAc as eluent to obtain specified in the subtitle compound as a colourless oil. Yield: 2.1 g

1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 6.93 (d, J=8.7 Hz, 1H), 3.85-3.70 (m, 4H), 3.80 (s, 2H), 2.71-2.49 (m, 4H).

MS: APCI (+ve): 222 (M+1)

Stage (C) 4-formyl-2-(morpholinomethyl)phenyl-triftorbyenzola

N-Phenyltrichlorosilane (5,09 g, 14.24 from mmol) was added to a solution of 4-hydroxy-3-(morpholine is Teal)benzaldehyde (2.1 g, 9,49 mmol) and triethylamine (3,97 ml, 28,47 mmol) in DCM (20 ml), cooled to 0°C. the Mixture was left to reach K.T. and was stirred for another 16 hours the Solution was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue was purified by chromatography with 30%mixture of EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a colourless oil. Output: 3,17 g

1H NMR (400 MHz, CDCl3) δ of 10.05 (s, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8,3, 2.2 Hz, 1H), 7.44 (d, J=8,4 Hz, 7H), 3.71 (m, 4H), 3.62 (s, 2H), 2.48 (m, 4H).

MS: APCI (+ve): 354 (M+1)

Stage (d) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

The potassium carbonate solution (at 2,426 g, 17,55 mmol) in water (30 ml), 4-formyl-2-(morpholinomethyl)phenyl-triftorbyenzola (2,481 g, 7,02 mmol) and tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (3.25 g, of 5.85 mmol) were added sequentially to a stirred solution of palladium(II) acetate (0,131 g, 0.59 mmol) and S-Phos (to 0.480 g at 1.17 mmol) in acetonitrile (50 ml) and heated at 70°C for 2 hours the Mixture was cooled to K.T., was extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with 30%mixture of EtOAc/isohexane as eluent is obtaining specified in the subtitle compound as a brown foam. Yield: 2.3 g

1H NMR (400 MHz, CDCl3) δ 10,07 (s, 1H), 8.37 (m, 1H), 8.06 (d, J=3.1 Hz, 1H), 8.00 (m, 1H), 7.96 (d, J=8,2 Hz, 1H), 7.85 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 4.49 (m, 1H), 4.17 (m, 1H), 3.63 (m, 1H), 3.58 (m, 4H), 3.49 (s, 2H), 2.36 (m, 4H), 1.88-1.46 (m, 8H), 1.42 (s, 9H).

MS: APCI (+ve): 633 (M+1)

Stage (e) N-((1s,4s)-4-aminocyclohexane)-2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1.2 g, 1,90 mmol) in DCM (300 ml) was added dimethylamine (1,832 ml, with 3.79 mmol) 2.07 M in MTBE. The mixture was left to mix with K.T. for 30 min, then was added acetic acid (0,217 ml, with 3.79 mmol), then sodium triacetoxyborohydride (0,804 g, with 3.79 mmol). The reaction mixture was stirred at K.T. within 20 hours the Reaction was suppressed 2 M aqueous HCl (300 ml), was extracted with EtOAc, washed with water and brine, dried (Na2SO4) and was evaporated in vacuum. Acid leaching was partially removed group VOS and correspondingly large portion of the product was in the water layer, which was then podslushivaet 2 M aqueous NaOH and was extracted with EtOAc. All organic extracts were combined, dried (MgSO4) and concentrated in vacuum. The residue was dissolved in DCM (15 ml) was added 4M HCl in dioxane (8 ml, 32.00 mmol)and the mixture was stirred for 30 minutes. The solvents were removed in vacuo, and the residue triturated what with diethyl ether to obtain a solid substance. The solid substance was collected by filtration to obtain specified in the subtitle compound as a white solid. Output: 0,952,

1H NMR (300 MHz, DMSO) δ 11.05 (s, 1H), 8.37 (d, J=6,5 Hz, 1H), 8.29 (d, J=3.1 Hz, 1H), 8.15 (m, 3H), 8.05 (dd, J=8,1, 3.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.33 (m, 1H), 7.25 (m, 2H), 4.35 (m, 4H), 4.01-3.68 (m, 5H), 3.15 (m, 2H), 2.85 (m, 2H), 2.78 (s, 3H), 2.76 (s, 3H), 1.93-1.56 (m, 8H).

MS: [M+H]+=562 (expect.=562) (multimode+)

Stage (f) N-((1s,4s)-4-(2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

HATU (116 mg, 0.30 mmol) was added in one portion to N-((1s,4s)-4-aminocyclohexane)-2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating (170 mg, 0.25 mmol), 2-methylthiazole-4-carboxylic acid (39.9 mg, 0.28 mmol) and DIPEA (0,221 ml of 1.27 mmol) in DMF (2 ml) at 25°C in nitrogen atmosphere. The resulting solution was stirred at 25°C for 2 h, the Reaction mixture was diluted with methanol (2 ml) and acidified with HCl. The crude reaction mixture was then purified on HPLC with reversed phase 95/05 MeOH/TFA. Specified in the title compound was obtained as a white solid after freeze drying. Yield: 90 mg

1H NMR (300 MHz, DMSO) δ 8.37 (d, J=6,9 Hz, 1H), 8.28 (d, J=2,9 Hz, 1H), 8.09 (s, 1H), 8.05 (dd, J=7,9, or 2.9 Hz, 1H), 7.78 (s, 1H), 7.66-7.52 (m, 3H), 7.46 (d, J=7.9 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.22 (m, 2H), 4.33 (s, 6H), 3.99 (s, 1H), 3.88 (s, 1H), 3.65 (s, 4H), 2.79 (s, 8H), 2.68 (s, 3H), 1.69 (m, 8H).

MS: [M+H]+=67 (expect.=687) (multimode+)

Example 120

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating

HATU (116 mg, 0.30 mmol) was added in one portion to N-((1s,4s)-4-aminocyclohexane)-2-(4'-((dimethylamino)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating (170 mg, 0.25 mmol), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (39,1 mg, 0.28 mmol) and DIPEA (0,221 ml of 1.27 mmol) in DMF (2 ml) at 25°C. in nitrogen atmosphere. The resulting solution was stirred at 25°C for 2 h, the Reaction mixture was diluted with methanol (2 ml) and acidified with HCl. The crude reaction mixture was then purified on HPLC with reversed phase 95/05 MeOH/TFA. Specified in the title compound was obtained as a white solid after freeze drying. Output: 132 mg.

1H NMR (300 MHz, DMSO) δ 8.36 (d, J=7,1 Hz, 1H), 8.28 (d, J=3.1 Hz, 1H), 8.05 (dd, J=8.0 a, 3.0 Hz, 1H), 7.77 (s, 1H), 7.67-7.52 (m, 3H), 7.48 (d, J=7.9 Hz, 1H), 7.22 (m, 3H), 6.40 (s, 1H), 4.33 (s, 6H), 3.96 (s, 1H), 3.84 (s, 1H), 3.75 (s, 3H), 3.66 (s, 4H), 2.79 (s, 8H), 2.26 (s, 3H), 1.70 (m, 8H).

MS: [M+H]+=684 (expect.=684) (multimode+)

Example 121

6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

Stage (a) 3-(4-bromophenyl)propan-1-ol

To a stirred solution of 3-(4-bromophenyl)propanoic acid (7 g, 30,56 mmol) in THF (50,9 ml) at -10°C. add the Yali complex borohydride and tetrahydrofuran (1 M in THF) (153 ml, 152,79 mmol) dropwise over 1 h, keeping the temperature below 0°C. the Reaction mixture was left to warm to K.T. overnight, then was cooled to 5°C and extinguished the Meon (50 ml). The reaction mixture was stirred at K.T. for 1 h and then concentrated to obtain oil. The oil was distributed between ether (120 ml) and 2 M NaOH (60 ml). The organic layer is then washed with water (60 ml) and brine, dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 6,17 g

1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.5 Hz, 2H), 3.66 (t, J=6.3 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.90-1.82 (m, 2H).

Stage (b) 3-(4-bromophenyl)propyl-methanesulfonate

To a stirred solution of 3-(4-bromophenyl)propan-1-ol (6,17 g, 28,69 mmol) in dichloromethane (40 ml) was added triethylamine (4,80 ml, 34,42 mmol) and methanesulfonamide (2,68 ml, 34,42 mmol). The reaction mixture was stirred at K.T. in nitrogen atmosphere overnight. The reaction mixture is evaporated to dryness and was distributed between EtOAc (50 ml) and water (25 ml), the aqueous portion was extracted with EtOAc (2×25 ml). The combined organic substance was washed with 2 M hydrochloric acid (2×25 ml) and saturated brine (25 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 8,60

1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 4.22 (t, J=6.5 Hz, 2H), 3.00 (s, 3H), 2.71 (t, J=8.0 Hz, 2H), 2.09-2.01 (m, 2H).

Stage (C) tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate

To a stirred solution of 3-(4-bromophenyl)propylenecarbonate (4,2 g, 14,33 mmol) in acetonitrile (33,2 ml) was added tert-butyl piperazine-1-carboxylate (3,47 g, 18,62 mmol) and triethylamine (2,60 ml, 18,62 mmol). The reaction mixture was heated to 75°C during the night. The reaction mixture was evaporated to dryness and pererestorani in EtOAc (40 ml), and washed with a mixture of 2:8 saturated brine:water (45 ml). The aqueous layer was extracted with EtOAc (2×25 ml), organics combined and washed with a mixture of 2:8 saturated brine:water (2×45 ml) and saturated brine (25 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column of silica Isco Companion, 50 g, gradient elution of 30-50% EtOAc in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow oil. Output: 2,4,

1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=10.4 Hz, 2H), 7.05 (d, J=8,3 Hz, 2H), 3.43 (t, J=5.4 Hz, 4H), 2.59 (t, J=7.8 Hz, 2H), 2.38-2.31 (m, 6H), 1.78 (quintet, J=7,4 Hz, 2H), 1.46 (s, 9H).

MS: [M+H]+=of 383.0 (multimode+)

Stage (d) tert-butyl 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)piperazine-1-carboxylate

p> To a stirred solution of tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate (2.4 g, 6.26 mmol) in acetonitrile (12 ml) was added triethylamine (2,62 ml, 18,78 mmol) and Pd-118 (0,122 g 0,19 mmol). The reaction mixture was stirred at K.T. in nitrogen atmosphere for 10 minutes was Added 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1,363 ml, 9,39 mmol)and the reaction mixture was heated up to 80°C for 1 h, the Reaction mixture was evaporated to dryness and pererestorani in EtOAc and washed with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column of silica Isco Companion, 100 g, gradient elution of 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a brown oil. Yield: 0.9 g

1R NMR (400 MHz, CDCl3) δ 7.72 (d, J=7,1 Hz, 2H), 7.21-7.16 (m, 2H), 3.45-3.40 (m, 4H), 2.67-2.61 (m, 2H), 2.39-2.32 (m, 6H), 1.86-1.77 (m, 2H), 1.45 (s, 9H), 1.24 (s, 12H).

MS: [M+H]+=431,2 (multimode+)

Stage (e) tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (1,587 g, 3,49 mmol) and tert-butyl 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)PI is erasin-1-carboxylate (1.5 g, to 3.49 mmol) in THF (22.85 ml) was added sodium carbonate (0,584 ml, 13,94 mmol), water (11,42 ml) and tetrakis(triphenylphosphine)palladium(0) (0,201 g, 0,17 mmol). The mixture was heated up to 80°C for 36 h, the Mixture was cooled, poured into water and the organic matter was extracted with EtOAc (×2). The extraction were combined, dried and evaporated to obtain an oil. It was purified using column chromatography (eluent = 4% 7 N NH3in a mixture of methanol/DCM) to obtain specified in the subtitle compound as oil. Yield: 1.5 g

MS: [M+H]+=632,43 (multimode+)

Stage (f) 6-fluoro-N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)imidazo[1,2-a]pyridine-2-carboxamide

To a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (2 ml) were added hydrochloride 6-torymidae[1,2-a]pyridine-2-carboxylic acid (51,4 mg, 0.24 mmol) and triethylamine (0,331 ml, is 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 1 h the Mixture was poured into a feast upon. NaHCO3(aq.), and organic matter was extracted with EtOAc (×2). The extraction were combined, dried (MgSO4) and was evaporated to obtain a residue. It was dissolved in DCM (2 ml)to which was added TFA (2 ml)and the mixture was stirred at K. the. within 20 minutes the Solvents were removed in vacuum and the residue was dissolved in methanol and purified using preparative chromatography with reversed phase, using eluent = TFA (aq.)/Meon). The appropriate fractions were combined and evaporated to obtain the residue, which when crushed with ether gave a solid. The solid was dried overnight under vacuum at 40°C To produce specified in the connection header. Yield: 64 mg

1H NMR (400 MHz, CD3OD) δ 8.57 (t, J=3.1 Hz, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 8,12-8.05 (m, 2H), 7.59-7.44 (m, 5H), 7.43-7.37 (m, 2H), 7.21 (d, J=8,2 Hz, 2H), 7.18-7.12 (m, 1H), 4.15-4.10 (m, 1H), 4.05-4.00 (m, 1H), 3.48-3.44 (m, 4H), 3.35-3.31 (m, 4H), 3.05-2.99 (m, 2H), 2.69 (t, J=7.4 Hz, 2H), 2.05-1.96 (m, 2H), 1.92-1.70 (m, 8H).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 122

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1.0 g, was 1.58 mmol) and (2S,6R)-2,6-dimethylpiperazine (0,361 g, and 3.16 mmol) was stirred in DCM (30 ml) for 15 minutes was Added acetic acid (0,181 ml, and 3.16 mmol), then sodium triacetoxy borgere (0,670 g, and 3.16 mmol)and the reaction mixture was stirred for another 20 hours the Reaction was suppressed 2 M HCl (30 ml), was extracted with EtOAc, washed with water and brine, dried (Na2SO4) and was evaporated in vacuum. The residue was purified by chromatography on silica with 5%mixture of MeOH/DCM as eluent to obtain specified in the subtitle compound as a white solid. Output: 1,05 g

1H NMR (300 MHz, CDCl3) δ 8.36 (m, 1H), 8.06 (d, J=3.2 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.38 (m, 2H), 7.35 (m, 1H), 7.30 (m, 1H), 7.27 (m, 3H), 7.14 (m, 1H), 4.49 (m, 1H), 4.16 (m, 1H), 3.55 (m, 8H), 3.41 (s, 2H), 3.01 (m, 2H), 2.80 (m, 2H), 2.33 (m, 4H), 1.88-1.43 (m, 8H), 1.42 (s, 9H), 1.10 (d, J=6,6 Hz, 6N).

MS: APCI (+ve): 731 (M+1)

Stage (b) N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline hydrochloride

A mixture of HCl/dioxane (10 ml, 329.12 mmol) was added to a solution of tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate (1.0 g, 1.37 mmol) in DCM (20 ml) and was stirred for 2 hours, Evaporated in vacuum to obtain specified in the subtitle compound as a white the solids. Yield: 1.1 g

1H NMR (300 MHz, DMSO) δ 8.38 (d, J=6,4 Hz, 1H), 8.28 (d, J=3,4 Hz, 1H), 8.22-8.14 (m, 1H), 8.14-8.03 (m, 2H), 8.04 (m, 5H), 7.76-7.65 (m, 1H), 7.56 (t, J=8,1 Hz, 1H), 7.45 (d, J=8,1 Hz, 1H), 7.31 (m, 1H), 7.21 (m, 2H), 4.46-4.07 (m, 3H), 4.00-3.04 (m, 12H), 2.85-2.66 (m, 4H), 1.93-1.56 (m, 8H), 1.30 (d, J=6,8 Hz, 6N)./p>

MS: APCI (+ve): 631 (M+1)

Stage (C) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-methylthiazole-4-carboxamide

HATU (0,113 g, 0.30 mmol) was added to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline HCl (0.2 g, 0.27 mmol), 6-torymidae[1,2-a]pyridine-2-carboxylic acid (0,064 g, 0.30 mmol) and DIPEA (0,236 ml, 1.35 mmol) in DMF (5 ml)and the solution was stirred at K.T. within 20 hours the Mixture was purified by HPLC with a reversed phase with aq-TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 203 mg

1H NMR (400 MHz, CD3OD) δ 8.73 (m, 1H), 8.45 (s, 1H), 8.13 (d, J=3.3 Hz, 1H), 8.04 (m, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.60 (m, 3H), 7.42 (d, J=7.9 Hz, 1H), 7.32 (m, 1H), 7.21 (m, 1H), 7.18 (m, 1H), 4.43 (s, 2H), 4.15-4.02 (m, 2H), 4.07 (s, 2H), 3.87-3.64 (m, 4H), 3.56 (m, 2H), 3.38 (m, 2H), 3.31-3.09 (m, 2H), 2.98-2.75 (m, 2H), 2.66 (t, J=12,7 Hz, 2H), 1.97-1.75 (m, 8H), 1.32 (d, J=6.3 Hz, 6N).

MS: APCI (+ve): 793 (M+1).

Example 123

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

HATU (0,113 g, 0.30 mmol) was added to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline HCl (0.2 g, 0.27 mmol), methylimidazo[1,2-a]pyridine-2-carboxylic acid (0,052 g, 0.30 mmol) and DIPEA (0,236 ml, 1.35 mmol) in DMF (5 ml)and the solution was stirred at K.T. within 20 hours the Mixture was purified by HPLC with a reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Output: 253 mg

1H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H), 8.12 (d, J=3.3 Hz, 1H), 8.03 (m, 1H), 7.89 (m, 1H), 7.84 (m, 1H), 7.74 (d, J=8,8 Hz, 1H), 7.59 (m, 2H), 7.44 (d, J=8,3 Hz, 1H), 7.32 (m, 2H), 7.20 (m, 2H), 4.44 (s, 2H), 4.17-4.05 (m, 4H), 4.14 (s, 2H), 3.87-3.66 (m, 4H), 3.64-3.55 (m, 2H), 3.44 (m, 2H), 3.31-3.09 (m, 2H), 2.99-2.81 (m, 2H), 2.79 (s, 3H), 2.77 (m, 2H), 2.00-1.80 (m, 8H), 1.33 (d, J=6,9 Hz, 6N).

MS: APCI (+ve): 789 (M+1).

Example 124

N-((1s,4s)-4-(2-(4'-(((38,5K)is 3.5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

HATU (0,113 g, 0.30 mmol) was added to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline (0.2 g, 0.27 mmol), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (0,049 g, 0.30 mmol) and DIPEA (0,236 ml of 1.35 mmol) in DMF (5 ml)and the solution was stirred at K.T. within 20 hours the Mixture was purified by HPLC with a reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 144 mg

1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=3.1 Hz, 1H), 8.06 (m, 1H), 8.03 (m, 1H), 7.68 (m, 1H),7.60 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.33 (m, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.21 (m, 1H), 6.41 (s, 1H), 4.47 (s, 2H), 4.46 (s, 2H), 4.09 (t, J=6.3 Hz, 2H), 3.97 (m, 1H), 3.86-3.75 (m, 6N), 3.71 (m, 2H,), 3.34-3.18 (m, 4H), 2.97-2.75 (m, 2H), 2.79 (t, J=6,7 Hz, 2H), 2.03 (m, 2H), 1.91-1.67 (m, 12H), 1.40 (d, J=6,4 Hz, 6N).

MS: APCI (+ve): 779 (M+1)

Example 125

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fornicating)cyclohexyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0,031 g 0,19 mmol) was dissolved in acetonitrile (5 ml), then was added DIPEA (0,067 ml, 0.38 mmol) and HATU (0,073 g 0,19 mmol), then stirred for 20 minutes All this was added to a stirred solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fioricetonline hydrochloride (probably three) (0,120 g, 0.18 mmol) in acetonitrile (5 ml) and DIPEA (0,064 ml of 0.37 mmol). The reaction mixture was stirred overnight and then added water 880 ammonia (2 ml)and the reaction mixture was stirred for 4 h the Reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified preparative HPLC on a Sunfire column using a 95-5%gradient of aqueous 0.1% of TFA in methanol as eluent. The fractions containing relevo the connection, was evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 100 mg

1H NMR (400 MHz, DMSO) δ 9.30 (dd, J=7,0, 1,6 Hz, 1H), 8.58 (dd, J=4.2, and 1.5 Hz, 1H), 8.55 (s, 1H), 8.48 (d, J=7.5 Hz, 1H), 8.24 (d, J=3.1 Hz, 1H), 8.03 (dd, J=8,0, 3.1 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.49-7.36 (m, 4H), 7.19 (dd, J=7,0, 4,2 Hz, 1H), 7.15-7.11 (m, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.05-3.77 (m, 4H), 3.45-3.30 (m, 2H), 3.28-3.13 (m, 2H), 1.82-1.63 (m, 8H), 1.18 (d, J=6,4 Hz, 6N). The remaining protons obscured by solvent.

MS: [M+H]+=693 (expect.=693) (multimode+)

Example 126

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-fornicating

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide

To a stirred solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodinase)nicotinamide (0,350 g, 0.61 mmol) in THF (4.04 ml) was added 3-(3-hydroxypropyl)phenylboronic acid (0,120 g, 0.67 mmol) and sodium carbonate (0,193 g, 1.82 mmol) in water (2,021 ml). Added tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol)and the reaction mixture was heated to 70°C during the night. The reaction mixture was poured into water and was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on diox the de silicon, using a column with silica Isco Companion, 50 g, gradient elution of 1-5% methanol in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow solid. Exit; 0,293 g

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8.9, 3.2 Hz, 1H), 8.08 (d, J=3,4 Hz, 2H), 7.54-7.51 (m, 2H), 7.41-7.36 (m, 3H), 7.32 (t, J=7.7 Hz, 1H), 7.20-7.14 (m, 2H), 6.70-6.65 (m, 1H), 6.50 (s, 1H), 4.27-4.20 (m, 1H), 4.10-4.02 (m, 1H), 3.68 (t, J=6.6 Hz, 2H), 3.66 (s, 3H), 2.74 (t, J=7.7 Hz, 2H), 2.24 (s, 3H), 1.96-1.79 (m, 8H), 1.68-1.58 (m, 2H).

MS: [M+H]+=586,2 (multimode+)

Stage (b) 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl-methanesulfonate

To a stirred solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide (0,293 g, 0.50 mmol) in dichloromethane (3 ml) was added pyridine (rate £ 0.162 ml, 2.00 mmol), then methanesulfonanilide (0,156 ml, 2.00 mmol). The reaction mixture was stirred at K.T. in nitrogen atmosphere overnight. The reaction mixture was diluted with dichloromethane and washed with 2 M hydrochloric acid, water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound that was used without further purification.

1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J=8,7, 4,4 Hz, 1 H), 8.07 (d, J=2,9 Hz, 2H), 7.55-7.52 m, 2H), 7.44-7.41 (m, 3H), 7.34 (t, J=7,6 Hz, 1H), 7.21-7.17 (m, 2H), 6.94 (d, J=7,3 Hz, 1H), 6.52 (s, 1H), 4.23 (t, J=6.2 Hz, 2H), 4.25-4.19 (m, 1H), 4.12-4.04 (m, 1H), 3.72 (s, 3H), 2.99 (s, 3H), 2.79 (t, J=7,3 Hz, 2H), 2.27 (s, 3H), 2.10 (quintet, J=6.9 Hz, 2H), 1.92-1.82 (m, 6H), 1.70-1.60 (m, 2H)

MS: [M+H]+=663,9 (multimode+)

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating

In the vial for microwave processing was added 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propylaminosulfonyl (0,150 g, 0.23 mmol) and (2S,6R)-2,6-dimethylpiperazine (0,103 g, 0.90 mmol) in acetonitrile (1 ml). The reaction mixture was heated to 80°C. by microwave for 30 minutes the Reaction mixture was concentrated to obtain the crude product, which was purified preparative HPLC column Phenomenex Gemini using 95-15%water gradient with 0.2%TFA in methanol as eluent. The fractions containing the desired compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 21 mg

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=3.3 Hz, 1H), 8.06 (dd, J=7,8, and 2.8 Hz, 1H), 7.48 (d, J=5.0 Hz, 2H), 7.45-7.41 (m, 3H), 7.31 (t, J=7.8 Hz, 1H), 7.21-7.13 (m, 2H), 6.38 (s, 1H), 4.15-4.08 (m, 1H), 3.95-3.87 (m, 1H), 3.78 (d, J=13,0 Hz, 4H), 3.69 (s, 3H), 3.23-3.16 (m, 2H), 3.03 (t, J=11.7 Hz, 2H), 2.71 (t, J=7.8 Hz, 2H), 2.23 (s, 3H), 2.14-2.04 (m, 2H), 1.90-1.73 (m, 6H), 1.72-1.61 (m, 2H), 1.37 (d, J=3,9 Hz, 6H).

