Novel compounds, isomers thereof or pharmacutically acceptable salts thereof as vanilloid receptor antagonists and pharmaceutical composition containing said compounds

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

 

Technical area

The present invention relates to new compounds, their isomers or their pharmaceutically acceptable salts as an antagonist of TRPV1; and containing pharmaceutical compositions.

The level of technology

Vanilloideae receptor 1 (VR1, or transient receptor potential vanilloid-1, TRPV1) is a receptor for capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent ingredient in hot peppers. In 1997 it was reported the molecular cloning of TRPV1 (Caterina et al., 1997, Nature, 389, pp816-824), which belongs to the family of TRP channels non-selective cation channels. TRPV1 is activated or sensitize stimuli, such as capsaicin, resiniferatoxin, high temperature, acid, anandamide, metabolites, lipids and the like; thus, it plays a critical role as a molecular integrator of toxic stimuli in mammals (Tominaga et al., 1998, Neuron, 21 pp531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). TRPV1 largely is expressed in primary afferent sensory neurons, and is also reportedly expressed in various organs and tissues such as the bladder, kidney, lung, intestine, skin, Central nervous system (CNS) and not neural tissue (Mezey et al., 2000, PNAS, 97, pp3655-3660; Stander et al., 2004, Exp. Dermatol. 13, pp129-139; Cortright et al., 2001, BBRC, 281, pp1183-1189)and, in addition, protein TRPV1 is activated by painful morbid with what taniah. Activation of TRPV1 endogenous/exogenous stimuli leads not only to the transfer of toxic stimuli, but also to the release of neuropeptides such as substance P, CGRP (Peptide Associated with Calcitonin Gene) in neurons, thus causing neurogenic inflammation. Mouse knockout for TRPV1 show normal reactions in a variety of behavioral tests, including toxic, mechanical and acute thermal stimuli, but show a small thermal hypersensitivity in States of inflammation (Caterina et al., 2000, Science, 288, pp306-313; Davis et al., 2000, Nature, 405, pp183-187; Karai et al., 2004, J. Clin. Invest., 113, pp1344-1352).

As stated above, the mouse knockout for TRPV1 show reduced response to thermal or toxic stimuli, as evidenced by the effects of TRPV1 antagonists in various pain models in animals (Immke et al., 2006, Semin. Cell. Dev. Biol., 17(5), pp582-91; Ma et al., 2007, Expert Opin. Ther. Targets, 11(3), pp307-20). Known antagonist of TRPV1, capsazepine, reduces hyperalgesia caused by physical stimuli in several models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp56-62; Garcia-Martinez et al., 2002, PNAS, 99, 2374-2379). In addition, treatment of primary cultures of afferent sensory neurons-TRPV1 agonist, capsaicin, etc. leads to dysfunction of the nerve and, in addition, to the death of nerve cells. The TRPV1 antagonist exerts a protective effect against such violations funk is the third nerve and death of nerve cells (Holzer P., 1991, Pharmacological Reviews, 43, pp143-201; Mezey et al., 2000, PNAS, 97, 3655-3660). TRPV1 is expressed on sensory neurons, distributed in all regions of the gastrointestinal tract and is highly expressed in inflammatory disorders, such as irritable bowel syndrome and inflammatory bowel disease (Chan et al., 2003, Lancet, 361, pp385-391; Yiangou et al., 2001, Lancet, 357, pp1338-1339). In addition, activation of TRPV1 stimulates sensory nerves, which in turn triggers the release of neuropeptides, which are known to play a critical role in the pathogenesis of gastrointestinal disorders such as gastroesophageal reflux disease (GERD) and ulcers of the stomach and duodenum (Holzer P., 2004, Eur. J. Pharmacol. 500, pp231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp1313-1320).