MS: m/z (ACI+), (M+H)+=682,4

Example 127

N-((1s,4s)-4-(2-(4'-(3-(1,4-diazepan-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Tetrakis(triphenylphosphine)palladium(0) (0,011 g, 9,94 mmol) was added to a mixture of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (0.3 g, 0.50 mmol), 4-(3-hydroxypropyl)phenylboronic acid (0,098 g, 0.55 mmol) and sodium carbonate (0,158 g, 1,49 mmol) in water (2,500 ml) and THF (5 ml). The mixture was heated at 70°C for 18 hours the Reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica (Biotage, 100 g), elwira 100%EtOAc, then 5%methanol in EtOAc. Pure fractions were combined and evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 0.25 g

MS: m/z (APCI+), (M+H)+=612

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylamino the methanesulphonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,b,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (0.3 g, 0.49 mmol) and pyridine (0,079 ml, 0.98 mmol) in DCM (2 ml), was added methanesulfonamide (0,080 ml of 1.03 mmol)and the reaction mixture was stirred at K.T. during the night.

The reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain oil. The oil was dissolved in DCM, then added isohexane until the solid is not broke. The suspension was concentrated in vacuo to obtain an oil. The oil was again dissolved in DCM and added isohexane until the solid is not broke (repeated × 4). When the concentration specified in the header of the connection was not quite white foam. Yield: 0.25 g

MS: [M+H]+=690 (multimode+)

Stage (C) N-((1s,4s)-4-(2-(4'-(3-(1,4-diazepan-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propylenecarbonate (0.125 g, 0.18 mmol) in acetonitrile (1 ml) was added 1,4-diazepan (0,363 g, 3.62 mmol).

The mixture was heated up to 80°C in the microwave for 30 min. Crude product which was purified preparative HPLC column Phenomenex Gemini, using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 43 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=10,8 Hz, 1H), 8.11 (d, J=4,8 Hz, 1H), 8.07-8.03 (m, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.48-7.46 (m, 2H), 7.39-7.37 (m, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.16-7.13 (m, 1H), 6.38 (s, 1H), 4.13-4.07 (m, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.98-3.92 (m, 1H), 3.68-3.59 (m, 3H), 3.52-3.45 (m, 1H), 3.40 (t, J=7,6 Hz, 2H), 3.22-3.18 (m, 2H), 2.80-2.71 (m, 4H), 2.26-2.20 (m, 2H), 2.11-1.97 (m, 4H), 1.87-1.77 (m, 8H), 1.73-1.65 (m, 2H), 0,89-of 0.82 (m, 2H).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 128

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methansulfonate (0.125 g, 0.18 mmol) in acetonitrile (1 ml) was added 3-aminopropan-1-ol (0,069 ml of 0.91 mmol). The mixture was heated up to 80°C in the microwave for 20 minutes the Crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compound as a white solid prophetic the STV. Yield: 59 mg

1H NMR (400 MHz, CD3OD) δ 8.44 (d, J=to 15.0 Hz, 1H), 8.11 (d, J=3.3 Hz, 1H), 8.07-8.04 (m, 1H), 7.53 (d, J=7,4 Hz, 2H), 7.47 (d, J=7,4 Hz, 2H), 7.40-7.38 (m, 1H), 7.25 (d, J=6.2 Hz, 2H), 7.16-7.12 (m, 1H), 6.38 (s, 1H), 4.15-4.08 (m, 1H), 4.01 (t, J=5,9 Hz, 2H), 3.98-3.92 (m, 1H), 3.66 (t, J=7,0 Hz, 2H), 3.10 (t, J=7.9 Hz, 2H), 3.03-2.98 (m, 2H), 2.80-2.71 (m, 4H), 2.03-1.96 (m, 4H), 1.88-1.78 (m, 10H), 1.74-1.64 (m, 2H).

MS: [M+H]+=669 (expect.=669) (multimode+)

Example 129

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fornicating

To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (32,0 mg, 0.23 mmol) in acetonitrile (3,00 ml) was added DIPEA (0,080 ml, 0.46 mmol) and HATU (87 mg, 0.23 mmol). After stirring for 5 min the solution was then added to a mixture of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-3'-hydroxybiphenyl-3-yloxy)-5-fioricetonline trihydrochloride (150 mg, 0.23 mmol) and DIPEA (0,080 ml, 0.46 mmol) in acetonitrile (3 ml). The mixture was left to mix with K.T. within 1 h To this solution was then added 2 ml 0,88 NH3(aq.), and the mixture was left to mix for 1 h the Reaction mixture was evaporated to dryness, and the residue was then dissolved in methanol and acidified using 0.2 ml TFA was then purified using preparative HPLC with a reversed phase (eluent = TFA (aq.)/MeCN). The appropriate fractions were combined and evaporated the obtaining of balance, when rubbing with ether gave a solid. The solid was dried over night at 40°C To produce specified in the connection header. Yield: 88 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.51-7.43 (m, 2H), 7.36 (t, J=1.9 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.18 (dt, J=7,8, 1.9 Hz, 1H), 7.13-7.10 (m, 2H), 6.42 (s,, 1H), 4.17 (s, 2H), 4.11-4.08 (m, 1H), 3.97-3.91 (m, 1H), 3.73 (s, 3H), 3.63-3.56 (m, 2H), 3.53-3.47 (m, 2H), 2.75 (t, J=12,6 Hz, 2H), 2.26 (s, 3H), 1.86-1.77 (m, 6H), 1.74-1.64 (m, 2H), 1.33 (d, J=6,7 Hz, 6H).

MS: [M+H]+=670 (expect.=670) (multimode+)

Example 130

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide

In a test tube for microwave treatment were loaded 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate (90 mg, 0.14 mmol), tert-butyl piperazine-1-carboxylate (76 mg, 0.41 mmol) and acetonitrile (1,667 ml). The reaction mixture was heated up to 80°C for 3 hours the Reaction mixture was evaporated to dryness, then dissolved in DCM (5 ml). To it was added TFA (5 ml, 65,29 mmol)and the reaction mixture was stirred over night. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 57 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7,4 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 1H), 7.52 (d, J8,2 Hz, 2H), 7.48-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.25 (d, J=8,2 Hz, 2H), 7.17-7.11 (m, 1H), 6.42 (s, 1H), 4.15-4.07 (m, 1H), 3.98-3.89 (m, 1H), 3.72 (s, 3H), 3.39 (t, J=5.3 Hz, 4H), 3.22-3.11 (m, 4H), 2.92-2.86 (m, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.26 (s, 3H), 2.03-1.93 (m, 2H), 1.89-1.75 (m, 6N), 1.74-1.64 (m, 2H).

MS: [M+H]+=654 (expect.=654) (multimode+)

Example 131

N-((1s,4s)-4-(5-fluoro-2-(3'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,300 g, 0.52 mmol) in THF (3.45 ml) was added 3-(3-hydroxypropyl)phenylboronic acid (0,112 g of 0.62 mmol) and sodium carbonate (0,164 g, 1.55 mmol) in water (1,723 ml). Added tetrakis(triphenylphosphine)palladium(0) (0,030 g, 0.03 mmol)and the reaction mixture was heated to 70°C for 2 days. The reaction mixture was stirred, poured into water and was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column with silica Isco Companion, 50 g, gradient elution of 1-5% methanol in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in subheading connect the Oia as not quite white solid. Output: 0,235 g

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=7,1, 2.1 Hz, 1H), 8.12-8.08 (m, 2H), 7.90 (s, 1H), 7.52 (s, 1H), 7.40-7.36 (m, 3H), 7.32 (t, J=7,6 Hz, 1H), 7.21-7.15 (m, 3H), 4.30-4.22 (m, 1H), 4.12-4.02 (m, 1H), 3.68 (t, J=6.3 Hz, 2H), 2.74 (t, J=7,0 Hz, 2H), 2.60 (s, 3H), 1.99-1.77 (m, 8H), 1.72-1.58 (m, 2H).

MS: [M+H]+=589,2 (multimode+)

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-3-yl)propyl-methanesulfonate

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(3'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide (0,235 g, 0.40 mmol) in dichloromethane (1,742 ml) was added pyridine (0,129 ml, 1.60 mmol) and methanesulfonamide (0,124 ml of 1.60 mmol). The reaction mixture was stirred at K.T. in nitrogen atmosphere overnight. The reaction mixture was diluted with dichloromethane and washed with 2 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound that was used in the next stage without additional purification. Output: 0,260 g

1H NMR (400 MHz, CDCl3) δ 8.37-8.33 (m, 1H), 8.12-8.06 (m, 2H), 8.01 (s, 1H), 7.68 (d, J=7,3 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (s, 2H), 7.34 (t, J=7.9 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.21-7.16 (m, 2H), 4.24 (t, J=6.2 Hz, 2H), 4.19-4.10 (m, 1H), 2.99 (s, MN), 2.80 (t, J=8.0 Hz, 2H), 2.76 (s, 3H), 2.10 (quintet, J=6.6 Hz, 2H), 1.96-1.66 (m, 8H).

MS: [M+H]+=667,2 (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(3'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nick is minamida)cyclohexyl)-2-methylthiazole-4-carboxamide

In the vial for microwave processing was added 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-3-yl)propyl-methanesulfonate (0,260 g 0,39 mmol) and piperazine (0,672 g, 7,80 mmol) in acetonitrile (2 ml). The reaction mixture was heated up to 80°C for 30 minutes the Reaction mixture was concentrated to obtain the crude product.

The crude product was purified preparative HPLC on a column (Waters X-Bridge, using 95-15%water gradient with 0.2%TFA in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to obtain specified in the title compounds as white solids. Output: of 0.081 g

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7,6 Hz, 1H), 8.12 (d, J=2,9 Hz, 1H), 8.06 (dd, J=7,6, 2,9 Hz, 1H), 7.95 (s, 1H), 7.50-7.47 (m, 2H), 7.45-7.40 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.21-7.15 (m, 3H), 4.17-4.10 (m, 1H), 3.99-3.92 (m, 1H), 3.48 (m, 4H), 3.42-3.36 (m, 4H), 3.12-3.07 (m, 2H), 2.72 (t, J=7,3 Hz, 2H), 2.61 (s, 3H), 2.08-1.99 (m, 2H), 1.91-1.63 (m, 8H).

MS: [M+H]+=657.2 (multimode+)

Example 132

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (2 ml) was added pyrazolo[1,5-a]pyridine-2-carboxylic acid (8.5 mg, 0.24 mmol) and triethylamine (0,331 ml, is 2.37 mmol). 1-Papapostolou acid cyclic anhydride, then added 1,57M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 1 h the Mixture was poured into a feast upon. NaHCO3(aq.), and organic matter was extracted with EtOAc (×2). The extraction were combined, dried (MgSO4) and was evaporated to obtain a residue. It was dissolved in dichloromethane (2 ml)to which was added TFA (2 ml)and the mixture was stirred at K.T. within 20 minutes the Solvents were removed in vacuo, and the residue was dissolved in methanol and purified using preparative chromatography with reversed phase, using eluent = TFA (aq.)/Meon. The appropriate fractions were combined and evaporated to obtain the residue, which when crushed with ether gave a solid. The solid was dried overnight under vacuum at 40°C To produce specified in the connection header. Yield: 58 mg

1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=7.2 Hz, 1H), 8.41 (d, J=6,9 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.07 (dd, J=7,9, 3.1 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.50-7.45 (m, 4H), 7.42-7.41 (m, 1H), 7.25-7.20 (m, 1H), 7.18-7.13 (m, 3H), 6.96-6.92 (m, 2H), 4.17-4.12 (m, 1H), 4.04-3.98 (m, 1H), 3.41 (t, J=5.4 Hz, 4H), 3.24-3.19 (m, 4H), 2.94-2.89 (m, 2H), 2.64 (t, J=7,6 Hz, 2H), 1.99-1.68 (m, 10H).

MS: [M+H]+=676 (expect.=676) (multimode+)

Example 133

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,b-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

To a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (2 ml) was added 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (36,1 mg, 0.24 mmol) and triethylamine (0,331 ml, 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1,57M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 1 h the Mixture was poured into a feast upon. NaHCO3(aq.), and organics were extracted into EtOAc (×2). The extraction were combined, dried (MgSO4) and was evaporated to obtain a residue. It was dissolved in DCM (2 ml)to which was added TFA (2 ml)and the mixture was stirred at K.T. within 20 minutes the Solvents were removed in vacuo, and the residue was dissolved in methanol and purified using preparative chromatography with reversed phase, using eluent = TFA (aq.)/Meon. The appropriate fractions were combined and evaporated to obtain the residue, which when crushed with ether gave a solid. The solid was dried overnight under vacuum at 40°C To produce specified in the connection header. Yield: 48 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.51 (d, J=8,2 Hz, 2H), 7.47 (d, J=5,1 Hz, 2H), 7.40-7.39 (m, 1H), 7.24 (d, J=8,2 Hz, 2H), 7.15-7.12 (m, 1H), 6.39 (s, 1H), 4.14-4.07 (m, 1H), 4.03 (t, J=7,3 Hz, 2H), .99-3 .92 (m, 1H), 3.41 (t, J=5.1 Hz, 4H), 3.24-3.19 (m, 4H), 2.95-2.90 (m, 2H), 2.87 (t, J=7,3 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.61-2.53 (m, 2H), 2.04-1.95 (m, 2H), 1.87-1.77 (m, 6H), 1.73-1.64 (m, 2H).

MS: [M+H]+=666 (expect.=666) (multimode+)

Example 134

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(4-methyl-1,4-diazepan-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methansulfonate (0.125 g, 0,19 mmol) in acetonitrile (1 ml) was added 1-methyl-1,4-diazepan (0,117 ml of 0.94 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes, the Crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 49 mg

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=11,4 Hz, 1H), 8.12 (d, J=6,7 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.97 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.48-7.46 (m, 2H), 7.40-7.38 (m, 1H), 7.26 (d, J=8,2 Hz, 2H), 7.16-7.13 (m, 1H), 4.15-4.10 (m, 1H), 3.99-3.93 (m, 1H), 3.71 (s, 4H), 3.52-3.45 (m, 4H), 2.94 (s, 3H), 2.72 (t, J=7.5 Hz, 2H), 2.62 (s, 3H), 2.29-2.23 (m, 2H), 2.11-2.03 (m, 2H), 1.88-1.79 (m, 6N), 1.75-1.67 (m, 2H), 0,89-0,82 (m, 2H).

MS: [M+H]+=685 (expect.=685) (multimode+)

Example 135

N-((1s,4s)-4-(2-(4'-(3-(1,4-diazepan-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-mate the thiazole-4-carboxamide

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methansulfonate (0.125 g, 0,19 mmol) in acetonitrile (1 ml) was added 1,4-diazepan (0,376 g, 3.75 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes, the Crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, triturated with DCM and isohexanol, then dried under vacuum at 45°C. overnight to obtain specified in the title compounds as white solids. Yield: 48 mg

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=11.0 cm Hz, 1H), 8.12 (d, J=4.4 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 2H), 7.40-7.38 (m, 1H), 7.26 (d, J=7,3 Hz, 2H), 7.17-7.13 (m, 1H), 4.15-4.10 (m, 1H), 3.99-3.93 (m, 1H), 3.68-3.58 (m, 4H), 3.52-3.45 (m, 2H), 3.40 (t, J=6.0 Hz, 2H), 2.73 (t, J=6,7 Hz, 2H), 2.62 (s, 3H), 2.27-2.21 (m, 2H), 2.11-2.04 (m, 2H), 1.89-1.78 (m, 6H), 1.75-1.65 (m, 2H), 0.88 to 0,83 (m, 2H).

MS: [M+H]+=671 (expect.=671) (multimode+)

Example 136

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methansulfonate (0.12 g, 0.18 mmol) in acetonitrile (1 ml) is obavljale 3-aminopropan-1-ol (0,068 ml, 0.90 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes, the Crude product was purified by preparative HPLC on a column of Phenomenex Gemini using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the desired compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 71 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7.5 Hz, 1H), 8.11 (d, J=10.3 Hz, 1H), 8.07-8.04 (m, 1H), 7.96 (d, J=4.0 Hz, 1H), 7.53 (d, J=10,9 Hz, 2H), 7.49-7.46 (m, 2H), 7.40-7.39 (m, 1H), 7.24 (d, J=8,9 Hz, 2H), 7.17-7.13 (m, 1H), 4.15-4.09 (m, 1H), 4.00-3.93 (m, 1H), 3.66 (t, J=7.4 Hz, 2H), 3.10 (t, J=8,2 Hz, 2H), 3.01 (t, J=7.9 Hz, 2H), 2.72 (t, J=8,4 Hz, 2H), 2.62 (s, 3H), 2.03-1.95 (m, 2H), 1.91-1.77 (m, 8H), 1.76-1.65 (m, 2H).

MS: [M+H]+=646 (expect.=646) (multimode+)

Example 137

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

To a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (2 ml) was added 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (39,5 mg, 0.24 mmol) and triethylamine (0,331 ml, is 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1,57M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 1 h the Mixture was poured into us. NaHCO 3(aq.), and organic matter was extracted with EtOAc (×2). The extraction were combined, dried (MgSO4) and was evaporated to obtain a residue. It was dissolved in DCM (2 ml)to which was added TFA (2 ml)and the mixture was stirred at K.T. within 20 minutes the Solvents were removed in vacuo, and the residue was dissolved in methanol and purified using preparative chromatography with reversed phase, using eluent = TFA (aq.)/Meon. The appropriate fractions were combined and evaporated to obtain the residue, which when crushed with ether gave a solid. The solid was dried overnight under vacuum at 40°C To produce specified in the connection header. Yield: 42 mg

1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=6,9 Hz, 1H), 8.10-8.06 (m, 2H), 7.74 (s, 1H), 7.53 (d, J=8,2 Hz, 2H), 7.50-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.28 (d, J=8,2 Hz, 2H), 7.16-7.12 (m, 1H), 4.15-4.08 (m, 3H), 3.98-3.91 (m, 1H), 3.40 (t, J=5.4 Hz, 4H), 3.21-3.16 (m, 4H), 2.97-2.89 (m, 4H), 2.72 (t, J=7.4 Hz, 2H), 2.07-1.96 (m, 6H), 1.92-1.80 (m, 6H), 1.75-1.66 (m, 2H).

MS: [M+H]+=680 (expect.=680) (multimode+)

Example 138

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide

Stage (a) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

A solution of potassium carbonate (0,144 g, 1.04 mmol) in water (3 ml), 4-formyl-2-(morph is linoleyl)phenyl-triftorbyenzola (0,147 g, 0.42 mmol) and N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide (0.2 g, 0.35 mmol) were added sequentially to a stirred solution of palladium(II) acetate (7,78 mg, 0.03 mmol) and S-Phos (0,028 g, 0.07 mmol) in acetonitrile (5 ml) and heated at 70°C for 2 hours the Mixture was cooled to K.T., was extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated in vacuum. The residue was purified by chromatography on silica with 5%mixture of MeOH/DCM as eluent to obtain specified in the subtitle compound as a brown foam. Output: 0,13 g

1H NMR (400 MHz, CDCl3) δ of 10.05 (s, 1H), 8.37 (m, 1H), 8.07 (d, J=3,4 Hz, 1H), 8.04-7.98 (m, 2H), 7.78 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.33 (m, 2H), 7.22 (m, 1H), 6.67 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 4.22 (m, 1H), 4.06 (m, 1H), 3.71 (s, 3H), 3.58 (m, 4H), 3.47 (s, 2H), 2.35 (m, 4H), 2.28 (s, 3H), 1.96-1.53 (m, 8H).

MS: APCI (+ve): 655 (M+1).

Stage (b) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide

Thiomorpholine level (0.041 g, 0.40 mmol) was added to a solution of N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (of 0.13 g, 0.20 mmol) in DCM (5 ml) and was stirred for 15 minutes was Added Asón (to 0.011 ml, 0.20 mmol), then triacetoxyborohydride sodium (0,084 g, 0,0 mmol), and the reaction mixture was stirred for 20 hours the Reaction was suppressed aqueous NaHCO3, was extracted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue was purified by HPLC with reversed phases with obtaining specified in the title compounds as white solids. Output: is 0.102 g

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7.7 Hz, 1H), 8.13 (d, J=3.2 Hz, 1H), 8.03 (m, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.62 (m, 2H), 7.50 (d, J=7.7 Hz, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 6.45 (s, 1H), 4.44 (s, 2H), 4.41 (s, 2H), 4.09 (m, 1H), 3.96 (m, 1H), 3.82-3.71 (m, 4H), 3.77 (s, 3H), 3.20-2.78 (m, 12H), 2.28 (s, 3H), 1.88-1.68 (m, 8H).

MS: APCI (+ve): 742 (M+1).

Example 139

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-(3-((S)-3-methylpiperazin-1-yl)propyl)biphenyl-3-yloxy)-nicotinamide

In the vial for microwave processing was added 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl-methanesulfonate (0,120 g, 0.18 mmol), (S)-tert-butyl-2-methylpiperazin-1-carboxylate (0,145 g to 0.72 mmol) and triethylamine (0,076 ml, 0.54 mmol) in acetonitrile (1 ml). The reaction mixture was heated to 80°C. with microwaves for 3 hours the Reaction mixture was evaporated to dryness and pererestorani in DCM. Was added a mixture of 4 M HCl/dioxane (0,904 ml, 3.62 mmol)and the reaction mixture was stirred at K.T. within 3 hours the Reaction mixture to which has centriole to obtain the crude product, which was purified by preparative HPLC on a column of Phenomenex Gemini using 95-15%water gradient with 0.2%TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 56 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=8,9 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J=8,9 Hz, 1H), 7.49-7.46 (m, 2H), 7.45-7.41 (m, 3H), 7.31 (t, J=7.8 Hz, 1H), 7.21-7.14 (m, 2H), 6.38 (s, 1H), 4.16-4.06 (m, 1H), 3.95-3.85 (m, 1H), 3.69 (s, 3H), 3.64 (t, J=13.3 Hz, 4H), 3.43-3.34 (m, 1H), 3.12-3.02 (m, 3H), 2.89 (t, J=13.3 Hz, 1H), 2.70 (t, J=7.8 Hz, 2H), 2.24 (s, 3H), 2.03 (quintet, J=8.0 Hz, 2H), 1.91-1.74 (m, 6H), 1.72-1.61 (m, 2H), 1.35 (d, J=6,7 Hz, 3H).