TRPV1-expression of afferent nerves in abundance observed in the mucosa of the respiratory tract and bronchial hypersensitivity is a mechanism very similar hyperalgesia. Protons and lipoxygenase products, known as the endogenous ligand for TRPV1, known as the critical factors responsible for the development of asthma and chronic obstructive pulmonary disease (Hwang et al., 2002, Curr. Opin. Pharmacol. pp235-242; Spina et al., 2002, Curr. Opin. Pharmacol. pp264-272). In addition, it was reported that air polluting substances, which are a type of cause asthma substances, i.e. particles specifically de is available in TRPV1 and this effect is inhibited by capsazepine (Veronesi et al., 2001, NeuroToxicology, 22, pp795-810). Hypersensitivity of the bladder and urinary incontinence are caused by various disorders or injuries of the Central/peripheral nerves, and TRPV1 expressed in afferent nerves, and urothelial cells play an important role in inflammation of the bladder (Birder et al., 2001, PNAS, 98, pp13396-13401). Furthermore, mice with a knockout on TRPV1 are anatomically normal, but have a higher frequency of low-amplitude, neporozhnaya contractions of the bladder and reduced reflex emptying during filling of the bladder compared with wild-type mice, thus indicating that TRPV1 affects the functioning of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp856-860). TRPV1 is distributed in the keratinocytes of the human epidermis, and also in primary afferent sensory nerves (Denda et al., 2001, Biochem. Biophys. Res. Commun., 285, pp1250-1252; Inoue et al., 2002, Biochem. Biophys. Res. Commun., 291, pp124-129), and it participates in the transfer of various toxic stimuli and pain effects such as skin irritation and itching of the skin, thus revealing a close correlation with the etiology of dermatological diseases and disorders, such as inflammation of the skin, due to neurogenic/non-neurogenic factors. This is confirmed by the established fact that the TRPV1 antagonist, capsazepine, inhibits inflammatory mediators in human skin cells (Southall et al., 2003, J. Pharacol. Exp. Ther., 304, pp217-222). In recent years they have accumulated evidence of other roles TRPV1. TRPV1 can participate in the flow/pressure control through the touch release vasoactive neuropeptide in the regulation of plasma glucose levels or in the pathogenesis of type 1 diabetes (Inoue et al., Cir. Res., 2006, 99, pp119-31; Razavi et al., 2006, Cell 127, pp1123-35; Gram et al., 2007, Eur. J. Neurosci., 25, pp213-23). Further, it is reported that mice with a knockout on TRPV1 less show less associated with anxiety behavior than their congeners of the wild type, with no differences in locomotion (Marsch et al., 2007, J. Neurosci.,27(4), pp832-9).

Based on the above information, the development of various antagonists of TRPV1 is in full swing, and published some of the patents and patent applications relating to develop antagonists of TRPV1 (Szallasi et al., 2007, Nat. Rev. Drug Discov., 6, pp.357-72; Appendino et al., 2006, Progress in Medicinal Chemistry, 44, pp.145-180; Rami et al., 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp.97-104; Correll et al., 2006, Expert Opin. Ther. Patents, 16, pp.783-795; Kyle et al., 2006, Expert Opin. Ther. Patents, 16, pp.977-996).

Compounds according to the present invention can be used for the prevention and treatment of diseases associated with the activity of TRPV1 (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369), including, but not limited to, pain, such as acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritis pain, postge petchesky neuralgia, neuralgia, headache, dental pain, pelvic pain, migraine pain and cancer pain bone, mastalgia and visceral pain (Petersen et al., 2000, Pain 88, pp.125-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp.56-62; Morgan et al., 2005, J. Orofac. Pain, 19, pp.248-60; Dinis et al., 2005, Eur. Urol., 48, pp.162-7; Akerman et al., 2004, Br. J. Pharmcol., 142, pp.1354-1360; Ghilardi et al., 2005, J. Neurosci., 25, 3126-31; Gopinath et al., 2005, BMC Womens Health, 5, 2-9); associated with nerve diseases such as neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration and stroke (Park et al., 1999, Arch. Pharm. Res. 22, pp.432-434; Kim et al., 2005, J. Neurosci. 25(3), pp.662-671); diabetic neuropathy (Kamei et al., 2001, Eur. J. Pharmacol. 422, pp.83-86); the urge for defecation; irritable bowel syndrome (Chan et al., 2003, Lancet, 361, pp.385-391); inflammatory bowel disease (Yiangou et al., 2001, Lancet 357, pp1338-1339); gastrointestinal disorders such as gastroesophageal reflux disease (GERD), stomach ulcers and duodenal ulcers and Crohn's Disease (Holzer P, 2004, Eur. J. Pharm., 500, pp.231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp.1313-1320); respiratory diseases such as asthma, chronic obstructive pulmonary disease, cough (Hwang et al., 2002, Curr. Opin. Pharmacol. pp.235-242; Spina et al., 2002, Curr. Opin. Pharmacol. pp.264-272; Geppetti et al., 2006, Eur. J. Pharmacol., 533, pp207-214; McLeod et al., 2006, Cough, 2, 10); incontinence (Birder et al., 2002, Nat. Neuroscience 5, pp.856-860); hypersensitivity of the bladder (Birder et al., 2001, PNAS, 98, pp.13396-13401); neuropathic/allergic/inflammatory skin disease, such as p is orias, pruritus, prurigo and dermatitis (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp.217-222); irritation of skin, eyes or mucous membranes (Tominaga et al., 1998, Neuron 21 pp.531-543); hypernormal hearing; tinnitus, vestibular hypersensitivity (Balaban et al., 2003, Hear Res. 175, pp.165-70); heart disease, such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95, pp1027-1034; Pan et al., 2004, Circulation 110, pp.1826-1831); hemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245(6), pp.964-70); disorders associated with growth of hair, such as hirsutism, effluvium, alopecia (Bodó et al., 2005, Am. J. Patho. 166, pp.985-998; Bíró et al., 2006, J. Invest. Dermatol. pp.1-4); rhinitis (Seki et al., 2006, Rhinology, 44, pp128-34); pancreatitis (Hutter et al., 2005, Pancreas, 30, pp260-5); cystitis (Dinis et al., 2004, J. Neurosci., 24, pp11253-63; Sculptoreanu et al., 2005, Neurosci. Lett. 381, pp42-6); vulvodynia (Tympanidis et al., 2004, Eur. J. Pain, 8, pp.12-33); psychiatric disorders such as anxiety or fears (Marsch et al., 2007, J. Neurosci., 27 (4), pp.832-9).

Connections that are associated with activities VR1, are discussed, for example, in WO 02/61317, WO 02/090326, WO 02/16318, WO 02/16319, WO 03/053945, WO 03/099284, WO 03/049702, WO 03/049702, WO 03/029199, WO 03/70247, WO 04/07495, WO 04/72068, WO 04/035549, WO 04/014871, WO 04/024154, WO 04/024710, WO 04/029031, WO 04/089877, WO 04/089881, WO 04/072069, WO 04/111009, WO 05/03084, WO 05/073193, WO 05/051390, WO 05/049613, WO 05/049601, WO 05/047280, WO 05/047279, WO 05/044802, WO 05/044786, WO 06/097817, WO 06/098554, WO 06/100520, WO 06/101321, WO 06/102645, WO 06/103503, WO 06/111346, WO 06/101321, WO 06/101318, WO 06/1113769, WO 06/116563, WO 06/120481, WO 06/122250, WO 06/122799, WO 06/129164, WO 06/51378, WO 06/95263, WO 07/42906, WO 07/45462, WO 07/50732, WO 07/54474, WO 07/54480, WO 07/63925, WO 07/65663, WO 07/65888, WO 07/67619, WO 07/67710, WO 07/67711, WO 07/67756 WO 07/67757, WO 07/63925, WO 07/65662, WO 07/65663, WO 07/65888, WO 07/69773, US 20070149517 or US 20070149513.

More specifically, WO 06/101321 and WO 06/101318 related modulators of VR1 with a partial structure of biphenyl. As a result of extensive and intensive research, the authors of the present invention have synthesized new compounds having VR1-antagonistic activity, by replacing one of the phenyl rings substituted heterocyclic ring. In addition, the authors present invention also unexpectedly identified that replacing one of the phenyl rings, as described above, provides an improvement in their physical-chemical characteristics, such as metabolic stability or pharmacokinetic profiles.