MS: [M+H]+=668 (multimode+)

Example 140

N-((1s,4s)-4-(2-(4'-(3-((33,5P)for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexylcarbamate (3 g, 5.40 mmol), 4-(3-hydroxypropyl)phenylboronic acid (1,021 g, 5,67 mmol) and sodium carbonate (with 4.64 g, 16,21 mmol) was added to THF (36.0 ml) and degassed water (to 18.01 ml) in nitrogen atmosphere. Then added tetrakis(triphenylphosphine)palladium(0) (0.125 g, 0.11 mmol)and the reaction mixture was heated under reflux overnight. The mixture pouring is whether on the water and was extracted with EtOAc (×2). The extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a light brown foam. The crude substance was purified using the Biotage (eluent = pure EtOAc) to obtain specified in the subtitle compound as a white foam after evaporation. Yield: 2.6 g

1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J=8,2, 3.1 Hz, 1H), 8.07 (d, J=3.1 Hz, 1H), 8.04 (d, J=7.5 Hz, 1 H), 7.55-7.49 (m, 4H), 7.36-7.34 (m, 1H), 7.29 (d, J=8,2 Hz, 2H), 7.14-7.08 (m, 1H), 4.42-4.29 (m, 1H), 4.22-4.14 (m, 1H), 3.71 (t, J=6.4 Hz, 2H), 3.65-3.55 (m, 1H), 2.76 (t, J=7.7 Hz, 2H), 1.98-1.88 (m, 2H), 1.87-1.66 (m, 6H), 1.63-1.51 (m, 2H), 1.40 (s, 9H).

MS: [M+H]+=564 (multimode+)

Stage (b) 3-(3'-(3-((1s,4s)-4-(tert-Butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)-biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1.5 g, of 2.66 mmol) and pyridine (0,646 ml, 7,98 mmol) in DCM (12 ml) was added methanesulfonamide (0,622 ml, 7,98 mmol)and the reaction mixture was stirred at K.T. during the night. The reaction was evaporated to obtain a residue, which was distributed between DCM and 2 M HCl (aq.). DCM layer was then washed with another aliquot of 2 M HCl (aq.), 2× with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain specified in the subtitle compound in the form of not-quite-white solid. Yield: 1.54 g

MS: [M+H]+=642 (expect.=642) (multimode+)

Stage (C) tertbutyl-(1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate

To a solution of 3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate (1.5 g, 2.34 mmol) in acetonitrile (10 ml) was added (2R,6S)-2,6-dimethylpiperazine (0,294 g, 2.57 mmol) and triethylamine (0,358 ml, 2.57 mmol). The reaction mixture was heated at 90°C during the night. The reaction mixture was cooled, then evaporated to dryness to obtain a brown foam. The foam is distributed between the feast upon. NaHCO3and EtOAc. The aqueous layer was extracted again with EtOAc. The organic fractions were combined, washed with brine, dried (MgSO4) and concentrated to obtain not just a white foam. The product was purified via Biotage (eluent = 2% 7 M ammonia in methanol/DCM) to obtain specified in the subtitle compound as a white foam. Output: 1,124 g

MS: [M+H]+=660 (multimode+)

Stage (d) N-((1s,4s)-4-Aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating

To a solution of tert-butyl(1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (1,124 g, 1.70 mmol) in DCM (20 ml) was added 4.0 M hydrogen chloride in dioxane (4.26 deaths ml, 17,03 mmol). The mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness to obtain specified in the subtitle compound cleaners containing hydrochloride salt as a white solid. Yield: 1.2 g

MS: [M+H]+=560 (multimodem the I+)

Stage (e) ((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.24 mmol) in acetonitrile (4 ml) was added 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (36,1 mg, 0.24 mmol) and triethylamine (0,330 ml, is 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness, and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 95 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7,4 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 1H), 7.52 (d, J=8,2 Hz, 2H), 7.48-7.45 (m, 2H), 7.40-7.37 (m, 1H), 7.25 (d, J=8,2 Hz, 2H), 7.17-7.11 (m, 1H), 6.39 (s, 1H), 4.15-4.07 (m, 1H), 4.04 (t, J=7,3 Hz, 2H), 3.98-3.91 (m, 1H), 3.58-3.47 (m, 4H), 2.94-2.83 (m, 4H), 2.71 (t, J=7,1 Hz, 2H), 2.64-2.52 (m, 4H), 2.06-1.93 (m, 2H), 1.89-1.76 (m, 6H), 1.74-1.63 (m, 2H), 1.33 (d, J=6.2 Hz, 6N).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 141

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

To a suspension of 2-(hydroxymethyl)thiazole-4-carboxylic acid (of 45.7 mg, 0.29 mmol) in DMF (4 ml) was added tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (145 mg, 0.23 mmol), HOBt (46,5 mg, 0.34 mmol) and EDCl (53,4 mg, 0.34 mmol). The mixture was stirred at K.T. during the night. The reaction mixture was poured into water and was extracted with EtOAc (×2). Organic extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a yellow oil. The oil was dissolved in DCM (5 ml). To it was added TFA (5 ml, 64,90 mmol)and the reaction mixture was stirred over night. It was purified using HPLC to obtain specified in the title compounds as white solids. Yield: 51 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=6.3 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 2H), 7.53-7.49 (m, 2H), 7.48-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.25-7.22 (m, 2H), 7.17-7.11 (m, 1H), 4.72 (s, 2H), 4.17-4.09 (m, 1H), 4.00-3.92 (m, 1H), 3.36 (t, J=5.3 Hz, 4H), 3.13-3.07 (m, 4H), 2.87-2.81 (m, 2H), 2.71 (t, J=8,1 Hz, 2H), 2.01-1.91 (m, 2H), 1.90-1.77 (m, 6H), 1.76-1.64 (m, 2H).

MS: [M+H]+=673 (expect.=673) (multimode+)

Example 142

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-((R)-2-methylpiperazin-1-yl)propyl)biphenyl-3-yloxy)nicotinamide

In a test tube for microwave treatment were loaded 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yl) - Rev. XI)-biphenyl-4-yl)propyl-methanesulfonate (95 mg, 0.14 mmol), (R)-tert-butyl-2-methylpiperazin-1-carboxylate (102 mg, 0.43 mmol) and acetonitrile (1,667 ml). The reaction mixture was heated up to 80°C for 3 hours was Added triethylamine (to 0.060 ml, 0.43 mmol)and the reaction mixture was heated at 80°C during the night. The reaction mixture was evaporated to dryness, then dissolved in DCM (5 ml). To it was added TFA (5 ml, 65,29 mmol)and the reaction mixture was stirred over night. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 60 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7.8 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 1H), 7.53-7.49 (m, 2H), 7.49-7.46 (m, 2H), 7.41-7.38 (m, 1H), 7.26-7.22 (m, 2H), 7.17-7.12 (m, 1H), 6.42 (s, 1H), 4.15-4.07 (m, 1H), 3.98-3.90 (m, 1H), 3.71 (s, 3H), 3.56-3.33 (m, 4H), 2.84-2.77 (m, 2H), 2.75-2.65 (m, 3H), 2.51 (t, J=12.3 Hz, 2H), 2.26 (s, 3H), 2.01-1.90 (m, 2H), 1.88-1.76 (m, 6H), 1.74-1.62 (m, 2H), 1.32 (d, J=6,7 Hz, 3H).

MS: [M+H]+=668 (expect.=668) (multimode+)

Example 143

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-pyrazolo[1,5-a]pyrimidine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.24 mmol) in acetonitrile (4 ml) was added pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (48,3 mg, 0.30 mmol) and triethylamine (0,330 ml, is 2.37 mmol). Then added 1-papandropoulos acid cyclic angeri is, 1.57 M solution in THF (0,189 ml, 0.30 mmol)and the mixture was stirred at K.T. within 2 hours the Mixture was evaporated to dryness, and the residue was dissolved in DCM (150 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 88 mg

1H NMR (400 MHz, CD3OD) δ 8.79 (d, J=7,4 Hz, 1H), 8.56-8.54 (m, 1H), 8.48 (d, J=6,9 Hz, 1H), 8.13 (d, J=3.1 Hz, 1H), 8.10-8.07 (m, 1H), 7.49-the 7.43 (m, 4H), 7.42-7.40 (m, 1H), 7.17-7.10 (m, 3H), 7.08-7.04 (m, 1H), 7.02 (s, 1H), 4.19-4.13 (m, 1H), 4.03-3.97 (m, 1H), 3.56-3.44 (m, 4H), 2.88-2.82 (m, 2H), 2.65-2.59 (m, 2H), 2.52 (t, J=12.2 Hz, 2H), 1.98-1.68 (m, 10H) 1.33 (d, J=6,4 Hz, 6N).

MS: [M+H]+=705 (expect.=705) (multimode+)

Example 144

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4-methylthiazole-2-carboxamide

EDCl (0,021 g, 0.11 mmol) was added to a solution of 4-methylthiazole-2-carboxylic acid (0,016 g, 0.11 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol hydrate (0,017 g, 0.11 mmol) in THF (2 ml) and was stirred for 10 minutes and Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline (0.075 g, 0.10 mmol) and triethylamine (0,042 ml, 0.30 mmol) in DMF (2 ml)and the reaction mixture was stirred for 20 hours, the Reaction mixture was diluted to 10% 2 M HCl/MeCN (1 ml) and purified p. the means of HPLC with reversed phase with aq. TFA/Meon as eluent to obtain specified in the title compounds as white solids. Yield: 70 mg

1H NMR (400 MHz, CD3OD) δ 8.14 (d, J=2,9 Hz, 1H), 8.04 (m, 1H), 7.74 (m, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.51 (m, 1H), 7.38 (m, 2H), 7.32 (m, 1H), 7.20 (m, 1H), 7.16 (m, 1H), 4.43 (s, 2H), 4.12 (m, 1H), 3.98 (m, 1H), 3.90-3.66 (m, 4H), 3.79 (s, 2H), 3.43 (m, 2H), 3.29-2.74 (m, 4H), 3.13 (m, 2H), 2.44 (s, 3H), 2.27 (t, J=12.3 Hz, 2H), 1.93-1.74 (m, 8H), 1.29 (d, J=6,6 Hz, 6N).

MS: APCI (+ve): 756 (M+1)

Example 145

2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(2-hydroxy-5-methylbenzamide)cyclohexyl)nicotinamide

EDCl (0,214 g, 1.11 mmol) was added to a solution of 2-hydroxy-5-methylbenzoic acid (0,017 g, 0.11 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol hydrate (0,171 g, 1.11 mmol) in THF (2 ml) and was stirred for 10 minutes and Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline (0.75 g, 1.01 mmol) and triethylamine (0,424 ml, totaling 3.04 mmol) in DMF (2 ml)and the reaction mixture was stirred for 20 hours the Reaction mixture was diluted with MeCN (1 ml), acidified with 2 M HCl (1 ml) and purified by HPLC with a reversed phase with aq. TFA/Meon as eluent to obtain specified in the title compounds as white solids. Yield: 50 mg

1H NMR (400 MHz, CD3OD) δ 8.14 (d, J=2,9 Hz, 1H), 8.03 (m, 1H), 7.70 (m, 1H), 7.57 (m, 2H), 7.48 (m, 1H), 7.34 (d, J=,0 Hz, 1H), 7.30 (m, 1H), 7.17 (m, MN), 6.77 (d, J=8.6 Hz, 1H), 4.40 (s, 2H), 4.11 (m, 1H), 3.97(m, 1H), 3.82-3.63 (m, 4H), 3.75 (s, 2H), 3.46-3.36 (m, 2H), 3.27-2.67 (m, 4H), 3.11 (m, 2H), 2.25 (s, 3H), 2.24 (t, J=12.1 Hz, 2H), 1.90-1.74 (m, 8H), 1.28 (d, J=7,0 Hz, 6H).

MS: APCI (+ve): 765 (M+1)

Example 146

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexyl)quinoline-8-carboxamide

EDCl (0,214 g, 1.11 mmol) was added to a solution of a quinoline-8-carboxylic acid (0,019 g, 0.11 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol hydrate (0,171 g, 1.11 mmol) in THF (2 ml) and was stirred for 10 minutes and Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline (0.75 g, 1.01 mmol) and triethylamine (0,424 ml, totaling 3.04 mmol) in DMF (2 ml)and the reaction mixture was stirred for 20 hours the Reaction mixture was diluted with MeCN (1 ml), acidified with 2 M HCl (1 ml) and purified by HPLC with a reversed phase with aq. TFA/MeOH as eluent to obtain specified in the title compounds as white solids. Yield: 67 mg

1H NMR (400 MHz, CD3OD) δ 8.83 (m, 1H), 8.67 (m, 1H), 8.52 (m, 1H), 8.15 (m, 1H), 8.13 (d, J=3.3 Hz, 1H), 8.04 (m, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.71 (m, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.53 (m, 1H), 7.45 (m, 1H), 7.32 (m, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.17 (m, 2H), 4.39 (s, 2H), 4.26 (m, 1H), 4.10 (m, 1H), 3.84 (s, 2H), 3.83-3.59 (m, 4H), 3.45 (m, 2H), 3.26-2.65 (m, 4H), 3.18 (m, 2H), 2.36 (t, J=11.8 Hz, 2H), 2.01-1.82 (m, 8H), 1.29 (d, J=7,0 Hz, 6N).

MS: APCI (+ve): 786 (M+1)

Note the p 147

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexyl)quinoline-2-carboxamide

EDCl (0,214 g, 1.11 mmol) was added to a solution of quinoline-2-carboxylic acid (0,019 g, 0.11 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol hydrate (0,171 g, 1.11 mmol) in THF (2 ml) and was stirred for 10 minutes and Then was added a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fioricetonline (0.75 g, 1.01 mmol) and triethylamine (0,424 ml, totaling 3.04 mmol) in DMF (2 ml)and the reaction mixture was stirred for 20 hours the Reaction mixture was diluted with MeCN (1 ml), acidified with 2 M HCl (1 ml) and purified by HPLC with a reversed phase with aq. TFA/Meon as eluent to obtain specified in the title compounds as white solids. Yield: 64 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=8,3 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 8.14 (d, J=3.3 Hz, 1H), 8.05 (m, 2H), 7.99 (m, 1H), 7.80 (m, 1H), 7.67 (m, 2H), 7.57 (t, J=8,2 Hz, 1H), 7.43 (m, 1H), 7.33 (m, 2H), 7.17 (m, 2H), 4.40 (s, 2H), 4.15 (m, 1H), 4.07 (m, 1H), 3.84-3.59 (m, 4H), 3.74 (s, 2H), 3.41 (m, 2H), 3.28-2.66 (m, 4H), 3.10 (m, 2H), 2.25 (t, J=11.8 Hz, 2H), 1.99-1.79 (m, 8H), 1.27 (d, J=7,2 Hz, 6N).

MS: APCI (+ve): 786 (M+1)

Example 148

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-methylthiazole-2-carboxamide

HATU (0,093 g, 0.24 mmol) was added to a solution of tre the-butyl-4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (0.14 g, 0.22 mmol), 4-methylthiazole-2-carboxylic acid (0.035 g, 0.24 mmol) and DIPEA (0,194 ml, 1.11 mmol) in DMF (5 ml)and the solution was stirred at K.T. within 20 hours the Mixture is extinguished with water, was extracted with EtOAc (50 ml), washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue was dissolved in DCM (10 ml)was added 4 M HCl/dioxane (5 ml, 20.00 mmol) and was stirred for 2 hours the Mixture was evaporated in vacuo, and the residue was purified by HPLC with a reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. It was stirred in DCM (2 ml) and Meon (1 ml) with triethylamine (0,031 ml, 0.22 mmol) and PS-benzaldehyde (0.07 g, 0.22 mmol) for 48 hours was Filtered and purified by HPLC with a reversed phase with Meon/aq. TFA as eluent to obtain specified in the title compounds as white solids. Yield: 40 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7,3 Hz, 1H), 8.12 (d, J=3.3 Hz, 1H), 8.06 (m, 1H), 7.98 (m, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.36 (s, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.14 (m, 1H), 4.13 (m, 1H), 3.96 (m, 1H), 3.41 (t, J=5.7 Hz, 4H), 3.20 (m, 4H), 2.92 (m, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.39 (s, 3H), 2.03-1.70 (m, 10H).

MS: APCI (+ve): 657 (M+1)

Example 149

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

To a suspension of 2-(hydroxy shall ethyl)thiazole-4-carboxylic acid (to 44.0 mg, 0.28 mmol) in DMF (4 ml) was added N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating (140 mg, 0.22 mmol), triethylamine (0,123 ml, 0.89 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (44,9 mg, 0.33 mmol) and EDCl (of 51.5 mg, 0.33 mmol). The mixture was stirred at K.T. during the night. The reaction mixture was poured into water and was extracted with EtOAc (×2). Organic extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a yellow oil. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 48 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7.8 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.09-8.04 (m, 2H), 7.53-7.49 (m, 2H), 7.48-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.26-7.21 (m, 2H), 7.17-7.10 (m, 1H), 4.71 (s, 2H), 4.18-4.10 (m, 1H), 4.00-3.91 (m, 2H), 3.54-3.41 (m, 4H), 2.88-2.81 (m, 2H), 2.70 (t, J=7,3 Hz, 2H), 2.47 (t, J=11,6 Hz, 2H), 2.03-1.92 (m, 2H), 1.91-1.76 (m, 6N), 1.75-1.64 (m, 2H), 1.32 (d, J=6,7 Hz, 6N).

MS: [M+H]+=701 (expect.=701) (multimode+)

Example 150

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4-(hydroxymethyl)thiazol-2-carboxamide

Stage (a) ethyl-4-(acetoxymethyl)thiazole-2-carboxylate

Ethyl-2-amino-2-dioxoolean (0.5 g, 3.75 mmol) and 3-chloro-2-oxopropyl-acetate (0.565 g, 3.75 mmol) was dissolved in toluene (10 ml) and heated in a microwave at 100°C for 1 h, then was heated for another 3 h at 20°C. Was cooled to K.T., was evaporated in vacuum and purified by chromatography on silica with 20%mixture of EtOAc/isohexane as eluent to obtain specified in the subtitle compound as a pale yellow solid. Yield: 0.7 g

1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 5.29 (s, 2H), 4.50 (q, J=7,0 Hz, 2H), 2.13 (s, 3H), 1.45 (t, J=7,3 Hz, 3H).

Stage (b) 4-(hydroxymethyl)thiazole-2-carboxylic acid

2M NaOH (4.58 ml, 9,16 mmol) was added to a solution of ethyl-4-(acetoxymethyl)thiazole-2-carboxylate (0.7 g, of 3.05 mmol) in Meon (3 ml) and was stirred for 1 h was Acidified With 2 M HCl, purified by HPLC with a reversed phase with aq. TFA/Meon as eluent and freeze-dried to obtain specified in the subtitle compound as a white solid. Output: 0,510 g

1H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 4.63 (s, 2H).

Stage (C) N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4-(hydroxymethyl)thiazol-2-carboxamide

To a suspension of 4-(hydroxymethyl)thiazole-2-carboxylic acid (to 44.0 mg, 0.28 mmol) in DMF (4 ml) was added N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating (140 mg, 0.22 mmol), triethylamine (0,123 ml, 0.89 mmol), HOBt (of 44.9 mg, 0.33 mmol) and EDCl (51,5 mg, 0.33 mmol). The mixture was stirred at K.T. during the night. The reaction mixture was poured into water and extraheavy and DCM (×2). Organic extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a yellow oil. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 78 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7.2 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.09-8.05 (m, 1H), 7.62-7.60 (m, 1H), 7.53-7.49 (m, 2H), 7.48-7.45 (m, 2H), 7.40-7.38 (m, 1H), 7.26-7.22 (m, 2H), 7.16-7.12 (m, 1H), 4.65-4.63 (m, 2H), 4.17-4.09 (m, 1H), 4.01-3.92 (m, 2H), 3.50-3.35 (m, 4H), 2.81-2.75 (m, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.39 (t, J=12.1 Hz, 2H), 2.00-1.70 (m, 10H), 1.31 (d, J=6,7 Hz, 6N).

MS: [M+H]+=701 (multimode+)

Example 151

N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexylcarbamate (1.5 g, 2,70 mmol), 3-formylphenylboronic acid (0,425 g, 2,84 mmol) and sodium carbonate (2,319 g, 8,10 mmol) was added to THF (to 18.01 ml) and degassed water (9,00 ml) in nitrogen atmosphere. Then added tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.05 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted with EtOAc (×2). The extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain yellow PE the s. The crude substance was purified using the Biotage (eluent = 40% EtOAc:isohexane) to give after evaporation specified in the subtitle compound in the form of not-quite-white foam. Yield: 1.2 g

1H NMR (400 MHz, CDCl3) δ of 10.09 (s, 1H), 8.38 (dd, J=8,2, 3.3 Hz, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.07 (t, J=3.1 Hz, 1H), 7.99 (d, J=7,4 Hz, 1H), 7.91-7.86 (m, 2H), 7.64 (t, J=7,6 Hz, 1H), 7.59 (d, J=5,1, 2H), 7.45-7.41 (m, 1H), 7.22-7.16 (m, 1H), 4.23-4.13 (m, 1H), 3.70-3.53 (m, 1H), 1.88-1.65 (m, 6H), 1.55-1.45 (m, 2H), 1.40 (s, 9H).

MS: [M+H]+=534 (multimode+)

Stage (b) tert-butyl(1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate

To a solution of tert-Butyl(1s,4s)-4-(5-fluoro-2-(3'-formylphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (250 mg, 0.47 mmol) in dichloromethane (10 ml) was added (2R,6S)-2,6-dimethylpiperazine (80 mg, 0.70 mmol). The mixture was left to mix with K.T. for 40 minutes, then added triacetoxyborohydride sodium (149 mg, 0.70 mmol). The reaction mixture was stirred at K.T. during the night. The mixture was diluted with dichloromethane and washed the feast upon. NaHCO3(aq.), dried (MgSO4) and was evaporated to obtain a yellow glass. It was purified using Biotage (eluent = 2,5% 7M ammonia in methanol/DCM) to give after evaporation specified in the subtitle compound as a white foam. Yield: 220 mg

MS: [M+H]+=632 (multimode+)

Stage (C) N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)shall iphenyl-3-yloxy)-5-fornicating

To a solution of tert-butyl(1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (220 mg, 0.35 mmol) in DCM (4 ml) was added 4.0 M hydrogen chloride in dioxane (0,871 ml of 3.48 mmol). The mixture was stirred at K.T. within 2 hours the Mixture was evaporated to dryness to obtain specified in the subtitle compound as a white solid. Yield: 210 mg

MS: [M+H]+=532 (multimode+)

Stage (d) N-((1s,4s)-4-(2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-pyrazolo[1,5-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)biphenyl-3-yloxy)-5-fioricetonline (210 mg, 0.35 mmol) in acetonitrile (4,2 ml) was added pyrazolo[1,5-a]pyridine-2-carboxylic acid (70,4 mg, 0.43 mmol) and triethylamine (484 μl, 3,47 mmol). Then added 1-papapostolou acid cyclic anhydride, 1,57M solution in THF (277 μl, 0.43 mmol)and the mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. It was purified by HPLC to obtain specified in the title compounds as white solids. Output: 197 mg.

1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7.2 Hz, 1H), 8.39 (d, J=7.5 Hz, 1H), 8.13 (d, J=3.1 Hz, 1H), 8.10-8.05 (m, 1H), 7.68-763 (m, 1H), 7.58-7.55 (m, 1H), 7.54-7.47 (m, 3H), 7.45-7.42 (m, 1H), 7.36-7.17 (m, 4H), 6.96-6.92 (m, 2H), 4.19-4.12 (m, 1H), 4.04-3.97 (m, 1H), 3.72 (s, 2H), 3.44-3.34 (m, 2H), 3.15-3.09 (m, 2H), 2.20 (t, J=12.4 Hz, 2H), 1.98-1.68 (m, 8H), 1.24 (d, J=6,7 Hz, 6N).

MS: [M+H]+=676 (expect.=676) (multimode+)

Example 152

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)-nicotinamide

To 3-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate (0.12 g, 0.18 mmol) in acetonitrile (1 ml) was added 3-aminopropan-1-ol (0,069 ml, 0.90 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes, the Crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5%gradient of aqueous 0.1%ammonia in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 50 mg

1H NMR (400 MHz, CDCl3) δ 8.40-8.34 (m, 1H), 8.11-8.06 (m, 2H), 7.57-7.47 (m, 4H), 7.38-7.36 (m, 1H), 7.28-7.20 (m, 2H), 7.17-7.13 (m, 1H), 6.72-6.68 (m, 1H), 6.52 (s, 1H), 4.28-4.20 (m, 1H), 4.11-4.04 (m, 1H), 3.86-3.78 (m, 2H), 3.69 (s, 3H), 3.20-3.06 (m, 2H), 2.94-2.88 (m, 2H), 2.73-2.66 (m, 4H), 2.25 (s, 3H), 1.95-1.59 (m, 10H).

MS: [M+H]+=643 (expect.=643) (multimode+)

Example 153

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-6-methylpyridine

To a stirred solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)-piperazine-1-carboxylate (0,080 g, 0.13 mmol) in acetonitrile (2 ml) was added 6-methilpiralidone acid (0.035 g, 0.25 mmol) and triethylamine (0,176 ml of 1.27 mmol). The reaction mixture was stirred at K.T. within 10 minutes was Added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (TR) (0,169 ml, 0.25 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was evaporated to dryness and pererestorani in DCM and washed with saturated sodium bicarbonate. The organic layer was treated with a mixture of 4 M HCl/dioxane (0,633 ml of 2.53 mmol) and left to mix with K.T. within 2 hours the Crude product was purified preparative HPLC on a column (Waters X-Bridge, using 75-0% water gradient with 0.2%TFA in methanol as eluent. The fractions containing the desired compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 17 mg

1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=3.3 Hz, 1H), 8.05 (dd, J=8,2, 3.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.50 (d, J=8,2 Hz, 2H), 7.47-7.44 (m, 2H), 7.41-7.39 (m, 1H), 7.37 (d, J=7,4 Hz, 1H), 7.23 (d, J=8,2 Hz, 2H), 7.16-7.12 (m, 1H), 4.16-4.10 (m, 1H), 4.02-3.95 (m, 1H), 3.56-3.46 (m, 8H), 3.19-3.14 (m, 2H), 2.71 (t, J=7.2 Hz, 2H), 2.45 (s, 3H), 2.06 (quintet, J=8,2 Hz, 2H), 1.90-1.79 (m, 6H), 1.79-1.66 (m, 2H).

MS: m/z (APCI+), (M+H)+=651,2

Example 154

N-((1s,4s)-4-(1,5-dimethyl-1 is-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-(4-(pyrrolidin-1-yl)piperidine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

In a test tube for microwave treatment were loaded 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate (120 mg, 0.18 mmol), 4-(pyrrolidin-1-yl)piperidine (85 mg, 0.55 mmol) and acetonitrile (1 ml). The reaction mixture was heated in a microwave at 80°C for 2 hours It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 65 mg

1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.9 Hz, 1H), 8.11 (d, J=3.3 Hz, 1H), 8.07-8.03 (m, 1H), 7.60-7.56 (m, 2H), 7.51-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.35-7.31 (m, 2H), 7.19-7.14 (m, 1H), 6.42 (s, 1H), 4.21-4.18 (m, 1H), 4.16-4.07 (m, 1H), 3.98-3.90 (m, 1H), 3.87-3.77 (m, 2H), 3.72 (s, 3H), 3.49-3.34 (m, 4H), 3.23-2.04 (m, 8H), 2.50-2.47 (m, 2H), 2.26 (s, 3H), 2.20-1.98 (m, 6H), 1.89-1.75 (m, 6H), 1.74-1.63 (m, 2H).

MS: [M+H]+=708 (expect.=708) (multimode+)

Example 155

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)thiazole-4-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.24 mmol) in acetonitrile (4 ml) was added thiazole-4-carboxylic acid (to 38.3 mg, 0.30 mmol) and triethylamine (0,330 ml, is 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (0,189 ml, 0.30 mmol)and the mixture was stirred at K.T. for the tion 2 hours The mixture was evaporated to dryness and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 68 mg

1H NMR (400 MHz, CD3OD) δ 8.88 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.05 (m, 1H), 7.52-7.45 (m, 5H), 7.43-7.40 (m, 1H), 7.23-7.19 (m, 2H), 7.14-7.09 (m, 1H), 4.17-4.10 (m, 1H), 4.02-3.95 (m, 1H), 2.91-2.78 (m, 4H), 2.63 (t, J=7.9 Hz, 2H), 2.39-2.33 (m, 2H), 1.92-1.66 (m, 9H), 1.60 (t, J=11,4 Hz, 2H), 1.04 (d, J=6,4 Hz, 6N).

MS: [M+H]+=671 (expect.=671) (multimode+)

Example 156

2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(3-methyl-1H-pyrazole-5-carboxamido)cyclohexyl)nicotinamide

To a suspension of 3-methyl-1H-pyrazole-5-carboxylic acid (34,9 mg, 0.28 mmol) in DMF (4 ml) was added N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline hydrochloride (140 mg, 0.22 mmol), triethylamine (0,123 ml, 0.89 mmol), HOBt (44.9 mg, 0,33 mmol) and EDCl (51.5 mg, 0.33 mmol). The mixture was stirred at K.T. during the night. The reaction mixture was poured into water and was extracted with EtOAc (×2). Organic extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a yellow oil. It was purified by HPLC to obtain specified in the connection header in VI is e white solid. Output: 0,110,

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=8.0 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7,9, 3.1 Hz, 1H), 7.54-7.50 (m, 2H), 7.48-7,44 (m, 2H), 7.40-7.37 (m, 1H), 7.26-7.22 (m, 2H), 7.16-7.10 (m, 1H), 6.44 (s, 1H), 4.14-4.06 (m, 1H), 3.99-3.92 (m, 1H), 3.64-3.53 (m, 4H), 3.03-2.96 (m, 2H), 2.75-2.66 (m, 4H), 2.28 (s, 3H), 2.07-1.98 (m, 2H), 1.88-1.64 (m, 6H), 1.35 (d, J=6,4 Hz, 6N).

MS: [M+H]+=668 (expect.=668) (multimode+)

Example 157

5-fluoro-N-((1s,4s)-4-(5-methyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)-nicotinamide

To a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (2 ml) was added 5-methyl-1H-pyrazole-3-carboxylic acid (29,9 mg, 0.24 mmol) and triethylamine (0,331 ml, is 2.37 mmol). Then added 1-papapostolou acid cyclic anhydride, 1,57M solution in THF (strength of 0.159 ml, 0.25 mmol)and the mixture was stirred at K.T. within 1 hour. The mixture was poured into saturated NaHCO3(aq.) and organics were extracted into EtOAc (×2). The extraction were combined, dried (MgSO4) and was evaporated to obtain a residue. It was dissolved in dichloromethane (2 ml)to which was added TFA (2 ml)and the mixture was stirred at K.T. within 20 minutes. The solvents were removed in vacuum and the residue was dissolved in methanol and twice was purified using preparative chromatography with reversed phase, using elwen is = TFA (aq.)/Meon and then eluent = NH 3(aq.)/Meon. To the residue remaining after cleanup, added water and a few drops of TFA. Then it liofilizirovanny obtaining specified in the title compounds as white solids. Yield: 19 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=6,8 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.07-8.04 (m, 1 H), 7.52 (d, J=8,2 Hz, 2H), 7.47-7.45 (m, 2H), 7.39-7.37 (m, 1 H), 7.24 (d, J=8,2 Hz, 2H), 7.15-7.12 (m, 1H), 6.44 (s, 1H), 4.11-4.08 (m, 1H), 3.97-3.93 (m, 1H), 3.43 (t, J=5.4 Hz, 4H), 3.29-3.23 (m, 4H), 3.00-2.95 (m, 2H), 2.72 (s, 2H), 2.28 (s, 3H), 2.05-1.97 (m, 2H), 1.86-1.78 (m, 6H), 1.74-1.66 (m, 2H).

MS: [M+H]+=640 (expect.=640) (multimode+)

Example 158

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)-6-methylpyridine

Stage (a) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide

To tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.9 g, to 1.60 mmol) in dichloromethane (5 ml) was added 4 M HCl in dioxane (4 ml, 16,00 mmol). The reaction mixture was stirred at K.T. within 2 hours. The reaction mixture was concentrated in vacuo and triturated with ether and filtered to obtain cleaners containing hydrochloride salt specified in the subtitle compound in the form of not-quite-white solid. Output: 0,690,

MS: [M+H]+=464 (expect.=464) (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)Niko is enamide)cyclohexyl)-6-methylpyridine

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide hydrochloride (0.1 g, 0.22 mmol) and 6-metilakrilovoe acid (0,030 g, 0.22 mmol) in acetonitrile (1 ml) under nitrogen atmosphere was added DIPEA (0.075 ml, 0.43 mmol) in K.T. Solution was stirred for 10 minutes. To this solution was added HATU (0,164 g, 0.43 mmol). The reaction mixture was diluted with EtOAc and washed with saturated solution of sodium bicarbonate. Organic matter was extracted (×3), dried (MgSO4) and concentrated to a yellow gum. The crude product was purified on silica (Isolute, 10 g), elwira 100%EtOAc. Pure fractions were combined to obtain specified in the subtitle compound as a pale yellow solid. Output: 0,120 g

MS: [M+H]+=583 (expect.=583) (multimode+)

Stage (C) 3-(3'-(5-fluoro-3-((1s,4s)-4-(6-methylphthalimide)-cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-6-methylphthalimide (0.12 g, 0.21 mmol) and pyridine (0,033 ml, 0.41 mmol) in DCM (1 ml) was added methanesulfonamide (0,034 ml, 0.43 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and conc the Wali of obtaining oil. The oil was dissolved in DCM, then added isohexane until the solid is not broke. The suspension was concentrated in vacuo to obtain an oil. The oil was again dissolved in DCM and added isohexane until the solid is not broke (repeated × 4). When the concentration specified in the subtitle compound was not quite white foam. Output: 0,110,

MS: [M-H]-=659 (expect.=659) (multimode+)

Stage (d) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)-6-methylpyridine

To a solution of 3-(3'-(5-fluoro-3-((1s,4s)-4-(6-methylphthalimide)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methansulfonate (0.1 g, 0.15 mmol) in acetonitrile (1 ml) was added 3-aminopropan-1-ol (0,058 ml, from 0.76 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes. The crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5% gradient of aqueous 0.2%of aqueous ammonia in methanol as eluent. The fractions containing the desired compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 35 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=8,2, 3.1 Hz, 1H), 8.14 (d, J=15.6 Hz, 1H), 8.09-8.04 (m, 2H), 7.97 (d, J=6,7 Hz, 1H), 7.70 (t, J=7,3 Hz, 1H), 7.52-7.45 (m, 4H), 7.38-7.37 (m, 1H), 7.24-7.13 (m, 4H), 4.31-4.24 (m, 1H), 4.14-4.06 (m, 1H), 3.82 (t, J=5.3 Hz, 2H), 2.90 (t, J=5.0 Hz, 2H), 2.70-2.65 (m, 4H), 2.44 (s, 3H), 1.98-1.63 (m, 12H).

MS: [+H]+=640 (expect.=640) (multimode+)

Example 159

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)-cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

To a stirred solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(3-iodinase)nicotinamide (0,500 g, 1.10 mmol) in acetonitrile (5 ml) was added pyrazolo[1,5-a]pyridine-2-carboxylic acid (0,196 g of 1.21 mmol) and triethylamine (1.5 ml, 10,98 mmol). The reaction mixture was left to mix with K.T. in nitrogen atmosphere for 15 minutes was Added 1-papapostolou acid cyclic anhydride (EMM, 1.5 M in THF) (0,805 ml of 1.21 mmol) and the reaction mixture was stirred at K.T. within 5 hours the Reaction mixture was evaporated to dryness and pererestorani in dichloromethane and washed with saturated sodium bicarbonate and saturated brine. Organics were dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column with silica Isco Companion, 50 g, gradient elution 70-00% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a white solid. Output: 0,322,

MS: [M+H]+=600 (RASSC is so=600) (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide (0,320 g of 0.53 mmol) in THF (1,780 ml) was added 4-(3-hydroxypropyl)phenylboronic acid (0,144 g, 0.80 mmol) and sodium carbonate (0,170 g to 1.60 mmol) in water (0,890 ml). Added tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.03 mmol) and the reaction mixture was heated to 70°C for 3 days. The reaction mixture was poured into water and was extracted in EtOAc. Organics were dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0-5% methanol in dichloromethane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow oil. Output: 0,259,

MS: [M+H]+=608 (expect.=608) (multimode+)

Stage (C) 3-(3'-(5-fluoro-3-((1s,4s)-4-(pyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide (0,259 g, 0.43 mmol) in dichloromethane (2.5 ml) was added pyridine (0,103 m is, 1.28 mmol) and methanesulfonamide (0.100 ml, 1.28 mmol). The reaction mixture was stirred at K.T. overnight, then was diluted with dichloromethane and washed with 2 M hydrochloric acid. Organics were dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 0,307,

MS: [M+H]+=686 (expect.=686) (multimode+)

Stage (d) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)pyrazolo[1,5-a]pyridine-2-carboxamide

In the vial for microwave processing was added 3-(3'-(5-fluoro-3-((1s,4s)-4-(pyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)-pyridine-2-yloxy)biphenyl-4-yl)propylaminosulfonyl (0,307 g, 0.45 mmol) and 3-aminopropan-1-ol (0,034 ml, 0.45 mmol) in acetonitrile (3 ml). The reaction mixture was heated to 80°C. by microwave for 1 h, then concentrated to obtain the crude product. The crude product was purified preparative HPLC column Phenomenex Gemini using a 75-5% gradient of aqueous 0.1%ammonia in methanol as eluent. The fractions containing the desired compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 32 mg

1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=6,9 Hz, 1H), 8.12-8.06 (m, 2H), 7.64 (d, J=8,2 Hz, 1H), 7.48-7.43 (m, 6H), 7.21 (t, J=7.9 Hz, 1H), 7.14-7.10 (m, 3H), 6.94 (s, 1H), 4.17-4.12 (m, 1H), 4.04-3.96 (m, N), 3.59 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.60-2.55 (m, 4H), 1.97-1.66 (m, 12H).

MS: [M+H]+=665 (expect.=665) (multimode+)

Example 160

5-fluoro-N-((1s,4s)-4-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide

To a stirred solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (0.08 g, 0.13 mmol) in acetonitrile (2 ml) was added 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0,049 g, 0.25 mmol) and triethylamine (0,176 ml of 1.27 mmol). The reaction mixture was stirred at K.T. within 10 minutes was Added 1-papapostolou acid cyclic anhydride (EMM, 1.5 M in THF) (0,169 ml, 0.25 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was evaporated to dryness and pererestorani in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was treated with a mixture of 4 M HCl/dioxane (0,633 ml of 2.53 mmol) and left to mix with K.T. within 2 hours the Crude product was purified preparative HPLC on a column (Waters X-Bridge, using 75-0% gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 22 mg

1H NMR (400 MHz, C 3OD) δ 8.46 (d, J=7.9 Hz, 1H), 8.12 (d, J=3,9 Hz, 1H), 8.08 (dd, J=7,1, 3,9 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.48 (d, J=4,7 Hz, 2H), 7.41 (s, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.17-7.13 (m, 1H),7.07(s, 1H), 4.17-4.09 (m, 1H), 3.98-3.90 (m, 1H), 3.94 (s, 3H), 3.35 (t, J=5.5 Hz, 4H), 3.12-3.04 (m, 4H), 2.82 (t, J=7.9 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 1.99-1.62 (m, 10H).

MS: [M+H]+=708 (expect.=708) (multimode+)

Example 161

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)-propyl) - biphenyl-3-yloxy)nicotinamide)cyclohexyl)quinoline-8-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)quinoline-8-carboxamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide (0.14 g, 0.30 mmol) and quinoline-8-carboxylic acid (0,058 g, 0.33 mmol) in acetonitrile (1 ml) under nitrogen atmosphere was added triethylamine (0,421 ml, to 3.02 mmol) at K.T. Solution was stirred for 10 minutes. To this solution was added 1-papapostolou acid cyclic anhydride (TR) (1.57 M in THF) (0,212 ml, 0.33 mmol). The reaction mixture was diluted with EtOAc and washed with saturated solution of sodium bicarbonate. Organic matter was extracted (×3), dried (MgSO4) and concentrated to obtain specified in the subtitle compound as a white foam. Output: 0,150,

MS: [M+H]+=619 (expect.=619) (multimode+)

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(quinoline-8-carboxamido)-cyclohexylcarbonyl)pyridine-2-ylox is)biphenyl-4-yl)propyl-methanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)quinoline-8-carboxamide (0.15 g, 0.24 mmol) and pyridine (0,038 ml, 0.47 mmol) in DCM (1 ml) was added methanesulfonamide (0,039 ml, 0.50 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain oil. The oil was dissolved in DCM, then added isohexane until the solid is not broke. The suspension was concentrated in vacuo to obtain an oil. The oil was again dissolved in DCM and added isohexane until the solid is not broke (repeated × 4). When the concentration specified in the subtitle compound was white foam. Output: 0,170,

MS: [M+H]+=697 (expect.=697) (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)quinoline-8-carboxamide

To 3-(3'-(5-fluoro-3-((1s,4s)-4-(quinoline-8-carboxamido)-cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate in acetonitrile (1 ml) was added 3-aminopropan-1-ol. The mixture was heated up to 80°C in the microwave for 30 minutes. The crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5% gradient of aqueous 0.1%ammonia in methanol in quality is the firmness of the eluent. The fractions containing the target compound, freeze-dried to obtain the product, which was re-purified preparative HPLC column Phenomenex Gemini using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 65 mg

1H NMR (400 MHz, CD3OD) δ 8.64-8.59 (m, 2H), 8.53 (d, J=to 15.4 Hz, 1H), 8.38 (dd,J=8,3, 1.7 Hz, 1H),8.11-8.05 (m, 3H), 7.68 (t, J=8.0 Hz, 1H), 7.45-7.41 (m, 5H), 7.34-7.30 (m, 1H), 7.18-7.14 (m, 3H), 4.26-4.21 (m, 1H), 4.16-4.10 (m, 1 H), 3.67 (t, J=6.2 Hz, 2H), 3.09 (t, J=7,3 Hz, 2H), 2.99 (t, J=8,2 Hz, 2H), 2.68 (t, J=6.5 Hz, 2H), 2.00-1.81 (m, 12H).

MS: [M+H]+=676 (expect.=676) (multimode+)

Example 162

N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Stage (a) 2-(3'-(3-((1s,4s)-4-(tert-Butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate

Methanesulfonanilide (0,338 ml, 4.37 mmol) and pyridine (0,353 ml, 4.37 mmol) was added to a stirred solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (1,200 g of 2.18 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at K.T. overnight, then was diluted with dichloromethane and washed with saturated is a sodium bicarbonate (×2), water and saturated brine. Organics were dried over sodium sulfate, filtered and evaporated to obtain the crude product, which was triturated with ether to obtain specified in the subtitle compound as a colourless oil. Output: 1,09,

MS: [M-Boc]+=528 (expect.=528) (multimode+)

Stage (b) tert-Butyl(1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate

To a solution/suspension of 2-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl-methanesulfonate (0.4 g, 0.64 mmol) in acetonitrile (2 ml) was added CIS-2,6-dimethylpiperazine (0,291 g, 2.55 mmol). The mixture was heated in a sealed tube for microwave treatment at 100°C for 2 minutes. The mixture was diluted with EtOAc and washed with saturated NaHCO3(aq.), brine and evaporated to obtain the crude product. It was purified using column chromatography (eluent = 2% 7N NH3in MeOH/DCM) to obtain specified in the subtitle compound as a yellow foam. Output: 0,25,

MS: [M+H]+=646 (expect.=646) (multimode+)

Stage (C) N-((1s,4s)-4-Aminocyclohexane)-2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating

To a solution of tert-butyl(1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate is a (250 mg, 0,39 mmol) in DCM (2 ml) was added a 4.0 M solution of hydrogen chloride in dioxane (3 ml, 12.00 mmol). The mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness to obtain specified in subheading cleaners containing hydrochloride salt of the compound in the form of a cream solid. Output: 0,295,

MS: [M+H]+=546 (expect.=546) (multimode+)

Stage (d) N-((1s,4s)-4-(2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of trihydrochloride N-((1s,4s)-4-aminocyclohexane)-2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fioricetonline (140 mg, 0.21 mmol) and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (35,5 mg, 0.21 mmol) in acetonitrile (2 ml) was added triethylamine (0,298 ml, 2.14 mmol). The mixture was left to mix, until it became a solution. Then added 1,57M solution of 1-papapostolou acid cyclic anhydride in THF (EMM) (0,667 ml, 1.05 mmol) and the mixture was left to mix for 2 hours. Added additional equivalent of acid and TR. The mixture was concentrated in vacuo and the residue was distributed between EtOAc and saturated NaHCO3(aq.). EtOAc was evaporated and the residue was purified using preparative chromatography with reversed phase (eluent = TFA (aq.)/MeCN). The appropriate fractions were combined and evaporated to obtain the mod is and, which was dissolved in water and liofilizirovanny obtaining specified in the title compounds as white solids. Yield: 38 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=8.0 Hz, 3.1 Hz, 1H), 7.52 (d, J=8,2 Hz, 2H), 7.48-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.27 (d, J=8,2 Hz, 2H), 7.18-7.12 (m, 1H), 6.38 (s, 1H), 4.11 (s, 1H), 4.01 (t, J=6,1 Hz, 2H), 3.98-3.92 (m, 1H), 3.48-3.34 (m, 4H), 2.92 (s, 4H), 2.77 (t, J=6.4 Hz, 2H), 2.36 (t, J=12.1 Hz, 2H), 2.04-1.96 (m, 2H), 1.87-1.78 (m, 8H), 1.73-1.65 (m, 2H), 1.32 (d, J=6,5 Hz, 6N).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 163

2-(4'-(2-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(1-methyl-1H-pyrazole-3-carboxamido)-cyclohexyl)nicotinamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(2-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)ethyl)biphenyl-3-yloxy)-5-fioricetonline trihydrochloride (140 mg, 0.21 mmol) and 1-methyl-1H-pyrazole-3-carboxylic acid (27.0 mg, 0.21 mmol) in acetonitrile (2 ml) was added triethylamine (0,298 ml, 2.14 mmol). The mixture was left to mix, until it became a solution. Then added a 1.57 M solution of 1-papapostolou acid cyclic anhydride (TR) in THF (0,667 ml, 1.05 mmol)and the mixture was left to mix for 2 hours. Was added 1 EQ. and acid, and TR. The mixture was concentrated in vacuo, and the residue was distributed between EtOAc and saturated NaHCO3(aq.). EtOAc was evaporated, and the residue was purified using preparative the Yu chromatography with reversed phase (eluent = TFA (aq.)/Meon). The appropriate fractions were combined and evaporated to obtain the residue, which liofilizirovanny obtaining specified in the title compound as a white solid. Yield: 35 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7,0 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=8.0 Hz, 3.1 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.53 (d, J=8,2 Hz, 2H), 7.47 (dd, J=6,7 Hz, 3.3 Hz, 2H), 7.40 (d, J=1.2 Hz, 1H), 7.28 (d, J=8,2 Hz, 2H), 7.17-7.13 (m, 1H), 6.65 (d, J=2.3 Hz, 1H), 4.12 (s, 1H), 3.96 (s, 1H), 3.84 (s, 3H), 3.51-3.41 (m, 4H), 3.00-2.91 (m, 4H), 2.45 (t, J=12.0 Hz, 2H), 1.89-1.78 (m, 6H), 1.75-1.65 (m, 2H), 1.33 (d, J=6,5 Hz, 6N).