Therefore, an object of the present invention are new compounds which can be used as a powerful antagonist of TRPV1, their isomers and their pharmaceutically acceptable salts; and containing pharmaceutical composition.

Disclosure of invention

The present invention relates to a new compound of the following formula (I), its isomer or pharmaceutically acceptable salt:

(I)

in which

X represents CR11=CR12, CHR11CHR12,,or C≡C, and R11and R12if they are present, are independently hydrogen, halogen or C1-C10 what Kilom;

Y and Z independently represent CH, CR6or N, so that at least one of Y and Z represents N;

R1denotes hydrogen, halogen or alkyl (preferably C1-C10 alkyl);

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), halogenated (preferably halogen (C1-C10) alkyl), alkenyl (preferably C2-C10 of alkenyl), quinil (preferably C2-C10 quinil), carboxy, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl) or alkylthio (preferably C1-C10 alkylthio);

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), alkenyl (preferably C2-C10 of alkenyl), quinil (preferably C2-C10 quinil), alkylthio (preferably C1-C10 alkylthio), alkylsulfonyl (preferably C1-C10 alkylsulfonyl), alkylaryl (preferably C1-C10 alkylaryl), alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), alkenylacyl (preferably C2-C10 alkenylamine), alkoxyalkyl (preferably C1-C10 alkoxy (C1-C10) alkoxy), alkoxyalkyl (preferably C1-C10 alkoxy (C1-C10) alkoxy (C1-C10) alkyl), piperidyl, piperazinil, alkoxyalkyl (preferably C1-C10 alkoxy (C1-C10) al is ylamino), alkylamino (preferably C1-C10 alkylamino), dialkylamino (preferably di(C1-C10 alkyl)amino), cycloalkyl (preferably C3-C8 cycloalkyl), cyclooctylamine (preferably C3-C8, cyclooctylamino), cycloalkane (preferably C3-C8, cycloalkane), oxacillinase (preferably C3-C8, oxacillinase), N-alkoxyalkyl-N-alkylamino (preferably N-(C1-C10)alkoxy(C1-C10)alkyl-N-(C1-C10)alkylamino), N-cycloalkyl-N-alkylamino (preferably N-(C3-C8)cycloalkyl-N-(C1-C10)alkylamino), N-aryl-N-alkylamino (preferably N-aryl-N-(C1-C10)alkylamino, more preferably N-phenyl-N-(C1-C10)alkylamino), aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl the groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 alkyl or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroarenes or heteroaromatic may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;

and

R10represents alkyl (preferably C1-C10 alkyl), halogenated (preferably halogen (C1-C10) alkyl) or alkenyl (preferably C2-C10 of alkenyl).

The present invention relates to a new connection shadowsforsale (I), to its isomer or pharmaceutically acceptable salt:

(I)

in which

X represents CR11=CR12, CHR11CHR12or C≡C, and R11and R12if they are present, are independently hydrogen, halogen or C1-C5-alkyl;

Y and Z independently represent CH, CR6or N, so that at least one of Y and Z represents N, R1denotes hydrogen, halogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aryl is IO, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 alkyl or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroarenes or heteroaromatic may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, e.g. the R, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;

and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl,

and moreover, in one embodiment, preferably Z represents N, Y represents CR6and R7represents C3-C6 alkyl or halo (C1-C5 alkyl), for example, trifluoromethyl, and in another embodiment, these compounds of the formula I preferably X represents CR11=CR12or C≡C, Z represents N, Y represents CR6, R6different from hydrogen, and R7denotes halogen (C1-C5 alkyl), particularly preferably trifluoromethyl.