[M+H]+=654 (expect.=654) (multimode+)

Example 164

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)-biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)PP (0.1 g, 0.22 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.035 g, 0.22 mmol) in acetonitrile (1 ml) was added triethylamine (0,301 ml of 2.16 mmol) and the reaction mixture was stirred for 10 minutes. Was added 1-papapostolou acid cyclic anhydride (TR) (1,57M in THF) (0,151 ml, 0.24 mmol) and the reaction mixture was stirred over night. The solution was diluted with EtOAc and washed with water (×3). Organic matter obyedinenie washed with brine (×3), dried (MgSO4) and concentrated to obtain specified in the subtitle compound as a white foam. Output: 0,120,

MS: [M+H]+=609 (expect.=609) (multimode+)

Stage (b) 3-(3'-(5-fluoro-3-((1s,4s)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.11 g, 0.18 mmol) and pyridine (0,029 ml, 0.36 mmol) in DCM (1 ml) was added methanesulfonamide (0,030 ml, 0.38 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain oil.

The oil was dissolved in DCM, then added isohexane until the solid is not broke. The suspension was concentrated in vacuo to obtain an oil. The oil was again dissolved in DCM and added isohexane until the solid is not broke (repeated ×4). When the concentration specified in the subtitle compound was beige foam. Output: 0,110,

MS: [M+H]+=687 (expect.=687) (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To 3-(3'-(5-fluoro--((1s,4s)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate (0.11 g, 0.16 mmol) in acetonitrile (1 ml) was added 3-aminopropan-1-ol (0,061 ml, 0.80 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes. The crude product was purified preparative HPLC on a column of Phenomenex N-X, using a 95-5%gradient of aqueous 0.1%ammonia in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 17 mg

1H NMR (400 MHz, CD3OD) δ 8.93 (dd, J=5,3, 5.3 Hz, 1H), 8.49 (s, 1H), 8.26 (dd, J=3.2, and 3.2 Hz, 1H), 8.12-8.06 (m, 2H), 7.46-7.43 (m, 4H), 7.41-7.38 (m, 2H), 7.13-7.09 (m, 3H), 6.94-6.91 (m, 1H). 4.18-4.07 (m, 2H), 3.60 (t, J=7,3 Hz, 2H), 2.68-2.57 (m, 6H), 1.95-1.66 (m, 12H).

MS: [M+H]+=666 (expect.=666) (multimode+)

Example 165

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)-1 H-benzo[d]imidazol-4-carboxamid

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide (0.1 g, 0.22 mmol) and 1H-benzo[d]imidazole-4-carboxylic acid (0.035 g, 0.22 mmol) in acetonitrile in the atmosphere of nitrogen was added DIPEA (0.075 ml, 0.43 mmol) in K.T. Solution was stirred for 10 minutes. To this solution was added HATU (0,164 g, 0.43 mmol). The reaction mixture was diluted with EtOAc and the industry is Ali a saturated solution of sodium bicarbonate. Organic matter was extracted (×3), dried (MgSO4) and concentrated to obtain specified in the subtitle compound as a yellow solid. Output: 0,120,

MS: [M+H]+=608 (expect.=608) (multimode+)

Stage (b) 3-(3'-(3-((1s,4s)-4-(1H-Benzo[d]imidazol-4-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate

To a solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(3-hydroxypropyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-1H-benzo[d]imidazole-4-carboxamide (0.12 g, 0.20 mmol) and pyridine (0,032 ml to 0.39 mmol) in DCM (1 ml) was added methanesulfonamide (to 0.032 ml, 0.41 mmol)and the reaction mixture was stirred at K.T. during the night. The reaction mixture was diluted with aqueous 2 M HCl and was extracted with DCM (×3) and EtOAc (×3). Organic substances were combined and dried (MgSO4) and concentrated to obtain oil.

The oil was dissolved in DCM, then added isohexane until the solid is not broke. The suspension was concentrated in vacuo to obtain an oil. The oil was again dissolved in DCM and added isohexane until the solid is not broke (repeated × 4). When the concentration specified in the subtitle compound was not quite white foam. Output: 0,110,

MS: [M-H]-=684 (expect.=684) (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(3-hydroxypropylamino)propyl)biphenyl-3-yloxy)nicotinamide)-cyclohex who yl)-1H-benzo[d]imidazol-4-carboxamid

To 3-(3'-(3-((1s,4s)-4-(1H-benzo[d]imidazol-4-carboxamido)-cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl-methanesulfonate (0.11 g, 0.16 mmol) in acetonitrile (1 ml) was added 3-aminopropan-1-ol (0,061 ml, 0.80 mmol). The mixture was heated up to 80°C in the microwave for 30 minutes. The crude product was purified preparative HPLC on a Sunfire column using a 95-5%gradient of water with 0.1%TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 64 mg

1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.50 (d,J=13.3 Hz, 1H), 8.11 (d, J=6.8 Hz, 3H), 8.08 (dd, J=7,9, 3.1 Hz, 1H), 7.92 (d, J=11.0 cm Hz, 1H), 7.85 (d, J=9.4 Hz, 1H), 7.52-7.45 (m, 5H), 7.42-7.40 (m, 1H), 7.22-7.14 (m, 1H), 4.17-4.11 (m, 2H), 3.66 (t, J=4,7 Hz, 2H), 3.10 (t, J=6.5 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 2.70 (t, J=7.8 Hz, 2H), 2.01-1.79 (m, 12H).

MS: [M+H]+=665 (expect.=665) (multimode+)

Example 166

2-(4'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(1-methyl-1H-pyrazole-3-carboxamido)-cyclohexyl)nicotinamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline (150 mg, 0.24 mmol) in acetonitrile (4 ml) was added 1-methyl-1H-pyrazole-3-carboxylic acid (37 mg, 0.30 mmol) and triethylamine (0,330 ml, is 2.37 mmol). Then added 1-papapostolou acid cycle is the anhydride, 1.57 M solution in THF (0,189 ml, 0.30 mmol) and the mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 84 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7.5 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.08-8.04 (m, 1H), 7.58-7.56 (m, 1H), 7.54-7.50 (m, 2H), 7.48-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.26-7.23 (m, 2H), 7.17-7.12 (m, 1H), 6.65 (d, J=2.3 Hz, 1H), 4.16-4.08 (m, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.58-3.46 (m, 4H), 2.95-2.87 (m, 2H), 2.71 (t, J=7,6 Hz, 2H), 2.57 (t, J=12,8 Hz, 2H), 2.05-1.94 (m, 2H), 1.91-1.77 (m, 6H), 1.74-1.62 (m, 2H), 1.33 (d, J=6,7 Hz, 6N).

MS: [M+H]+=668 (expect.=668) (multimode+)

Example 167

N-((1s,4s)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

To a solution of 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl-methanesulfonate (120 mg, 0.18 mmol) in acetonitrile (1 ml) was added 1-methyl-1,4-diazepan (0,069 ml, 0.55 mmol). The reaction mixture was left to mix with K.T. during the night. It was purified by HPLC to obtain specified in the title compound as a white solid. Yield: 42 mg

1H NMR (400 MHz, CDCl3) δ 8.48-8.42 (m, 1H), 8.12-8.10 (m, H), 8.09-8.03 (m, 1H), 7.60-7.56 (m, 2H), 7.51-7.47 (m, 2H), 7.41-7.39 (m, 1H), 7.35-7.30 (m, 2H), 7.19-7.14 (m, 1H), 6.42 (s, 1H), 4.17-4.07 (m, 1H), 3.96-3.84 (m, 1H), 3.77-3.70 (m, 7H), 3.58-3.38 (m, 6H), 3.10-3.03 (m, 2H), 2.96 (s, 3H), 2.33-2.24 (m, 3H), 1.96-1.62 (m, 10H).

MS: [M+H]+=668 (expect.=668) (multimode+)

Example 168

N-((1s,4s)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-(2-(4-methylpiperazin-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

To a solution of 2-(3'-(3-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl-methanesulfonate (120 mg, 0.18 mmol) in acetonitrile (2 ml) was added 1-methylpiperazine (0,061 ml, 0.55 mmol). The reaction mixture was left to mix with K.T. during the night. It was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 65 mg

1H NMR (400 MHz, CDCl3) δ 8.47-8.42 (m, 1H), 8.12-8.10 (m, 1H), 8.07-8.03 (m, 1H), 7.55-7.51 (m, 2H), 7.50-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.30-7.26 (m, 2H), 7.17-7.12 (m, 1H), 6.42 (s, 1H), 4.18-4.08 (m, 1H), 3.97-3.91 (m, 1H), 3.92 (s, 3H), 3.72 (s, 3H), 3.23-2.87 (m, 12H), 2.83 (s, 3H), 1.90-1.75 (m, 6H), 1.74-1.62 (m, 2H).

MS: [M+H]+=654 (expect.=654) (multimode+)

Example 169

N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxamide

Stage (a) 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxylic acid

Ethyl-5-hydroxy-1H-feast of the ol-3-carboxylate (0.5 g, 3,20 mmol), 1,3-dibromopropane (0,358 ml, 3.52 mmol) and potassium carbonate (1,770 g, 12,81 mmol) was heated under reflux in acetonitrile (20 ml) for 20 h, then was cooled to K.T., filtered and evaporated in vacuum. The residue was dissolved in a mixture of Meon (10 ml) and water (20 ml), was added NaOH (0,384 g, being 9.61 mmol) and was stirred for 2 hours, the Reaction mixture was brought to pH 5 with 2 M HCl and purified by HPLC with a reversed phase with MeCN/aq. TFA as eluent. The solvent was evaporated in vacuo to ~15 ml and freeze-dried to obtain specified in the subtitle compound as a white solid. Yield: 440 mg

1H NMR (400 MHz, DMSO) δ 5.87 (s, 1H), 4.30 (t, J=5,2 Hz, 2H), 4.14 (t, J=6.3 Hz, 2H), 2.50 (m, 2H).

Stage (b) N-((1s,4s)-4-(2-(4'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxamide

HATU (0,063 g, 0.16 mmol) was added to a solution of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fioricetonline (0.1 g, 0.15 mmol), 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxylic acid (0,028 g, 0.16 mmol) and DIPEA (0,131 ml, 0.75 mmol) in DMF (2 ml)and the solution was stirred at K.T. within 20 hours the Mixture was purified by HPLC with a reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 62 mg

1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=3.1 Hz, 1H), 8.06 (m, 1H), 7.52 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.83 (s, 1H), 4.27 (m, 2H), 4.11 (m, 1H), 4.05 (t, J=6.2 Hz, 2H), 3.92 (m, 1H), 3.56 (m, 4H), 2.96 (m, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.66 (t, J=13.5 Hz, 2H), 2.20 (m, 2H), 2.02 (m, 2H), 1.89-1.61 (m, 8H), 1.34 (d, J=6,5 Hz, 6N).

MS: [M+H]+=710 (expect.=710) (multimode+)

Example 170

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

Stage (a) 4-Bromo-3-(thiomorpholine)benzonitrile

To a solution of 4-bromo-3-(methyl bromide)benzonitrile (0.95 g, 3.46 mmol) in DMF (13,40 ml) was added thiomorpholine (0,417 ml, 4,15 mmol) and potassium carbonate (0,573 g, 4,15 mmol). The reaction mixture was left to mix with K.T. during the night. The reaction mixture was poured into water and was extracted with EtOAc (×2). Organic extraction were combined, washed with brine (×3), dried (MgSO4) and was evaporated to obtain a yellow oil. It was purified by flash chromatography on silica (Biotage column) (eluent = 25% ether/isohexane) obtaining specified in the subtitle compound as a colourless oil. Output: 0,951,

1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=2.1 Hz, 1H), 7.65 (d, J=8,2 Hz, 1H), 7.39 (dd, J=8,3, 2.2 Hz, 1H), 3.59 (s, 2H), 2.82-2.67 (m, 8H).

Stage (b) 4-Bromo-3-(thiomorpholine)benzaldehyde

To a solution of 4-bromo-3-(thiomorpholine)benzonitrile (0,92 g, 3,10 m is ol) in DCM (10,67 ml) at 0°C was added diisobutylaluminium (3,40 ml, 3,40 mmol). The reaction mixture was allowed to mix at 0°C for 10 minutes. The reaction mixture was poured into a mixture of crushed ice and 6M HCl and was stirred for 1 hour. The organic phase was separated, washed with saturated NaHCO3, brine, dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a pink oil. Output: 0,735,

MS: [M+H]+=300/302 (expect.=300/302) (multimode+)

Stage (C) 4-(2-Bromo-5-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-benzyl)thiomorpholine

To a solution of 4-bromo-3-(thiomorpholine)benzaldehyde (0.73 g, 2,43 mmol) in dichloromethane (24,32 ml) was added (2R,6S)-2,6-dimethylpiperazine (0,416 g, 3.65 mmol). The mixture was left to mix with K.T. for 40 minutes, then was added sodium triacetoxyborohydride (0,773 g, 3.65 mmol). The reaction mixture was stirred at K.T. within 2 hours. The mixture was diluted with dichloromethane and washed with saturated NaHCO3(aq.), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a pale yellow oil. Output: 0,92,

MS: [M+H]+=398/400 (expect.=398/400) (multimode+)

Stage (d) tert-Butyl(1s,4s)-4-(2-(4'-(((3,S5R)for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (1.283 g, .31 mmol), 4-(2-bromo-5-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)benzyl)thiomorpholine (0,92 g, 2.31 mmol) and sodium carbonate (1,983 g, 6,93 mmol) was added to THF (15.39 ml) and degassed water (7,70 ml) in nitrogen atmosphere. Then added tetrakis(triphenylphosphine)palladium(0) (0,053 g, 0.05 mmol) and the reaction mixture was heated under reflux overnight. The mixture was poured into water and was extracted into EtOAc (×2). The extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a light brown foam. The crude substance was purified by flash chromatography on silica (Biotage column) (eluent = 4% 7M ammonia in methanol/DCM) to obtain specified in the subtitle compound as a pale brown oil. Output: 1,25,

MS: [M+H]+=747 (expect.=747) (multimode+)

Stage (e) N-((1s,4s)-4-Aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fornicating

To a solution of tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (1.24 g, of 1.66 mmol) in DCM (20 ml) was added 4.0 M hydrogen chloride in dioxane (4,15 ml, 16,60 mmol). The mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness to obtain hydrochloride specified in the subtitle compound as a white solid. Output: 1,32,

MS: [M+H]=647 (expect.=647) (multimode+)

Stage (f) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-6-torymidae[1,2-a]pyridine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-5-fioricetonline hydrochloride (150 mg, 0,19 mmol) in acetonitrile (2,29 ml) was added 6-torymidae[1,2-a]pyridine-2-carboxylic acid (49.2 mg, 0.23 mmol) and triethylamine (0,264 ml, 1,89 mmol). Then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (0,151 ml, 0.24 mmol) and the mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. The crude product was purified preparative HPLC using a 95-5%gradient of water with 0.2%TFA in methanol as the eluent, to obtain specified in the title compounds as white solids. Yield: 64 mg

1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.16 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7.7, 3.1 Hz, 1H), 7.76-7.74 (m, 1H), 7.66 (dd, J=10,0, a 4.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1 H), 7.55-7.49 (m, 2H), 7.39 (d, J=7.9 Hz, 1 H), 7.35-7.30 (m, 1H), 7.22-7.18 (m, 1H), 7.17-7.15 (m, 1H), 4.42 (s, 2H), 4.15-4.02 (m, 2H), 3.88 (s, 2H), 3.53-3.42 (m, 2H), 3.00-2.59 (m, 8H), 2.40 (t, J=12.0 Hz, 2H), 1,94-1.73 (m, 8H), 1.30 (d, J=6,4 Hz, 6N).

MS: [M+H]+=809 (expect.=809) (multimode+)

Example 171

N-((1s,4s)-4-(5-FPO is-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.28 g, 0.44 mmol) and thiomorpholine (0,091 g, 0.89 mmol) was stirred in DCM (30 ml) for 15 minutes was Added acetic acid (0,051 ml, 0.89 mmol), then sodium triacetoxyborohydride (0,188 g, 0.89 mmol) and the reaction mixture was stirred for another 20 hours the Reaction was suppressed 2 M HCl (30 ml), was extracted with EtOAc, washed with water and brine, dried (Na2SO4) and was evaporated in vacuum to obtain specified in the subtitle compound as a white solid. Output: 0,300,

1H NMR (400 MHz, CDCl3) δ 8.36 (m, 1H), 8.06 (d, J=3.1 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.35 (m, 1H), 7.29 (m, 1H), 7.27 (s, 1H), 7.14 (m, 1H), 4.54-4.08 (m, 2H), 3.77-3.47 (m, 2H), 3.56 (m, 4H), 3.41 (s, 2H), 2.70 (m, 8H), 2.33 (m, 2H), 1.87-1.46 (m, 10H), 1.42 (s, 9H).

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)-nicotinamide

4 M HCl in dioxane (5 ml, 20.00 mmol) was added to a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)-biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.3 g, 0.42 mmol) in DCM (5 ml) and was stirred for 2 h the Solvent was evaporated in vacuum to obtain the specified podzagolovke cleaners containing hydrochloride salt compound as a pale yellow gum. Output: 0,280,

1H NMR (400 MHz, DMSO) δ 8.37 (d, J=6,8 Hz, 1H), 8.29 (d, J=3,4 Hz, 1H), 8.23-8.09 (m, 4H), 8.05 (m, 1H), 7.79 (d, J=8,1 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.46 (d, J=7,4 Hz, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.24 (m, 1H), 4.38 (s, 2H), 3.97-3.57 (m, 8H), 3.45-3.08 (m, 8H), 2.79 (m, 2H), 1.92-1.59 (m, 10H).

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-(hydroxymethyl)thiazole-4-carboxamide

HATU (0,094 g, 0.25 mmol) was added to a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine)-biphenyl-3-yloxy)nicotinamide hydrochloride (0.14 g, 0.23 mmol), 2-(hydroxymethyl)thiazole-4-carboxylic acid (0,040 g, 0.25 mmol) and DIPEA (0,197 ml, 1.13 mmol) in DMF (2 ml) and the solution was stirred at K.T. in for 20 h the Mixture was purified by HPLC with a reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compounds as white solids. Yield: 45 mg

1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=3.1 Hz, 1H), 8.10 (s, 1H), 8.03 (m, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.61 (m, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.33 (m, 1H), 7.22 (m, 1H), 7.19 (m, 1H), 4.79 (s, 2H), 4.45 (s, 2H), 4.41 (s, 2H,), 4.11 (m, 1H), 3.99 (m, 1 H), 3.94-3.56 (m, 4H), 3.43-2.69 (m, 12H), 1.93-1.68 (m, 8H).

MS: [M+H]+=761 (expect.=761) (multimode+)

Example 172

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

Stage (a) N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-Tetra is Teal-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

A solution of 1,1'-bis(diphenylphosphino)ferrocene (0,034 g, 0.06 mmol) and complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and dichloromethane (0,049 g, 0.06 mmol) was stirred in nitrogen atmosphere for 10 minutes was Added potassium acetate (0,356 g, 3.63 mmol), N-((1s,4s)-4-(5-fluoro-2-(3-iodinase)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (at 0.730 g, to 1.21 mmol) and bis(pinacolato)LIBOR (0,399 g, 1.57 mmol)and the reaction mixture was heated up to 80°C during the night. The reaction mixture was poured into water and was extracted in EtOAc. Organics were dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column with silica Isco Companion, 100 g, elwira 100% EtOAc. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow oil. Output: 0,324,

MS: [M+H]+=604 (expect.=604) (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (0,320 g of 0.53 mmol) in THF (3 ml) was added 2-(4-bromophenyl)ethanol (0,111 ml, 0,80 IMO the ü) and sodium carbonate (0,169 g, to 1.59 mmol) in water (1,500 ml). Added tetrakis(triphenylphosphine)palladium(0) (0,031 g, 0.03 mmol) and the reaction mixture was heated to 70°C for 1 h, the Reaction mixture was poured into water and was extracted in EtOAc. Organics were dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column of silica Isco Companion, 50 g, gradient elution of 90-100% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a yellow oil. Yield: 68 mg

MS: [M+H]+=598 (expect.=598) (multimode+)

Stage (C) 2-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)-biphenyl-4-yl)ethyl methanesulfonate

To a stirred solution of N-((1s,4s)-4-(5-fluoro-2-(4'-(2-hydroxyethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (0,068 g, 0.11 mmol) in dichloromethane (1 ml) was added pyridine (0.037 ml, 0.46 mmol) and methanesulfonamide (or 0.035 ml, 0.46 mmol). The reaction mixture was stirred at K.T. within 3 days, then was diluted with dichloromethane and washed with 2 M hydrochloric acid and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product is KTA. Crude oil is triturated with diethyl ether to obtain solid, which was collected by filtration and dried in air to obtain specified in the subtitle compound (also contains some amount of N-((1s,4s)-4-(2-(4'-(2-chloroethyl) - biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) as a yellow solid. Yield: 60 mg

MS: [M+H]+=676 (expect.=676) (multimode+)

Stage (d) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

In the vial for microwave processing was added 2-(3'-(5-fluoro-3-((1s,4s)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate (to 0.060 g, 0.09 mmol) and 1-methyl-1,4-diazepan (0,033 ml, 0.27 mmol) in acetonitrile (0.5 ml). The reaction mixture was heated using microwaves to 80°C for 3 hours the Crude product was purified preparative HPLC on a column (Waters X-Bridge, using 65-0% gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 3 mg

1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=3.1 Hz, 1H), 8.06 (dd, J=8,2, 3.1 Hz, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.48 (d, J=5,9 Hz, 2H), 7.42-7.40 (m, 1H, 7.33 (d, J=8,2 Hz, 2H), 7.18-7.13 (m, 1H), 6.38 (s, 1H), 4.14-4.07 (m, 1H), 4.02 (t, J=6.6 Hz, 2H), 3.98-3.91 (m, 1H), 3.67 (s, 4H), 3.52-3.41 (m, 4H), 3.35 (t, J=8,4 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 2.93 (s, 3H), 2.78 (t, J=6.2 Hz, 2H), 2.30-2.22 (m, 2H), 2.04-1.96 (m, 2H), 1.88-1.76 (m, 8H), 1.74-1.62 (m, 2H).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 173

N-((1s,4s)-4-(2-(3'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate

In the vial for microwave processing was added 3-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-3-yl)propyl-methanesulfonate (0,150 g, 0.23 mmol) and (2S,6R)-2,6-dimethylpiperazine (0,214 g of 1.87 mmol) in acetonitrile (3 ml). The reaction mixture was heated up to 80°C using microwave for 40 minutes the Reaction mixture was evaporated to dryness and pererestorani in EtOAc and washed with saturated sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica, using a column of silica Isco Companion, 50 g, gradient elution with 2-4% 7 N. methanolic ammonia in dichloromethane. Net FR the work was evaporated to dryness to obtain specified in the subtitle compound as a yellow oil. Output: 0,120,

MS: [M+H]+=660 (expect.=660) (multimode+)

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating

To a stirred solution of tert-butyl(1s,4s)-4-(2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexylcarbamate (0,175 g, 0.27 mmol) in dichloromethane (1.2 ml) was added to a mixture of 4 M HCl/dioxane (0,995 ml, 3,98 mmol). The reaction mixture was stirred at K.T. in nitrogen atmosphere overnight, then concentrated to obtain hydrochloride specified in the subtitle compound as a yellow oil which was used without further purification. Output: 0,180,

MS: [M+H]+=560 (expect.=560) (multimode+)

Stage (C) N-((1s,4s)-4-(2-(3'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

To a stirred solution of N-((1s,4s)-4-aminocyclohexane)-2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fioricetonline hydrochloride (0,180 g, 0.28 mmol) in acetonitrile (2 ml) was added 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (0,052 g, 0.34 mmol) and triethylamine (0,397 ml, 2.85 mmol). The reaction mixture was stirred at K.T. within 10 minutes was Added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (0,228 ml, 0.34 mmol) and the reaction mixture re exively when K.T. in nitrogen atmosphere for 2 h, then concentrated to obtain the crude product. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using 70-20% gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 14 mg

1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 8.01 (d, J=8,3 Hz, 1H), 7.42 (s, 2H), 7.38-7.32 (m, 3H), 7.27-7.23 (m, 1H), 7.16-7.06 (m, 2H), 6.30 (s, 1H), 4.08-4.02 (m, 1H), 3.95-3.91 (m, 2H), 3.88-3.69 (m, 3H), 3.06-2.94 (m, 2H), 2.80-2.75 (m, 2H), 2.69-2.58 (m, 2H), 2.54-2.44 (m, 2H), 2.10-1.95 (m, 2H), 1.84-1.65 (m, 6H), 1.64-1.52 (m, 4H), 1.40-1.25 (m, 6H), 0,97-of 0.90 (m, 1H).

[M+H]+=694 (expect.=694) (multimode+)

Example 174

N-((1s,4s)-4-(3-Cyclopropyl-1H-pyrazole-5-carboxamido)-cyclohexyl)-5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)-nicotinamide

To a stirred solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)-piperazine-1-carboxylate (0,080 g, 0.13 mmol) in acetonitrile (2 ml) was added 3-cyclopropyl-1H-pyrazole-5-carboxylic acid (0,039 g, 0.25 mmol) and triethylamine (0,176 ml of 1.27 mmol). The reaction mixture was stirred at K.T. within 10 minutes was Added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (of 0.081 g, 0.25 mmol) and the reaction mixture was stirred at K.T. during the night. P is a promotional mixture was evaporated to dryness and pererestorani in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was treated with a mixture of 4 M HCl/dioxane (0,633 ml of 2.53 mmol) and left to mix with K.T. during the night. The crude product was purified preparative HPLC on a column (Waters X-Bridge, using 75-0% gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain the crude product, which was dissolved in a mixture of DCM/methanol, was added triethylamine (0.1 ml) and PS-benzaldehyde (0,030 g) and the solution was left to mix with K.T. within 3 days. The resin was filtered and the compound was purified preparative HPLC on a column (Waters X-Bridge, using 90-40% gradient of aqueous 0.2% of TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 8 mg

1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=8,1 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J=8,1 Hz, 1H), 7.51 (d, J=9,3 Hz, 2H), 7.47-7.44 (m, 2H), 7.38 (s, 1H), 7.23 (d, J=9,3 Hz, 2H), 7.15-7.11 (m, 1H), 6.32 (s, 1H), 4.13-4.06 (m, 1H), 3.97-3.89 (m, 1H), 3.41-3.36 (m, 4H), 3.19-3.12 (m, 4H), 2.92-2.84 (m, 2H), 2.71 (t, J=7,0 Hz, 2H), 2.02-1.63 (m, 11 H), and 0.98 (q, J=7,0 Hz, 2H), 0,69 (q, J=4,6 Hz, 2H).

MS: [M+H]+=666 (expect.=666) (multimode+)

Example 175

N-((1s,4s)-4-(2-(3'-(3-((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)propyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To N-((1s,4s)-4-aminocyclopent who yl)-2-(3'-(3-((3S,5R) - for 3,5-dimethylpiperazine-1-yl)propyl)biphenyl-3-yloxy)-5-fornicating (0.1 g, 0.18 mmol) and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (0,033 g, 0.20 mmol) in acetonitrile (1 ml) was added triethylamine (0,249 ml, to 1.79 mmol). The reaction mixture was stirred for 10 minutes, then was added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (TR) (0,137 ml, 0.21 mmol). The reaction mixture was stirred at K.T. within 1 hour. The crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5% gradient of aqueous 0.1% of TFA in methanol as eluent. The fractions containing the target compound, freeze-dried to obtain specified in the title compounds as white solids. Yield: 42 mg

1H NMR (300 MHz, CD3OD) δ 8.14-8.06 (m, 2H), 7.53-7.42 (m, 6H), 7.32 (t, J=9.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.36 (s, 1H), 4.19-4.09 (m, 1H), 4.03-3.90 (m, 3H), 3.87-3.67 (m, 4H), 3.22 (t, J=8.6 Hz, 2H), 3.06 (t, J=12.0 Hz, 2H), 2.79-2.70 (m, 4H), 2.16-1.96 (m, 4H), 1.93-1.61 (m, 10H), 1.39 (d, J=17,1 Hz, 6H).

MS: [M+H]+=708 (expect.=708) (multimode+)

Example 176

N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) (S)-4-Bromo-3-((3-methylmorpholine)methyl)benzonitrile

To a solution of 4-bromo-3-(methyl bromide)benzonitrile (0.9 g, 3.27 mmol) in DMF (to 13.09 ml) was added (3)-3-methylmorpholin (0,541 g, 3.93 mmol) and potassium carbonate (0,995 g, 7.20 mmol). Reacciona the mixture was left to mix with K.T. throughout the night. The reaction mixture was poured into water and was extracted with EtOAc (×2). Organic extraction were combined, washed with brine (×3), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a yellow oil. Output: 0,75,

MS: [M+H]+=295/297 (expect.=295/297) (multimode+)

Stage (b) (S)-4-Bromo-3-((3-methylmorpholine)methyl)benzaldehyde

A solution of (S)-4-bromo-3-((3-methylmorpholine)methyl)benzonitrile (0,750 g, 2.54 mmol) in DCM (10 ml) was cooled in an ice bath to 0°C and slowly treated with diisobutylaluminium (1M in DCM) (3.04 from ml, totaling 3.04 mmol). The ice bath was removed and the reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was poured into a mixture of ice water (100 ml) and 6 M HCl (20 ml) and was stirred for 1 hour. Added 2 M NaOH to make the solution alkaline (~pH 10), and diluted with DCM. The organic phase was separated, washed with saturated NaHCO3, dried (MgSO4) and was evaporated to obtain a pale yellow oil. The crude product was purified on Biotage (silica, 50g), elwira 30%EtOAc in isohexane. The fractions containing the product were combined and concentrated to obtain specified in the subtitle compound as a colourless oil. Output: 0,530,

MS: [M+H]+=298/300 (expect.=298/300) (multimode+)

Stage (s) (S)-4-(2-Bromo-5-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)benzyl)-3-methylmorpholin

(2S,6R)-2,6-dimethyl perazin (0,304 g, 2.67 mmol) and (S)-4-bromo-3-((3-methylmorpholine)methyl)benzaldehyde (0,530 g, 1.78 mmol) in DCM (10 ml) was stirred at K.T. in nitrogen atmosphere for 30 minutes. Then added sodium triacetoxyborohydride (0.565 g, to 2.67 mmol) and the resulting solution was stirred at CTV over the weekend. The reaction mixture was extinguished saturated NaHCO3. The reaction mixture was extracted with DCM (×3). The organic layer was dried over MgSO4, was filtered and was evaporated to obtain specified in the subtitle compound as a yellow oil. Output: 0,620,

MS: [M+H]+=396/398 (expect.=396/398) (multimode+)

Stage (d) tert-Butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)-biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate

Tetrakis(triphenylphosphine)palladium(0) (0,033 g, 0.03 mmol) was added to a mixture of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)cyclohexylcarbamate (0,790 g of 1.42 mmol), (S)-4-(2-bromo-5-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)benzyl)-3 methylmorpholine (0,62 g, 1.56 mmol) and sodium carbonate (0,452 g, 4,27 mmol) in water (5 ml) and THF (10 ml). The mixture was heated at 70°C for 18 hours the Reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain the crude product as a brown oil. The crude product is about what imali by flash chromatography on silica (Biotage, 100 g), elwira a mixture of 50%:50% EtOAc/isohexane, then missed 10/1/0,1 DCM/methanol/triethylamine. Pure fractions were combined and evaporated to dryness to obtain specified in the subtitle compound as a brown solid. Output: 0,50,

MS: [M-H]-=743 (expect.=743) (multimode+)

Stage (e) N-((1s,4s)-4-Aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)-biphenyl-3-yloxy)-5-fornicating

To tert-butyl(1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexylcarbamate (0.5 g, 0.67 mmol) in dichloromethane (5 ml) was added 4 M HCl in dioxane (1,678 ml of 6.71 mmol). The reaction mixture was stirred at K.T. within 2 hours. The reaction was concentrated in vacuo and triturated with ether and filtered to obtain cleaners containing hydrochloride salt specified in the subtitle compound in the form of not-quite-white solid. Output: 0,490,

MS: [M+H]+=645 (expect.=645) (multimode+)

Stage (f) N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-Dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

To N-((1s,4s)-4-aminocyclohexane)-2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-5-fioricetonline hydrochloride (0.126 g, 0.16 mmol) in acetonitrile (1 ml) was added 5-m is elimidate[1,2-a]pyridine-2-carboxylic acid (0,031 g, 0.18 mmol) and triethylamine (0,222 ml of 1.59 mmol) and the reaction mixture was stirred for 5 minutes. Was added 1-papapostolou acid cyclic anhydride (EMM) (1.57 M in THF) (0,112 ml, 0.18 mmol) and the reaction mixture was stirred for 30 minutes. Was added methanol, and then the crude product was purified preparative HPLC column Phenomenex Gemini using a 95-5% gradient of aqueous 0.1% of TFA in methanol as eluent. The fractions containing the target compound were concentrated, then triturated with ether to obtain specified in the title compounds as white solids. Yield: 22 mg

1H NMR (400 MHz, CD3OD) δ 8.50-8.43 (m, 2H), 8.13 (d, J=2.6 Hz, 1H), 8.04 (dd, J=7,9, 2.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.66-7.50 (m, 4H), 7.40 (d, J=8,2 Hz, 1H), 7.32 (d, J=8,9 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.17-7.16 (m, 1H), 7.10 (d, J=6,8 Hz, 1H), 4.20-4.07 (m, 3H), 3.90-3.79 (m, 3H), 3.76-3.59 (m, 2H), 3.56-3.45 (m, 3H), 3.25-3.16 (m, 2H), 3.06-2.97 (m, 2H), 2.73 (s, 3H), 1.95-1.59 (m, 8H), 1.34-1.21 (m, 6H), 1.04-0,99 (m, 3H).

[M+H]+=803 (expect.=803) (multimode+)

Example 176

5-fluoro-N-((1s,4s)-4-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide

Stage (a) Benzyl-4-(2-(3'-(3-((1,s4s)-4-(tert-butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate

Benzyl 1-piperidinecarboxylate (0,922 ml, 4,78 mmol) and 2-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)cyclohexene mail)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate (0,600 g, 0.96 mmol) was heated at 100°C and 50 watts in the microwave for 2 h 15 min Volatiles evaporated and the residue suspended in a small amount of EtOAc, then filtered to remove the obtained white solid substance. The filtrate was purified by flash chromatography on silica (Combi-Flash Companoin, 100 g SNAP cartridge), gradient elution of 60-100% EtOAc in isohexane. Pure fractions were evaporated to dryness to obtain specified in the subtitle compound as a colourless oil. Output: 0,453,

[M+H]+=752 (expect.=752) (multimode+)

Stage (b) Benzyl-4-(2-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate

TFA (2 ml, 25.96 mmol) was added slowly to a solution of benzyl-4-(2-(3'-(3-((1s,4s)-4-(tert-butoxycarbonylamino)cyclohexylcarbonyl)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0,453 g to 0.60 mmol) in dichloromethane (2 ml). The reaction mixture was stirred for 5 h at K.T., then concentrated. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate (×2), water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound as a colourless gum. Output: 0,368,

MS: [M+H]+=652 (expect.=652) (multimode+)

Stage (C) Benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate

1-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (to 0.055 g, 0.28 mmol) was dissolved in acetonitrile (1 ml), then was added DIPEA (of 0.066 ml, 0.38 mmol) and HATU (HATU) (to 0.108 g, 0.28 mmol) and the mixture was stirred for 20 minutes. It was then added to a stirred solution of benzyl-4-(2-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0,123 g 0,19 mmol) in acetonitrile (1 ml). The reaction mixture was stirred overnight, then diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 0,156,

MS: [M+H]+=828 (expect.=828) (multimode+)

Stage (d) 5-fluoro-N-((1s,4s)-4-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4'-(2-(piperazine-1-yl)ethyl)-biphenyl-3-yloxy)nicotinamide

Hydrobromic acid (33% in acetic acid) (1 ml, 5,79 mmol) was slowly added to a solution of benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamido)cyclohexylcarbonyl)-pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0.156 g, 0,19 mmol) in dichloromethane (1 ml). After stirring for 1 h at K.T. reaction mixture was diluted with dichloromethane (10 ml) and neutralized by adding a saturated solution of sodium bicarbonate. The layers were separated and the water with the Oh was extracted with additional dichloromethane. The combined organic extracts were washed with water and saturated brine and evaporated to obtain the crude product. The crude product was purified preparative HPLC on a column of Gemini-NX, using a 95-5% gradient of aqueous 0.1% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 26 mg

1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=7,3 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.09-8.06 (m, 1H), 7.55-7.52 (m, 2H), 7.49-7.48 (m, 2H), 7.42-7.40 (m, 1H), 7.28 (d, J=8,2 Hz, 2H), 7.18-7.13 (m, 1H), 7.07 (s, 1H), 4.16-4.11 (m, 1H), 3.97-3.91 (m, 4H), 3.38-3.35 (m, 4H), 3.13-3.09 (m, 4H), 3.05-2.99 (m, 2H), 2.96-2.91 (m, 2H), 1.93-1.67 (m, 8H).

MS: [M+H]+=694 (expect.=694) (multimode+)

Example 178

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Stage (a) Benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate

2-Methylthiazole-4-carboxylic acid (0,041 g, 0.28 mmol) was dissolved in acetonitrile (1 ml), then was added DIPEA (of 0.066 ml, 0.38 mmol) and HATU (HATU) (to 0.108 g, 0.28 mmol) and the mixture was stirred for 20 minutes. It was then added to a stirred solution of benzyl-4-(2-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate 0,123 g, 0,19 mmol) in acetonitrile (1,000 ml). The reaction mixture was stirred overnight, then diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 0,147,

MS: [M+H]+=777 (expect.=777) (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-2-methylthiazole-4-carboxamide

Hydrobromic acid (33% in acetic acid) (1 ml, 5,79 mmol) was slowly added to a solution of benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-(2-methylthiazole-4-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0,147 g 0,19 mmol) in dichloromethane (1 ml). After stirring for 1 h at K.T. reaction mixture was diluted with dichloromethane (10 ml) and neutralized by adding a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were washed with water and saturated brine, and evaporated to obtain the crude product. The crude product was purified preparative HPLC on a column of Gemini-NX, using a 95-5% gradient of aqueous 0.1% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the header connect the deposits in the form of a white solid. Yield: 18 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7,1 Hz, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.06 (dd, J=7,9, 3.1 Hz, 1H), 7.96 (s, 1H), 7.55-7.47 (m, 4H), 7.42-7.40 (m, 1H), 7.29 (d, J=8,2 Hz, 2H), 7.17-7.14 (m, 1H), 4.15-4.10 (m, 1H), 3.99-3.94 (m, 1H), 3.43-3.39 (m, 4H), 3.25-3.21 (m, 4H), 3.14-3.10 (m, 2H), 3.00-2.95 (m, 2H), 2.61 (s, 3H), 1.88-1.67 (m, 8H).

MS: [M+H]+=643 (expect.=643) (multimode+)

Example 179

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)-piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

To a stirred solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate (0.800 to g, 1.26 mmol) in dichloromethane (8 ml) was added N-isopropyl-2-(piperazine-1-yl)ndimethylacetamide (0,468 g of 2.53 mmol) and acetic acid (0,145 ml, 2.53 mmol). The reaction mixture was stirred at K.T. within 5 minutes was Added sodium triacetoxyborohydride (0,536 g of 2.53 mmol) and the reaction mixture was stirred at K.T. within 1 h, the Reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 0,781,

MS: [M+H]+=802 (expect.=802) (multimode+)

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

To a stirred solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0,781 g, 0.97 mmol) in dichloromethane (7.5 ml) was added 4 M HCl/dioxane (3,65 ml, 14,61 mmol). The reaction mixture was stirred at K.T. within 1 h, and then concentrated to obtain specified in the subtitle compound in the form of cleaners containing hydrochloride salt. Output: 0.800 to,

MS: [M+H]+=702 (expect.=702) (multimode+)

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide hydrochloride (0,200 g 0,19 mmol) in DMF (2 ml) was added 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0,040 g, 0.21 mmol) and DIPEA (0,234 ml of 1.34 mmol). Added HATU (0,087 g, 0.23 mmol) and the reaction mixture was stirred at K.T. during the night. The reaction mixture was acidified to pH 4 using 2 M HCl, and purified the preparative HPLC on a column (Waters X-Bridge, using 95-0% gradient of aqueous 0.2% of TFA in acetonitrile as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 36 mg

1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=6,8 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=3.8 Hz, 1H), 8.02 (dd, J=7.5, 3.0 Hz, 1H), 7.74 (s, 1H), 7.55-7.50 (m, 2H), 7.35 (d, J=8,3 Hz, 1H), 7.29 (dd, J=8.3, 2.3 Hz, 1H), 7.18-7.13 (m, 2H), 6.97 (s, 1H), 4.41 (s, 2H), 4.17-4.11 (m, 1H), 4.10-3.96 (m, 7H), 3.80-3.64 (m, 2H), 3.51 (s, 2H), 3.17-3.01 (m, 8H), 2.77 (s, 3H), 2.53 (s, 3H), 1.99-1.75 (m, 8H), 1.15 (d, J=6,8 Hz, 6N).

MS: [M+H]+=875 (expect.=875) (multimode+)

Example 180

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-2-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

tert-Butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)tikarcillina (1,526 g, a 2.75 mmol), (S)-4-bromo-3-((3-methylmorpholine)methyl)benzaldehyde (0,819 g, a 2.75 mmol) and sodium carbonate (2,359 g, 8,24 mmol) was added to THF (18 ml) and degassed water (9 ml) in the atmosphere of nitrogen. Then added tetrakis(triphenylphosphine)palladium(0) (0,063 g, 0.05 mmol) and the reaction mixture was heated under reflux overnight. The mixture howled the Ali on the water and was extracted with EtOAc (×2). The extraction were combined, washed with brine, dried (MgSO4) and was evaporated to obtain a light brown oil. The crude substance was purified by flash chromatography on silica (Biotage column) (eluent = 60/40 EtOAc/hexane) to give a light brown oil. Output: 1,42,

MS: [M+H]+=647 (expect.=647) (multimode+)

Stage (b) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate (0.7 g, a 1.08 mmol) in dichloromethane (10.5 ml) was added 2-(1,4-diazepan-1-yl)ethanol (0,283 ml, 2,17 mmol). The mixture was left to mix with K.T. for 40 minutes, then was added sodium triacetoxyborohydride (0,573 g, a 2.71 mmol). The reaction mixture was stirred at K.T. within 2 hours. The mixture was diluted with dichloromethane and washed with saturated NaHCO3(aq.), dried (MgSO4) and was evaporated to obtain a pale yellow foam. It was purified by flash chromatography on silica (Biotage column) (eluent = 4% 7 M ammonia in methanol/DCM) to obtain specified in the subtitle compound as a white solid. Output: 0,710 g

MS: [M+H]+=775 (expect.=775) (multimode+)

Stage (C) N-((1s,4s)-4-Aminocyclohexane)-5-FPO is-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)-biphenyl-3-yloxy)nicotinamide

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0.65 g, 0.84 mmol) in DCM (6 ml) was added 4.0 M hydrogen chloride in dioxane (2.1 ml, 8,39 mmol). The mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness to obtain cleaners containing hydrochloride salt specified in the subtitle compound as a white solid. Output: 0,69,

MS: [M+H]+=675 (expect.=675) (multimode+)

Stage (d) N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-nicotinamide)cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-2-carboxamide

To a suspension of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)-biphenyl-3-yloxy)nicotinamide hydrochloride (200 mg, 0.24 mmol) in acetonitrile (2,74 ml) was added 5,7-dimethylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (48,9 mg, 0.26 mmol) and triethylamine (0,340 ml of 2.44 mmol). Then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (0,171 ml, 0.27 mmol) and the mixture was stirred at K.T. within 2 hours. The mixture was evaporated to dryness and the residue was dissolved in DCM (150 ml) and washed with saturated NaHCO3(aq.), brine, dried (MgSO4) and was evaporated to obtain foam. The crude product was purified of preparation the th HPLC, using a 95-5%gradient of aqueous 0.2%of aqueous ammonia in methanol as eluent to obtain specified in the title compounds as white solids. Yield: 33 mg

1H NMR (400 MHz, CDCl3) δ 8.11-8.03 (m, 2H), 7.48-7.37 (m, 2H), 7.22-7.14 (m, 3H), 7.12-7.07 (m, 2H), 6.88 (d, J=6,9 Hz, 2H), 4.20-4.09 (m, 1H), 4.06-3.96 (m, 1H), 3.89 (d, J=13.1 Hz, 1H), 3.63-3.54 (m, 4H), 3.52-3.31 (m, 9H), 3.31-3.26 (m, 2H) 3.09-2.96 (m, 2H), 2.81-2.70 (m, 4H) 2.69-2.59 (m, 4H), 2.53 (s, 3H), 2.44-2.36 (m, 1H), 2.23-2.11 (m, 1H), 1.96-1.68 (m, 10H), is 0.75 (d, J=6.2 Hz, 3H).

MS: [M+H]+=848 (expect.=848) (multimode+)

Example 181

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)biphenyl-3-yloxy)-nicotinamide)cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(((S)-3-methylmorpholine)methyl)-biphenyl-3-yloxy)nicotinamide (200 mg, 0.24 mmol) in dry DMF (5 ml) under nitrogen atmosphere was added DIPEA (0,161 ml, 0.97 mmol) at K.T. Solution was stirred to homogeneity. To this solution was added dropwise a solution of 1H-benzo[d]imidazole-4-carboxylic acid (39,5 mg, 0.24 mmol) and 1,1'-carbonyldiimidazole (39.5 mg, 0.24 mmol) in dry DMF (5 ml) under nitrogen atmosphere, which was left to mix at 40°C for 1 hour. The reaction mixture was allowed to mix at 50°C during the night. The mixture was evaporated to dryness and the residue was dissolved in DCM (100 ml) and washed with the saturated NaHCO 3(aq.), brine, dried (MgSO4) and was evaporated to obtain a yellow oil. The crude product was purified preparative HPLC using a 95-5%gradient of aqueous 0.2% ammonia in methanol as eluent to obtain specified in the title compounds as white solids. Yield: 22 mg

1H NMR (400 MHz, CDCl3) δ 8.12-8.06 (m, 2H), 7.94-7.82 (m, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.38-7.31 (m, 2H), 7.24-7.10 (m, 5H), 7.07 (d, J=7.9 Hz, 1H), 4.25-4.18 (m, 1H), 4.16-4.09 (m, 1H), 3.82 (d, J=13,9 Hz, 1H), 3.64-3.58 (m, 5H), 3.49-3.43 (m, 1H), 3.40-3.31 (m, 1H) 3.03-2.93 (m, 2H), 2.81-2.73 (m, 5H) 2.72-2.62 (m, 7H), 2.39-2.31 (m, 1H), 2.12-2.03 (m, 1H), 1.98-1.74 (m, 10H), to 0.66 (d, J=6.2 Hz, 3H).