The present invention relates to a new compound of the following formula (I), its isomer or pharmaceutically acceptable salt:

(I)

in which

X represents CR11=CR12, CHR11CHR12,,or C≡C, and R11and R12if there are are independently hydrogen, halogen or C1-C5-alkyl;

Y and Z independently represent CH, CR6or N, so that at least one of Y and Z represents N;

R1denotes hydrogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, heteroallyl aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkilani is about or alkenylamine, may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroarenes or heteroaromatic may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl or hydroxyl;

and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

The present invention also relates to a new connection, following the formula (I), to its isomer or pharmaceutically acceptable salt; and containing pharmaceutical composition:

(I)

in which

X represents CR11=CR12, CHR11CHR12,,or C≡C, and R11and R12if they are present, are independently hydrogen, halogen or C1-C5-alkyl;

Y and Z independently represent CH, CR6or N, so that at least one of Y and Z represents N;

R1denotes hydrogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5, alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylaryl, C1-C5 alkoxycarbonyl, C2-C5, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazine, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, di(C1-C5 alkyl)amino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more C1-C3-alkyl, pyrrolidinyl, phenyl or morph what linglom, moreover, the phenyl can be unsubstituted or substituted by one or more substituents selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl; and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

Another aspect of the present invention relates to the connection according to the specified formula (I), its isomer or pharmaceutically acceptable salt,

in which

X represents CR11=CR12and R11and R12are independently hydrogen, halogen or C1-C3-alkyl;

R1denotes hydrogen or C1-C3 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5, alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylaryl, C1-C5 alkoxycarbonyl, C2-C5, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazine, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, di(C1-C3 alkyl)amino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, pyrrolidinyl, phenyl or Moholi the sludge, moreover, the phenyl can be unsubstituted or substituted by one or more substituents selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl; and

R10denotes a C1-C3 alkyl or C2-C3 of alkenyl.

According to one variant of implementation of the present invention in the compounds of formula I, as described hereinafter, R6different from hydrogen, and R7denotes halogen (C1-C5) alkyl, preferably halogen (C1-C4) alkyl, more preferably halogen (C1-C2) alkyl, such as CF2Cl or CF2CF3particularly preferably R7means CF3.

According to another variant implementation of the present invention in the compounds of formula (I)as described below

- Z represents N;

- Y represents CR6;

- X represents CR11=CR12, CHR11CHR12or C≡C;

- R7represents C3-C6 alkyl or halo (C1-C5) alkyl; and R7even more preferably denotes a tert-butyl, isopropyl, isobutyl or trifluoromethyl;

and

R6doesn't mean pyridinyl, pyridyloxy, piperazinil substituted by hydroxyl, alkylamino or substituted pyrrolidin. In some embodiments, the implementation of R6also does not denote hydrogen. In another embodiment, R6does not denote hydrogen, and also doesn't mean penalty.

Accordingly, one way of implementing this the image the program relates to the compound of formula (I), to its isomer or pharmaceutically acceptable salt:

(I)

in which

- X represents CR11=CR12or C≡C; and R11and R12if they are present, are independently hydrogen, halogen or C1-C5-alkyl;

- Z represents N;

- Y represents CR6;

R1denotes hydrogen, halogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6denotes hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, thienyl, heteroallyl, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl, provided that R6doesn't mean C is displaced by hydroxyl, alkylamino;

R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two halogen radicals and/or the methyl group, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroarenes or heteroaromatic may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

each piperidyl and morpholinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;

R7denotes halogen (C1-C5) alkyl;

and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

In another embodiment, in compounds of formula I, as described here,

X represents-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, C(CH 3)=C(CH3)-, -C(C2H5)=CH-, -CH=C(C2H5)-, -CF=CH-, -CH=CF -, or C≡C;

R1denotes hydrogen, fluorine, methyl or ethyl;