MS: [M+H]+=819 (expect.=819) (multimode+)

Example 182

N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)-biphenyl-3-yloxy)nicotinamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

A solution of 1-propylpiperazine of dihydrobromide (183 mg, to 0.63 mmol) in methanol (2 ml) and water (1 ml) was filtered through the cartridge PL-HCO3 MP-resin. The resin was washed with methanol (2×1 ml) and eluent was evaporated. The residue was treated with a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (200 mg, 0.32 mmol) in dichloromethane (6 ml) and acetic acid (,018 ml, 0.32 mmol), then triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred over night. The mixture was additionally treated with the free base of 1-propylpiperazine (1-propylpiperazine of dihydrobromide obtained as described above, 183 mg, 0,63 mmol), then triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred over the weekend. The mixture was treated with 1-propylpiperazine dihydrobromide (183 mg, 0,63 mmol), then DIPEA (0,221 ml of 1.26 mmol), was stirred for 1 h, and treated with sodium triacetoxyborohydride (134 mg, 0,63 mmol) and was stirred for 4 h the Mixture was diluted with dichloromethane, washed with 1 M aqueous solution of sodium bicarbonate, then brine, dried (Na2SO4) and was evaporated to obtain specified in the subtitle compound as a white foam. Output: 0,200,

[M+H]+=745 (expect.=745) (multimode+)

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (200 mg, 0.27 mmol) in dichloromethane (2 ml) was treated with 4 M HCl in dioxane (4 ml, 131,65 mmol) and was stirred for 1 h the Mixture was evaporated obtaining hydrochloride specified in the subtitle compound as a white solid prophetic is TBA. Output: 0,247,

MS: [M+H]+=645 (expect.=645) (multimode+)

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide

Mix a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(2'-(morpholinomethyl)-4'-((4-propylpiperazine-1-yl)methyl)biphenyl-3-yloxy)nicotinamide hydrochloride (174 mg, 0.27 mmol), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (of 37.8 mg, 0.27 mmol) and DIPEA (0,330 ml, 1,89 mmol) in DMF (10 ml) was treated with HATU (108 mg, 0.28 mmol) and was stirred for 2 hours, the Solution was evaporated to remove most of the DMF and the residue was transferred into dichloromethane, washed with water (3×), dried (Na2SO4) and was evaporated. The residue was purified preparative HPLC with a reversed phase column (Gemini-NX, using a gradient of methanol in 0.1%aqueous solution of TFA as eluent to obtain the gums. The gum was transferred into a small amount of dichloromethane and methanol and diluted with isohexane with precipitation of semi-solid substances. The solvent was evaporated and the residue triturated with ether and filtered. The solid was washed with ether and dried to obtain specified in the title compound as a white powder. Yield: 46 mg

1H NMR (400 MHz, DMSO) δ 10,32-10,16 (m, 1H), 9.63-9.47 (m, 1H), 8.36 (d, J=6,9 Hz, 1H), 8.26 (d,J=3.1 Hz, 1H), 8.04-8.00 (m, 2H), 7.65-7.59 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.48-7.42 (m, 1H), 7.38-7.32 (m, 1H), 7.28 (d, J=79 Hz, 1H), 7.19-7.14 (m, 2H), 6.59 (s, 1H), 4.45-4.21 (m, 1H), 3.96-3.89 (m, 1H), 3.92 (s, 3H), 3.82-3.42 (m, 7H), 3.25-2.63 (m, 7H), 2.55-2.35 (m, 8H), 2.14 (s, 3H), 1.84-1.59 (m, 10H), of 0.91 (t, J=7.4 Hz, 3H).

MS: [M+H]+=767 (expect.=767) (multimode+)

Example 3

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Stage (a) tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

To a solution/suspension of tert-butyl(1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide)-cyclohexylcarbamate (1 g, of 1.80 mmol), 4-bromo-3-(thiomorpholine)-benzaldehyde (0,540 g of 1.80 mmol) and sodium carbonate (0,572 g, 5.40 mmol) in THF (12.00 ml) and water was added tetrakis(triphenylphosphine)palladium(0) (0.104 g g, 0.09 mmol). The mixture was heated up to 80°C during the night. The mixture was poured into water and the organic substances were extracted into EtOAc (×3). The extraction were combined, dried (MgSO4) and was evaporated to obtain the crude product. It was purified using column chromatography (eluent=1:1 hexane:EtOAc), to obtain specified in the subtitle compound as oil. Output: 0,745,

MS: [M+H]+=649 (expect.=649) (multimode+)

Stage (b) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-is Loxy)-nicotinamide)cyclohexylcarbamate

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (0,740 g to 1.14 mmol) in DCM (10 ml) was added 2-(1,4-diazepan-1-yl)ethanol (0,298 ml, 2.28 mmol). The mixture was stirred at K.T. for 20 minutes, then added triacetoxyborohydride sodium (0,604 g, to 2.85 mmol). After 40 minutes the mixture was diluted with DCM, washed with saturated NaHCO3(aq.), dried (MgSO4) and was purified using column chromatography (eluent = 3% 7 N. NH3in a mixture of methanol/DCM). The appropriate fractions were combined and evaporated to obtain specified in the subtitle compound as oil. Yield: 0.5 g

MS: [M+H]+=777 (expect.=777) (multimode+)

Stage (C) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide

To a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)-nicotinamide)cyclohexylcarbamate (0.5 g, 0.64 mmol) in DCM (3 ml) was added TFA (3 ml, up 38.94 mmol). The mixture was stirred at K.T. within 40 minutes. The mixture was poured into saturated NaHCO3(aq.), and organic matter was extracted with DCM (×3). Dichloromethane was dried (MgSO4) and was evaporated to obtain specified in the subtitle compound as a foam. Output: 0,375,

MS: [M+H]+=677 (expect.=677) (multimode+)

Stage (d) N-((1s,4)-4-(5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-2'-(thiomorpholine)biphenyl-3-yloxy)nicotinamide (150 mg, 0.22 mmol) in acetonitrile (5 ml) was added 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42,4 mg, 0.22 mmol) and triethylamine (0,309 ml, 2,22 mmol). To this mixture was then added 1-papapostolou acid cyclic anhydride, 1.57 M solution in THF (0,148 ml, 0.23 mmol) and the reaction mixture was left to mix for 10 minutes. The mixture was diluted with DCM and then washed with saturated NaHCO3(aq.), dried (MgSO4) and was evaporated to obtain the crude product. It was purified using preparative chromatography with reversed phase (eluent = NH3(aq.)/methanol), the appropriate fractions were combined and evaporated to obtain an oil. When rubbing with a mixture of DCM/hexane received solid, which was dried overnight at 40°C. under vacuum to obtain specified in the connection header. Yield: 43 mg

1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=3.1 Hz, 1H), 8.08 (dd, J=7,9, 3.1 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.34 (s, 1H), 7.26 (t, J=1.9 Hz, 1H), 7.18 (dd, J=7,9, and 2.1 Hz, 2H), 7.13 (s, 2H), 6.91-6.87 (m, 2H), 4.18-4.13 (m, 1H), 4.04-3.98 (m, 1H), 3.62-3.56 (m, 4H), 3.37 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.62 (m, 9H), 2.54 (s, 3H), 2.46-2.43 (m, 4H), 2.41-2.38 (m, 4H), 1.94-1.72 (m, 10H).

MS: [M+H]+=850 (expect.=850) (multimode+)

Example 184

N-((1s,4s)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (200 mg, 0.32 mmol), 1-isopropylpiperazine (81 mg, 0,63 mmol) and acetic acid (0,018 ml, 0.32 mmol) in dichloromethane (6 ml) was treated with triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred over night. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, then brine, dried (Na2SO4) and was evaporated to obtain specified in the subtitle compound as a pale yellow glassy oil. Output: 0,208,

MS: [M+H]+=745 (expect.=745) (APCI)+ve

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (208 mg, 0.28 mmol) in dichloromethane (2 ml) was treated with 4 M HCl in dioxane (4 ml, 16,00 mmol) and was stirred for 1 h the Mixture was evaporated obtaining hydrochloride specified in the subtitle compound as a white solid. Output: 0,271,

Stage (C) N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide

Mix a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-isopropylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide hydrochloride (221 mg, 0.28 mmol), 1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (39,2 mg, 0.28 mmol) and DIPEA (0,342 ml, a 1.96 mmol) in DMF (10 ml) was treated with HATU (112 mg, 0.29 mmol) and was stirred over night. The solution was evaporated to remove most of the DMF and the residue was transferred into dichloromethane, washed with water (3×), dried (Na2SO4) and was evaporated. The residue was purified preparative HPLC with a reversed phase column (Sunfire™, using a gradient of methanol in 0.1% aqueous solution of TFA as eluent to obtain specified in the title compounds as white solids. Output: 110 mg.

1H NMR (400 MHz, DMSO) δ 10,18-9.97 (m, 1H), 9.44-9.23 (m, 1H), 8.36 (d, J=6,4 Hz, 1 H), 8.27 (d, J=3.1 Hz, 1 H), 8.04-8.00 (m, 2H), 7.65-7.61 (m, 1 H), 7.54 (t, J=7.9 Hz, 1 H), 7.50-7.45 (m, 1 H), 7.36 (d, J=7.9 Hz, 1 H), 7.29 (d, J=8,2 Hz, 1H), 7.22-7.14 (m, 2H), 6.59 (s, 1H), 4.36-3.59 (m, 20H), 3.51-3.38 (m, 2H), 3.21-2.94 (m, 4H), 2.82-2.64 (m, 1H), 2.52-2.38 (m, 2H), 2.14 (s, 3H), 1.84-1.60 (m, 8H), 1.25 (d,, J=6,4 Hz, 3H).

MS: [M+H]+=767 (expect.=767) (multimode+)

Example 185

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-methylthiazole-2-carboxamide

Stage (a) Benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-(4-methylthiazole-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate

4-Methylthiazole-2-carboxylic acid (0,041 g, 0.28 mmol) was dissolved in acetonitrile (1 ml), then was added DIPEA (of 0.066 ml, 0.38 mmol) and HATU (HATU) (to 0.108 g, 0.28 mmol) and the mixture was stirred for 20 minutes. It was then added to a stirred solution of benzyl-4-(2-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0,123 g 0,19 mmol) in acetonitrile (1,000 ml). The reaction mixture was stirred overnight, then diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain specified in the subtitle compound. Output: 0,147,

MS: [M+H]+=777 (expect.=777) (multimode+)

Stage (b) N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-methylthiazole-2-carboxamide

Hydrobromic acid (33% in acetic acid) (1 ml, 5,79 mmol) was slowly added to a solution of benzyl-4-(2-(3'-(5-fluoro-3-((1s,4s)-4-(4-methylthiazole-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl)piperazine-1-carboxylate (0,147 g 0,19 mmol) in dichloromethane (1 ml). After stirring for 1 h at K.T. reaction mixture was diluted with dichloromethane (10 ml) and neutral is savali by adding a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was additionally extracted with dichloromethane. The combined organic extracts were washed with water and saturated brine and evaporated. To a solution of the residue in acetic acid (1.2 ml) was added Pd/C (0,020 g 0,19 mmol). The reaction mixture was stirred at K.T. under hydrogen pressure of 4 bar (4×105PA) for 24 h, then filtered and the filtrate was concentrated to obtain the crude product. It was purified preparative HPLC column Phenomenex Gemini using 75-05% gradient of aqueous 0.2% of TFA in methanol as eluent. The fractions containing the target compound were evaporated to dryness to obtain specified in the title compounds as white solids. Yield: 7 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7,3 Hz, 1H), 8.12 (d, J=4.0 Hz, 1H), 8.07 (dd, J=8,1, 4.0 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 2H), 7.42-7.40 (m, 1H), 7.36 (s, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.17-7.13 (m, 1H), 4.17-4.09 (m, 1H), 3.99-3.93 (m, 1H), 3.34 (t, J=5.7 Hz, 4H), 3.09-3.03 (m, 4H), 2.99-2.89 (m, 4H), 2.39 (s, 3H), 1.91-1.68 (m, 8H).

MS: [M+H]+=643 (expect.=643) (multimode+)

Example 185

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)-cyclohexylcarbamate

Peremeshivajutsa tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (200 mg, 0.32 mmol), 1-methyl-1,4-diazepan (72.2 mg, 0,63 mmol) and acetic acid (0,018 ml, 0.32 mmol) in dichloromethane (6 ml) was treated with triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred over night. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, then brine, dried (Na2SO4) and was evaporated to obtain specified in the subtitle compound as a white foam. Output: 0,228,

MS: [M+H]+=731 (expect.=731) (APCI)+ve

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexylcarbamate (228 mg, 0.31 mmol) in dichloromethane (2 ml) was treated with 4 M HCl in dioxane (4 ml, 131,65 mmol) and was stirred for 1 h the Mixture was evaporated obtaining hydrochloride specified in the subtitle compound as white solids. Output: 0,341,

MS: [M+H]+=643 (expect.=643) (multimode+)

Example 186

N-((1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Stage (a) tert-Butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-roxanakatalina)-cyclohexylcarbamate

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-formyl-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)cyclohexylcarbamate (200 mg, 0.32 mmol), 1-methyl-1,4-diazepan (72.2 mg, 0,63 mmol) and acetic acid (0,018 ml, 0.32 mmol) in dichloromethane (6 ml) was treated with triacetoxyborohydride sodium (134 mg, 0,63 mmol) and was stirred over night. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, then brine, dried (Na2SO4) and was evaporated to obtain specified in the subtitle compound as a white foam. Output: 0,228,

MS: [M+H]+=731 (expect.=731) (APCI)+ve

Stage (b) N-((1s,4s)-4-Aminocyclohexane)-5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide

Mix a solution of tert-butyl(1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide)cyclohexylcarbamate (228 mg, 0.31 mmol) in dichloromethane (2 ml) was treated with 4 M HCl in dioxane (4 ml, 131,65 mmol) and was stirred for 1 h the Mixture was evaporated obtaining hydrochloride specified in the subtitle compound as white solids. Output: 0,341,

MS: [M+H]+=631 (expect.=631) (APCI)+ve

Stage (C) N-((1s,4s)-4-(5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)-cyclohexyl)-5-methylimidazo[1,2-a]pyridine-2-carboxamide

Premesis is Amy a solution of N-((1s,4s)-4-aminocyclohexane)-5-fluoro-2-(4'-((4-methyl-1,4-diazepan-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide (241 mg, 0.31 mmol), 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (54,6 mg, 0.31 mmol) and DIPEA (0,379 ml, 2,17 mmol) in DMF (10 ml) was treated with HATU (124 mg, 0.33 mmol) and was stirred over night. The solution was evaporated to remove most of the DMF and the residue was transferred into dichloromethane, washed with water (3×), dried (Na2SO4) and was evaporated. The residue was purified preparative HPLC with a reversed phase column (Sunfire™, using a gradient of methanol in 0.1% aqueous solution of TFA as eluent to obtain specified in the title compound as a white powder. Output: 0,150,

1H NMR (400 MHz, DMSO) δ 8.41-8.38 (m, 2H), 8.27 (d, J=3.1 Hz, 1H), 8.05 (dd, J=7.9,3.1 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.70-7.66 (m, 1H), 7.58-7.51 (m, 3H), 7.47-7.42 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.21-7.19 (m, 2H), 6.98 (d, J=6,9 Hz, 1H), 4.42-2.70 (m, 22H), 2.84 (s, 3H), 2.66 (s, 3H), 2.12-2.02 (m, 2H), 1.84-1.67 (m, 8H).

MS: [M+H]+=789 (expect.=789) (multimode+)

Example 187

N-((1s,4s)-4-(5-fluoro-2-(4'-(2-(piperazine-1-yl)ethyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)cinoxacin-2-carboxamide

In a test tube for microwave treatment were loaded 2-(3'-(5-fluoro-3-((1s,4s)-4-(cinoxacin-2-carboxamido)cyclohexylcarbonyl)pyridine-2-yloxy)biphenyl-4-yl)ethyl methanesulfonate (120 mg, 0.18 mmol), tert-butyl-1-piperidinecarboxylate (98 mg, of 0.53 mmol) and acetonitrile (1 ml). The reaction mixture was heated up to 80°C for 3 hours. The reaction mixture was evaporated to dryness, then dissolved in DCM (3 ml). To which it was added TFA (to 3.67 ml, 47,91 mmol) and the reaction mixture was stirred over night. The crude product was purified by HPLC to obtain specified in the title compounds as white solids. Yield: 56 mg

1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.16-8.03 (m, 3H), 7.98 (d, J=7.9 Hz, 1H), 7.94-7.80 (m, 2H), 7.51-7.37 (m, 5H), 7.14 (d, J=7.7 Hz, 3H), 4.22-4.10 (m,1H), 4.08-3.94 (m, 1H), 3.61-3.42 (m, 8H), 3.27-3.20 (m, 2H), 3.01-2.90 (m, 2H), 2.04-1.69 (m, 8H).

MS: [M+H]+=674 (expect.=674) (multimode+)

Example 188

N-((1s,4s)-4-(5-fluoro-2-(4'-(3-(piperazine-1-yl)propyl)biphenyl-3-yloxy)nicotinamide)cyclohexyl)-4-(hydroxymethyl)thiazol-2-carboxamide

HATU (0,093 g, 0.24 mmol) was added to a solution of tert-butyl 4-(3-(3'-(3-((1s,4s)-4-aminocyclohexanol)-5-herperidin-2-yloxy)biphenyl-4-yl)propyl)piperazine-1-carboxylate (0.14 g, 0.22 mmol), 4-(hydroxymethyl)thiazole-2-carboxylic acid (0,039 g, 0.24 mmol) and DIPEA (0,194 ml, 1.11 mmol) in DMF (5 ml) and the solution was stirred at K.T. within 20 hours the Mixture is extinguished with water, was extracted with EtOAc (50 ml), washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue was dissolved in DCM (10 ml)was added 4 M HCl/dioxane (5 ml, 20.00 mmol) and was stirred for 2 hours the Mixture was evaporated in vacuum and the residue was purified twice by HPLC with reversed phase with aq. TFA/MeCN as eluent to obtain specified in the title compound as a white solid substances the. Yield: 9 mg

1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=7,6 Hz, 1H), 8.11 (d, J=3.1 Hz, 1H), 8.07 (m, 1H), 7.61 (s, 1H), 7.52 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.25 (d, J=8,2 Hz, 2H), 7.14 (m, 1H), 4.64 (s, 2H), 4.13 (m, 1H), 3.96 (m, 1H), 3.45 (t, J=5.4 Hz, 4H), 3.30 (m, 4H), 3.01 (m, 2H), 2.72 (t, J=7.8 Hz, 2H), 2.02 (m, 2H), 1.92-1.69 (m, 8H).

MS: [M+H]+=673 (expect.=673) (multimode+)

Using a technique similar to that described in Examples 122, 169, 170, 175, 178, 179 and 180, the intermediate connection connection brought into interaction with the appropriate carboxylic acid to obtain the compounds described in Table 1.

Table 1
Etc.Connection nameStructureData1H NMRMS M+H+
189N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fornicating)-cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=3.1 Hz, 1H), 8.05-8.01 (m, 1H), 8.00(s, 1H), 7.73-7.71 (m, 1H), 7.58 (t, J=4.0 Hz, 1H), 7.53-7.50 (m, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.34-7.30 (m, 1H), 7.22-7.18 (m, 1H), 7.16-7.13 (m, 1H), 4.42 (s, 2H), 4.13-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.79 (s, 2H), 3.49-3.38 (m, 2H), 795

Etc.Connection nameStructureData1H NMRMS M+H+
3.17-3.10 (m, 2H), 2.96-2.75 (m, 12H) 2.68 (s, 4H), 2.27 (t, J=12.0 Hz, 2H), 1.89-1.70 (m, 8H), 1.29 (d, J=6,4 Hz, 6N).
190N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fornicating) cyclohexyl)-2-methylthiazole-4-carboxamide1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=3.1 Hz, 1H), 8.05-8.02 (m, 1H), 7.72-7.70 (m, 1H), 7.61-7.56 (m, 1H), 7.54-7.50 (m, 1H), 7.38(d, J=7.9 Hz, 1H), 7.34-7.30 (m, 1H),7.22-7.18 (m, 1H), 7.15-7.13 (m, 1H), 6.40(s, 1H), 4.41 (s, 2H), 4.09 (t, J=6.2 Hz, 3H), 4.01-3.93 (m, 1H), 3.77 (s, 2H), 3.48-3.37 (m, 2H), 3.16-3.07 (m, 2H), 2.94-2.57 (m, 7H) 2.23 (t, J=11.5 Hz, 2H), 2.08-1.99 (m, 2H), 1.90-1.67 (m, 8H), 1.28 (d, J=6,4 Hz, 6N).772

Etc.Connection nameStructureData1H NMRMS M+H+
191N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fornicating) cyclohexyl)-2-isopropylthiazole-4-carboxamid1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=3.1 Hz, 1H), 8.04-8.01 (m, 2H), 7.76 (s, 1H), 7.60-7.52 (m, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.31 (dd, J=8,3, 3.1 Hz, 1H), 7.19 (d, J=8,3 Hz, 1H), 7.16-7.14 (m, 1H), 4.42 (s, 2H), 4.14-4.08 (m, 1H), 4.03-3.94 (m, 1H), 3.88 (s, 2H), 3.85-3.61 (m, 4H), 3.52-3.44 (m, 2H), 3.25-3.18 (m, 4H), 2.96-2.78 (m, 2H), 2.39 (t, J=11.2 Hz, 2H), 1.89-1.74 (m, 8H), 1.54-1.40 (m, 1H), 1.37 (d, J=6,7 Hz, 6N), 1.30 (d,, J=5.4 Hz, 6H).784
1922-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(1-methyl-1H NMR (500 MHz, CD3OD) δ 8.56-8.47 (m, 1H), 8.21 (d, J=2,9 Hz, 1H), 8.14-8.03 (m, 1H), 7.75(s, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.55 (d, J=823

Etc.Connection nameStructureData1H NMRMS M+H+
5-(trifluoromethyl)-1H-pyrazole-3-carbox the amido)-cyclohexyl)-nicotinamide 7,0 Hz, 1H), 7.39 (dd, J=26,1 Hz, 7.9 Hz, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.17 (d, J=18.2 Hz, 2H), 4.46 (s, 2H), 4.16 (s, 1H), 4.09-4.05 (m, 3H), 4.03-3.99 (m, 1H), 3.78 (s, 2H), 3.45 (s, 2H), 3.13 (d, J=12,2 Hz, 2H), 2.87 (s, 8H), 2.24 (t, J=11.8 Hz, 2H), 2.00-1.76 (m, 8H), 1.32 (d, J=6,4 Hz, 6N).
193N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fornicating) cyclohexyl)-4-methylthiazole-2-carboxamide1H NMR (500 MHz, CD3OD) δ 8.40 (d, J=7,0 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 7.97 (dd, J=7,8 Hz, 3.0 Hz, 1H), 7.63 (s, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.32-7.28 (m, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.12 (d, J=7,8 Hz, 1H), 7.08 (s, 1H), 4.34 (s, 2H), 4.04 (s, 1H), 3.90 (s, 1H), 3.67 (s,772

Etc.Connection nameStructureData1H NMRMS M+H+
2H), 3.40-3.32 (m, 2H), 3.43-2.52 (m, 8H), 3.09-2.96 (m, 2H), 2.36 (s, 3H), 2.13 (t, J=12.0 Hz, 2H), 1.87-1.65 (m, 8H), 1.20 (d, J=6,5 Hz, 6N).
194 N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fornicating) cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=7,6 Hz, 1H), 8.39 (s, 1H), 8.08 (d, J=3.0 Hz, 1H), 7.94 (dd, J=7,8 Hz, 3.0, 1H), 7.60 (s, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.19 (t, J=7.2 Hz, 2H), 7.08 (d, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 4.31 (s, 2H), 4.06 (s, 1H), 3.99 (s, 1H), 3.65 (s, 2H), 3.40-3.31 (m, 2H), 3.53-2.48 (m, 8H), 3.03(t, J=17.6 Hz, 2H), 2.68 (s, 3H), 2.43 (s, 3H), 2.12 (t, J=12.0 Hz, 2H), 1.90-1.68 (m, 8H),820

Etc.Connection nameStructureData1H NMRMS M+H+
1.20 (d, J=6,6 Hz, 6N).
195N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((S)-3-methylmorpholine)-methyl) - biphenyl-3-yloxy)-5-fornicating) cyclohexyl)-4-methylthiazole-2-carboxamide1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=2.4 Hz, 1H, 8.04 (dd, J=7,8, 3.1 Hz, 1H), 7.95-7.92 (m, 1H), 7.61-7.50 (m, 2H), 7.41-7.38 (m, 2H), 7.34-7.31 (m, 1H), 7.20 (d, J=7,6 Hz, 2H), 7.16-7.14 (m, 2H), 4.19-4.10 (m, 2H), 4.01-3.95 (m, 3H), 3.86-3.81 (m, 1H), 3.75-3.51 (m, 7H), 3.03-2.99 (m, 1H), 2.47-2.39 (m, 5H), 1.89-1.59 (m, 8H), 1.31-1.25 (m, 6H), 1.04-1.00 (m, 3H).770
196N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((3)-3 methylmorpholine)-methyl) - biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-1H-1H NMR (400 MHz, CD3OD) δ 8.92-8.87 (m, 1H), 8.14 (d, J=3.0 Hz, 1H), 8.05 (dd, J=7,7, 3.0 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.97-7.93 (m, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.59-7.49 (m, 3H), 7.37-7.32789

PR.Connection nameStructureData1H NMRMS M+H+
benzo[d]imidazol-4-carboxamid(m, 2H), 7.22-7.17 (m, 2H), 4.17-3.99 (m, 4H), 3.83-3.46 (m, 5H), 3.02-2.95 (m, 1H), 2.60-2.50 (m, 2H), 1.97-1.57 (m, 8H), 1.35-1.22 (m, 6H), 1.05-1.00 (m, 3H).
197N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(((3)-3 methylmorpholine)-methyl) - biphenyl-3-is Loxy)-5-fornicating)cyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 1H NMR (400 MHz, CD3OD) δ 8.55-8.47 (m, 2H), 8.14 (d, J=6,1 Hz, 1H), 8.04 (dd, J=8,9, a 4.1 Hz, 1H), 7.78-7.75 (m, 1H), 7.56-7.47 (m, 2H), 7.30 (d, J=a 12.7 Hz, 2H), 7.20-7.12 (m, 2H), 6.98 (s, 1H), 4.18-4.05 (m, 3H), 3.87-3.79 (m, 3H), 3.74-3.56 (m, 2H), 3.54-3.44 (m, 3H), 3.22-3.15 (m, 2H), 3.03-2.95 (m, 2H), 2.78 (s, 3H), 2.54 (s, 3H), 2.05-1.60 (m, 8H), 1.38-1.20 (m, 6H), 1.06-1.01 (m, 3H).818

Etc.Connection nameStructureData1H NMRMS M+H+
198N-((1s,4s)-4-(5-fluoro-2-(2'-(morpholinomethyl)-4'-(thiomorpholine-methyl)biphenyl-3-yloxy)-nicotinamide)-cyclohexyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide1H NMR (400 MHz, CD3OD) δ 9.06 (dd, J=7,4, 1.9 Hz, 1H), at 8.62 (dd, J=4.2, 1.9 Hz, 1H), 8.54(s, 1H), 8.14 (d, J=3.3 Hz, 1H), 8.02 (dd, J=7,9, or 2.8 Hz, 1H),7.87 (d, J=0.9 Hz, 1H), 7.59-7.53 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.32 (dd, J=8.4,2.8 Hz, 1H), 7.19-7.14 (m, 3H), 4.41 (d, J=4.8 Hz, 4H), 4.16-4.06 (m, 2H), 3.78-3.70 (m, 5H), 3.05-2.83 (m, 6H), 1.94-1.77 (m, 8H).765
199N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)nicotinamide)- cyclohexyl)-4-methylthiazole-2- 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=8.4 Hz, 1H), 8.14 (d, J=2,8 Hz, 1H), 8.05 (dd, J=8.4, 3.7 Hz, 1H), 7.80(s, 1H), 7.62-7.56 (m, 2H), 7.45 (d, J=6,5 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J=7,7, 2.4 Hz, 1H), 7.21 (d, J=827

Etc.Connection nameStructureData1H NMRMS M+H+
carboxamid6,8 Hz, 1H), 7.18-7.16 (m, 1H), 4.44(s, 2H), 4.14-4.05 (m, 3H), 4.03-3.96 (m, 2H), 3.82-3.68 (m, 2H), 3.47 (s, 2H), 3.16-3.02 (m, 14H), 2.45 (s, 2H), 1.92-1.76 (m, 8H), 1.15 (d, J=7,1 Hz, 6H).
2005-fluoro-N-((1s,4s)-4-(1-methyl-1H-pyrazole-3-carboxamido)-cyclohexyl)-2-(2'-(morpholinomethyl)-4'-(thiomorpholine-methyl)biphenyl-3-yloxy)nicotinamide1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=5.6 Hz, 1H), 8.14 (d, J=3,7 Hz, 1H), 8.03 (dd, J=8,4, 2.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.65-7.58 (m, 3H), 7.51 (d, J=8,4 Hz, 1H), 7.34 (dd, J=8,0, 2.3 Hz, 1H), 7.22 (d, J=6,6 Hz, 1H), 7.16 (s,, 1H), 6.67 (d, J=2.5 Hz, 1H), 4.44-4.41 (m, 4H), 4.14-4.07 (m, 1H), 4.01-3.94 (m, 1H), 3.90 (s, 3H), 3.80-3.70 (m, 5H), 3.05-2.86 (m, 5H), 1.88-1.72 (m, 8H), 728

Etc.Connection nameStructureData1H NMRMS M+H+
1.33-1.26 (m, 1H).
201N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide)-cyclohexyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide1H NMR (400 MHz, CD3OD) δ 8.46 (d, J=8,1 Hz, 1H), 8.13 (d, J=2,8 Hz, 1H), 8.03 (dd, J=7,0, 3.0 Hz, 1H), 7.78 (s, 1H), 7.62-7.56 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.33 (dd, J=7,7, 2.8 Hz, 1H), 7.21 (d, J=8,1 Hz, 1H), 7.15-7.14 (m, 1H), 6.41 (s, 1H), 4.43 (s, 2H), 4.12-4.05 (m, 5H), 4.03-3.94 (m, 2H), 3.84-3.63 (m, 4H), 3.49 (s, 2H), 3.16-2.99 (m, 10H), 2.80 (t, J=5.5 Hz, 2H), 2.07-2.01 (m, 2H), 1.89-1.69 (m, 10H), 1.14 (d, J=8,3 Hz, 6N).850
202N-((1s,4s)-4-(5-fluoro-2-(4'-((4-(2-(isopropylamino)-2 - oxoethyl)piperazine-1-yl)methyl)-2'-1H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.13 (s, 1H), 8.04 (d, J=8.0 for the C, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.90 (d, J=846

Etc.Connection nameStructureData1H NMRMS M+H+
(morpholinomethyl)biphenyl-3-yloxy)-nicotinamide)-cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid7,0 Hz, 1H), 7.79 (s, 1H), 7.60-7.53 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.21-7.16 (m, 2H), 4.41 (s, 2H), 4.17-4.07 (m, 4H), 3.98 (quintet, J=6,8 Hz, 1H), 3.80-3.67 (m, 5H), 3.43 (s, 2H), 3.09 (d, J=18,8 Hz, M), 1.97-1.80 (m, 8H), 1.13 (d, J=8.7 Hz, 6N).
203N-((1s,4s)-4-(2-(4'-(((3S,5R) - for 3,5-dimethylpiperazine-1-yl)methyl)-2'-(thiomorpholine-methyl)biphenyl-3-yloxy)-5-fornicating)cyclohexyl)-1H-benzo[d]imidazol-4-carboxamid1H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.51 (d, J=8,9 Hz, 1H), 8.16 (d, J=2,8 Hz, 1H), 8.04 (dd, J=7,9, 3.1 Hz, 1H), 7.97 (d, J=7,4 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.68(s, 1H), 7.59-7.49 (m, 3H), 7.33-7.28 (m, 2H), 7.20-7.14 (m, 2H), 4.38 (s, 2H), 4.17-4.09 (m, 2H), 3.71 (s, 2H), 3.44-3.36 (m, 2H), 3.24-2.72 (m, 6H), 3.07 (d, J=11,9791

Etc.Connection nameStructureData1H NMRMS M+H+
Hz, 2H), 2.19 (t, J=12.0 Hz, 2H), 1.96-1.84 (m, 8H), 1.27(d, J=6,7 Hz, 6H).

Example

Radiometric analysis phosphodiesterase B2 man In the analysis used recombinant phosphodiesterase B2 man (PDE4B2), obtained in the laboratory (PrAZL0163), which was stored at -20°C. This analysis is based on the observation that 5 AMR (5'-adenosinemonophosphate) the product of the reaction catalyzed by PDE4, preferably bound to SPA beads of yttrium silicate (Amersham Biosciences, UK) compared with the substrate of camp. The connection in the appropriate concentration pre-incubated at 30°C for 30 min with an analytical buffer 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 μg/ml recombinant PDE4B2. The reaction was started by adding [3H]cyclic AMP obtaining a final concentration of 8 nm, and stopped after 20 min after addition of the substrate by adding SPA-granules yttrium silicate containing 18 mm ZnSO4. Bound [3H]cyclic AMP was measured using a Topcount NXT (Packard Bioscience, UK). pIC50 values (presented in Alice 2) was determined, using the approximation Xlfit3 curve using the model 205.

Table 2
Etc.PDE4B2 pIC50ExPDE4B2 pIC50
19,91911,0
210,82010,5
38,92110,3
47,22210,4
58,3239,5
68,52410,0
78,2258,5
89,226the 9.7
910,5279,2
1010,52810,6
1110,32910,4
1210,33010,4
1310,7319,3
1410,7329,5
1510,7339,2
1610,53410,6
178,8359,9
1810,83610,0
37the 9.769 9,4
3810,470the 10.1
3910,77110,6
409,17210,2
4110,07310,2
4210,37410,6
439,97510,5
4410,07610,2
4510,87710,2
469,978the 10.1
479,17910,5
4810,2 8010,4
4910,68110,5
509,58210,7
5110,08310,6
5210,3849,8
539,48510,2
5410,28610,5
5510,08710,6
5610,68810,5
5710,289the 10.1
5810,290the 9.7
59 the 10.1919,6
6010,3929,9
6110,79310,0
6210,69410,2
639,995the 9.7
649,996the 9.7
6510,4979,9
6610,59810,0
6710,099the 10.1
6810,61009,8
10110,213310,3
10210,413410,2
10310,513510,3
10410,513610,0
1059,213710,3
1069,613810,6
1079,8139the 10.1
10810,714010,5
10910,214110,2
110the 9.714210,6
111-143the 10.1
11210,4144 10,5
11310,314510,7
1149,814610,5
1159,214710,3
11610,514810,4
11710,014910,5
11810,4150the 10.1
119the 10.115110,2
12010,315210,4
12110,215310,5
12210,415410,5
123 10,215510,4
12410,31569,9
12510,2157the 10.1
12610,315810,5
127the 10.115910,3
1289,916011,0
12910,516110,9
13010,516210,4
1319,916310,4
13210,41649,9
16610,218410,4
16710,418510,7
16810,318610,4
16910,3187the 9.7
17010,718810,7
17110,318910,8
172the 10.119010,4
17310,219110,7
17410,419210,7
17510,019310,6
17610,719410,5
1771,3 19510,7
17810,319610,6
17910,419710,7
18010,319810,6
18110,819910,7
1829,620010,6
18310,420110,8
184the 9.720210,9

1. The compound of formula (I):

where
R1represents NR7C(O)R8or NR9R10;
R2represents hydrogen;
R3is a halogen;
R4represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3With1-4alkylthio, S(O)(C1-4 alkyl), S(O)2(C1-4alkyl), CO2N or CO2(C1-4alkyl);
R5represents a C1-6alkyl (substituted NR11R12or heterocyclyl, which represents a non-aromatic 5-7 membered ring containing 1 or 2 heteroatoms, independently selected from the group consisting of nitrogen, oxygen or sulfur);
R6represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly substituted by a group NR15R16, morpholinium or thiomorpholine);
R7represents hydrogen;
R8represents a C3-6cycloalkyl (possibly substituted by a group NR24R25), phenyl or heteroaryl, which is an aromatic 5-or 6-membered ring containing 1 to 3 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, and which may be condensed with one 6-membered aromatic or non-aromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the specified 6-membered aromatic heterocyclic ring containing from 1 to 3 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur;
R9represents hydrogen or C1-6alkyl (possibly replaced by Piazolla);
R10is the th C 1-6alkyl (possibly substituted phenyl group or heteroaryl, which is an aromatic 5 - or 6-membered ring containing 1 or 2 heteroatoms, independently selected from the group consisting of nitrogen, oxygen or sulfur, and which may be condensed with one 6-membered heterocyclic ring, where the specified 6-membered aromatic heterocyclic ring containing 1 or 2 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, or sulfur;
where the above-mentioned phenyl and heteroaryl groups in R8, R9and R10independently possibly substituted by the group: halogen, hydroxy, C(O)R42C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane,1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl;
if not specified, heterocyclyl possibly substituted by a group of C1-6alkyl, (C1-6alkyl)HE, (C1-6alkyl)C(O)NR51R52or pyrrolidinium;
R42represents a C1-6alkyl;
R12, R15and R25independently represents a C1-6alkyl (possibly substituted by a hydroxy group or NR55R56);
R11, R16, R24, R51, R52, R55and R56independently represent hydrogen or C1-6alkyl;
or its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, the de R 1represents NR7C(O)R8.

3. The compound of formula (I) according to claim 1, where R8represents phenyl or heteroaryl, possibly substituted by a group halogen, hydroxy, C(O)R42C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane,1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl.

4. The compound of formula (I) according to claim 1, where R5represents methyl, ethyl or propyl, substituted by piperidinyl, piperazinil, morpholinium, homomorpholine or homopiperazine.

5. The compound of formula (I) according to any one of claims 1 to 4:

or its pharmaceutically acceptable salt.

6. The compound of formula (I) according to any one of claims 1 to 4:

or its pharmaceutically acceptable salt.

7. The compound of formula (I) according to any one of claims 1 to 4:

or its pharmaceutically acceptable salt.

8. The compound of formula (I) according to any one of claims 1 to 4:

or its pharmaceutically acceptable salt.

9. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 8 for the treatment of PDE4(phosphodiesterase 4)-mediated disease condition.

10. A method of treating PDE4-mediated pathological state in a mammal suffering from a specified disease or having a risk of developing this is zabolevaniya, includes introduction to the mammal in need of such treatment, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 8.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 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: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel intermediate epoxy compound of general formula (2), where R1 represents hydrogen or a lower alkyl group; and R2 represents a piperidinyl group of general formula (A1), where R3 represents a phenoxy group, having a halogen-substituted lower alkoxy group, substituted with a phenyl group, and other similar groups; and n is an integer from 1 to 6, to obtain 2,3-dihydroimidazo[2,1-b]oxazole. The invention also relates to specific epoxy compounds, a method of producing epoxy compounds of formula (2) and a method of producing 2,3-dihydroimidazo[2,1-b]-oxazole using a novel intermediate epoxy compound.

EFFECT: obtaining 2,3-dihydroimidazo[2,1-b]oxazole with high output and high purity.

4 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel arylcyclohexyl esters of 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene derivatives of formula I where R1 is phenyl, optionally substituted with cyano, C1-7-alkyl, halogen-C1-7-alkyl, C1-7-alkoxy or halogen; naphthyl, pyrazinyl or pyridazinyl; pyridinyl, optionally substituted with halogen or C1-7-alkyl, pyrimidinyl, optionally substituted with C1-7-alkyl, R2 is H, C1-8-alkyl, optionally substituted with OH or halogen, -(CH2)q-Ra, where Ra is a 6-member heteroaryl containing one N as a heteroatom, -C(O)-C1-8-alkyl, -C(O)(CH2)qNRiRii, -C(O)O-C1-8-alkyl, -S(O)2-C1-8alkyl, -S(O)2NRiRii, where Ri and Rii are identical and denote C1-8-alkyl; q =1, R3 is Cl or F, pharmaceutically acceptable salts thereof and a pharmaceutical composition containing said compounds.

EFFECT: present compounds are V1a receptor antagonists and can be used in medicine.

21 cl, 111 ex, 10 tbl

Antiviral compounds // 2505540

FIELD: biotechnologies.

SUBSTANCE: invention pertains to new compounds that have the properties of HCV virus replication inhibitor. In expression I: , A1 is C6aryl, substituted by -X1-R7; X1 is -S-; R7 is C6aryl, not necessarily substituted by one RA; Z1 is -N(RB)-; each of W1 and W2 is N; R1 is hydrogen; R3 and R4 together with carbon atoms, to which they are connected, form 6-member heterocyclic ring containing N as heteroatom, where 6-member heterocyclic ring is not necessary substituted by one RA; A2 represents C6aryl or 5-member heterocyclyl containing N as heteroatom; R2 represents -N(Rb)C(O)C(R5R6)N(R8)-T-Rd, or -LK-B; R6 and R8 together with atoms, to which they are connected, form 5-member heterocyclic ring; the values of radicals RA, R5, T, RC, RD, RD' and RD", LK, B are given in the invention's expression. Invention also pertains to pharmaceutical composition containing the said compounds, method for inhibiting HCV virus replication, method for HCV infection curing and method for obtaining the said compounds.

EFFECT: improving compound application efficiency.

25 cl, 6 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-[5-(3-dimethylamino-acryloyl)-2-fluorophenyl]-N-methylacetamide of formula (I). The method is realised by reacting N-(5-acetyl-2-fluorophenyl)-N-methylacetamide of formula (VI) with excess N,N-dimethylformamide dimethylacetal (NNDMF-DMA) in the presence of a nonpolar solvent at temperature of 70-90°C. The invention discloses a method of producing a N-{2-fluoro-5-[3-(thiophene)-2-carbonyl-pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methylacetamide compound of formula (II), which involves methylation of N-(5-acetyl-2-fluorophenyl)-acetamide at temperature of 15-50°C, reacting the obtained compound of formula (VI) with NNDMF-DMA, and reacting the obtained compound of formula (I) with (5-amino-1H-pyrazol-4-yl)thiophen-2-yl-methanone in glacial acetic acid at temperature of 60-90°C in the presence of an aliphatic alcohol. The invention also relates to an intermediate compound of formula (VI).

EFFECT: improved method of producing a compound which is an intermediate compound in synthesis of compounds with affinity for the GABAA receptor.

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel imidazopyridine or imidazopyrimidine derivatives of formula (I) and to pharmaceutically acceptable salts and esters thereof, where A is N or C(R6); R1 is hydrogen, lower alkyl; R2 is halogen, C(O)NR7R8 or C(O)OR9; R3 is hydrogen, NR10R11; R4 is hydrogen, lower alkyl; R5 is phenyl or thiazolyl or pyridine, which can be substituted with one substitute independently selected from a group consisting of halogen; R6 is hydrogen, halogen, CN, C3-C6cycloalkyl; R7 and R8 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, fluoro-lower alkyl, C3-C6cycloalkyl, N(H,lower alkyl)-lower alkyl, hydroxy- lower alkyl, hydroxy-lower alkoxy- lower alkyl, N(lower alkyl2)C(O)- lower alkyl, lower alkoxy, hydroxy-lower alkyl-oxetanyl- lower alkyl, oxo-tetrahydrofuranyl, tetrahydrofuranyl-lower alkyl, hydroxy-fluoro-lower alkyl, tetrahydrofuranyl, phenyl and thiazolyl or pyridine, or R7 and R8 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of pyrrolidinyl, azetidinyl, morpholinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, 3,4-dihydro- 1H-pyrrolo[1,2-a]pyrazinyl, 2-oxa-6-aza-spiro[3.3]heptyl, 5,6-dihydro- 8H-imidazo[1,2-a]pyrazinyl, [1,4]oxazepanyl, piperazinyl, thiomorpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl, where the heterocyclyl is optionally substituted with 1 or 2 substitutes independently selected from a group consisting of halogen, lower alkyl, lower alkyl-C(O), lower alkoxy-lower alkyl, oxo, hydroxy, hydroxy-lower alkyl, N(lower alkyl2); R9 is lower alkyl; R10 and R11 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of piperidinyl, morpholinyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel imidazopyridine or imidazopyrimidine derivatives which are PDE10A inhibitors.

24 cl, 94 ex

FIELD: chemistry.

SUBSTANCE: described are novel triazolopyridazines of general formula , stereoisomeric or tautomeric forms thereof and physiologically acceptable salts thereof, where Q1 denotes H, -C1-6alkyl, optionally substituted with fluorine, or -C3-6cycloalkyl; Q2 and Q3 independently denote H, -C1-6alkyl; R1-R3 independently denote H, -C1-6 alkyl, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -O-C1-8alkyl, a heterocyclic residue etc; R4-R8 independently denote H, -C1-6 alkyl, -OH, -O-C1-8 alkyl, halogen, SF5 etc, a method for production thereof and use as medicinal agents.

EFFECT: compounds have antithrombotic activity and particularly inhibit the protease-activated receptor.

6 cl, 2 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formulas

and or pharmaceutically acceptable salts thereof, wherein the values R1-R13, Ra, Rb, Rc, Rd, Rf, Rq, n are presented in the patent claim possessing the properties of protein p53 activator.

EFFECT: compounds may be used in treating cancer and diseases caused by a fungal, bacterial or parasitic infection, eg malaria.

16 cl, 38 dwg, 12 tbl, 16 ex

Solid forms // 2496780

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to crystalline forms of 4-[9-(tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino]cyclohexan-1-ol of formula , which have kinase inhibiting properties and can be used to treat or prevent: (a) cancer; (b) an inflammatory condition or (c) an immunologic condition. The invention particularly relates to a crystalline form A, having an X-ray powder diffraction pattern with peaks at about 12.4, 16.0 and 18.5°2θ and further has peaks at about 17.7, 23.2 and 24.1°2θ; a hydrate crystalline form A, having an X-ray powder diffraction pattern with peaks at about 6.5, 13.0 and 23.0°2θ and further has peaks at about 13.4, 20.1 and 23.8°2θ; a crystalline form of a hydrochloride salt A, having an X-ray powder diffraction pattern with peaks at about 17.3, 18.7 and 22.4°2θ, and contains about two mole equivalents of chloride ions.

EFFECT: invention relates to methods of producing a crystalline form A, a pharmaceutical composition containing said crystalline forms and a treatment method.

15 cl, 16 dwg, 9 ex

FIELD: medicine.

SUBSTANCE: present invention describes compounds of formula I: wherein: X1 and X2 independently represent CH or N; R1 represents fluorine or hydrogen; R2 represents hydrogen, halogen; Ar represents phenyl substituted by 1-3 groups optionally substituted in each specific case in a group consisting of hydrogen, halogen, cyano group; R3 is independently specified in each specific case in a group consisting of: (i) CH2OH; (ii) CH2O-C(=O)(CH2)nCO2R4, wherein n has a value of 2 to 5; (iii) CH2O-C(=O)CH2OCH2CO2R4; (iv) CH2OCOR5; (v) CH2OC(=O)CHR6NH2; (vi) C(=O)R5, and (vii) CH2OP(=O)(OH)2; R4 represents hydrogen or C1-10 alkyl; R5 represents hydrogen or C1-10 alkyl, C1-3 dialkylamino-C1-10 alkyl, C1-6 alkoxy or pyridinyl, R6 represents C1-6 alkyl or a side chain of a natural amino acid; or a pharmaceutically acceptable salt thereof. Besides, the invention describes a pharmaceutical composition having HTVRT inhibitory activity and containing a compound according to cl.1.

EFFECT: there are prepared and described new compounds inhibiting HIV-1 reverse transcriptase and effective for preventing and treating HIV-1 infections and treating AIDS or ARC.

13 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

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