R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R6denotes hydroxy, fluorine, bromine, chlorine, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 of alkenyl, C2-C6 quinil, halogen (C1-C6) alkyl, halo (C1-C6) alkoxy, C2-C6, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, di(C1-C6 alkyl)amino, C1-C6, alkylamino, C1-C3 alkoxy (C1-C5) alkylamino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cyclooctylamine, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cycloalkane, C3-C6, oxacyclobutane, N-(C1-C2)alkoxy(C1-C3)alkyl-N(C1-C3)alkylamino, N-(C3-C6)cycloalkyl-N-(C1-C3)alkylamino, C1-C3 alkylpiperazine, piperidyl, pyrrolidinyl, halogenfree, phenyl, phenoxy, phenylamino, halogenfree, morpholinyl; C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkyl, di(C1-C3)alkylaminocarbonyl, (C1-C3) alkoxyphenyl, thienyl, (C3-C6) cycloalkyl (C1-C3) alkoxy, phenyl (C1-C3) alkoxy, C1-C5, alkylthio, phenyl (C1-C3) alkylamino, arylamino, N-phenyl-N-(C1-C3)alkylamino, (C1-C3) alkoxycarbonyl and the and piperidyl;

R7denotes halogen (C1-C5) alkyl, such as CF2Cl, CF2CF3or, particularly preferably, CF3;

R8and R9independently represent hydrogen, halogen or trifluoromethyl; and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

The present invention also relates to a new compound of the following formula (II), its isomer or pharmaceutically acceptable salt:

,

(II)

in which

R1denotes hydrogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, hydroxy (C1-C5) alkyl, C1-C5, alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylaryl, C1-C5 alkoxycarbonyl, C2-C5, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazine, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, di(C1-C5 alkyl)amino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more C1-C3-alkyl, pyrrolidinyl, phenyl or morpholinyl, being the m phenyl can be unsubstituted or substituted by one or more substituents, selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl;

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and

R11and R12independently represent hydrogen, C1-C5 alkyl or halogen.

One preferred aspect of the present invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt:

,

(III)

in which

R1denotes hydrogen, halogen or C1-C10 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), halogenated (preferably halogen (C1-C10) alkyl), alkenyl (preferably C2-C10 of alkenyl), quinil (C2-C10 quinil), carboxy, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl) or alkylthio (preferably C1-C10 alkylthio);

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), alkenyl (preferably C2-C10 of alkenyl), quinil (preferably C2-C10 quinil), alkylthio (preferably C1-C10 alkylthio), alkylsulfonyl (preferably C1-C10 alkylsulfonyl), alkylaryl (preferably C1-C10 alkylaryl), alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl the l), alkenylamine (preferably C2-C10 alkenylamine), alkoxyalkyl (preferably C1-C5 alkoxy (C1-C10) alkoxy), alkoxyalkyl (preferably C1-C5 alkoxy (C1-C10) alkoxy (C1-C10) alkyl), piperidyl, piperazinil, alkoxyalkyl (preferably C1-C10 alkoxy (C1-C10) alkylamino), alkylamino (preferably C1-C10 alkylamino), dialkylamino (preferably di(C1-C10 alkyl)amino), cycloalkyl (preferably C3-C8 cycloalkyl), cyclooctylamine (preferably C3-C8, cyclooctylamino), cycloalkane (preferably C3-C8, cycloalkane), oxacillinase (preferably C3-C8 oxocyclohexyl-hydroxy), N-alkoxyalkyl-N-alkylamino (preferably N-(C1-C10)alkoxy(C1-C10)alkyl-N-(C1-C10)alkylamino), N-cycloalkyl-N-alkylamino (preferably N-(C3-C8)cycloalkyl-N-(C1-C10)alkylamino), N-aryl-N-alkylamino (preferably N-aryl-N-(C1-C5)alkylamino, more preferably N-phenyl-N-(C1-C5)alkylamino), aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine can be independently researched the mo unsubstituted or substituted by one or more substituents, selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, also part of the group, for example, in arylamino, aryloxy, heteroaromatic or heteroarenes may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;

R represents alkyl (preferably C1-C10 alkyl), halogenated (preferably halogen (C1-C10) alkyl) or alkenyl (preferably C2-C10 of alkenyl); and

R11and R12independently represent hydrogen, C1-C5 alkyl or halogen.

The compound of formula (III), its isomer or pharmaceutically acceptable salt:

,

(III)

in which

R1denotes hydrogen, halogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8 oxocyclohexyl-hydroxy, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, predpochtite is the super phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroaromatic or heteroarenes may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycle is alkylamino, may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and

R11and R12independently represent hydrogen, C1-C5 alkyl or halogen, and in one embodiment, R6preferably different from hydrogen, and R7denotes halogen (C1-C5) alkyl.

One preferred aspect of the present invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt:

,

(III)

in which

R1denotes hydrogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 is alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8 oxocyclohexyl-hydroxy, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy or heteroaromatic may be independently unsubstituted or samewe is owned by one or more substituents, selected from halogen, unsubstituted C1-C5 alkyl or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

every piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl or hydroxyl;

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and

R11and R12independently represent hydrogen, C1-C5 alkyl or halogen.

One preferred aspect of the present invention relates to the compound of formula (I) or (III), its isomer or pharmaceutically acceptable salt:

,

(III)

in which

R1denotes hydrogen or C1-C5 alkyl;

R2, R3, R4and R5independently represent hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, carboxy, C1-C5 alkoxycarbonyl or C1-C5, alkylthio;

R6, R7, R8and R9independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) Ala is l, halogen (C1-C5) alkoxy, hydroxy (C1-C5) alkyl, C1-C5, alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylaryl, C1-C5 alkoxycarbonyl, C2-C5, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazine, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, di(C1-C5 alkyl)amino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more C1-C3-alkyl, pyrrolidinyl, phenyl or morpholinyl, and phenyl may be unsubstituted or substituted by one or more substituents selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl;

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and

R11and R12independently represent hydrogen, C1-C5 alkyl or halogen.

One preferred aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salts, as defined herein, in which X represents CR11=CR12or C≡C, particularly preferably CR11=CR12and R11and R12preferably denote hydrogen, halogen or C1-C3 alkyl, and even more preferably hydrogen or methyl.

Accordingly, one preferred aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salts, as defined herein, in which X is pre-selected from-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH3)=C(CH3)-, -C(C2H5)=CH-, -CH=C(C2H5)-, -CF=CH-, -CH=CF -, or C≡C, even more preferably-CH=CH-, -C(CH3)=CH - or-CH=C(CH3)and particularly preferably-CH=CH-.

One aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above,

in which R7represents C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, or C1-C5 alkyl, which may be galogenidov one or more radicals selected from chlorine, bromine or, preferably, fluorine. Examples are methylcyclopropyl, CF3, isopropyl, tert-butyl and isobutyl.

In one preferred embodiment of the present invention in the compounds of the formula (III), as described, R7represents C3-C6 alkyl or halo (C1-C5 alkyl), and R7even more preferably denotes a tert-butyl, isopropyl, isobutyl or trifluoromethyl. In one preferred embodiment of the present invention in the compounds of the formula (III), as described below, R7denotes halogen (C1-C5) alkyl or halo (C1-C4) alkyl, such as CF2Cl, CF2CF3or, particularly preferably, CF3.

In another embodiment of the present invention in connect the s of the formula (III) R 6doesn't mean pyridyloxy, phenylthio or substituted pyrrolidin. In another preferred aspect of the present disclosure, R6different from hydrogen.

In another embodiment, in compounds of formula (III), as described later,

- R7represents C3-C6 alkyl or halo (C1-C5 alkyl), and R7even more preferably denotes a tert-butyl, isopropyl, isobutyl or trifluoromethyl;

and

- R6doesn't mean pyridinyl, pyridyloxy, piperazinil substituted by hydroxyl, alkylamino or substituted pyrrolidin. In some embodiments, the implementation of R6also does not denote hydrogen and/or penalty.

Another aspect of the present invention relates to the compound of formula (I) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R6selected from hydrogen, bromine, chlorine, n-butyl, methoxy, isobutoxy, sec-Butylochka, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamine, n-butylamino, phenoxy, n-Butylochka, methoxyethylamine.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano.

The other and what aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R10denotes methyl.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R11and R12if they are present, are both hydrogen. In another embodiment, one of R11and R12denotes hydrogen and the other is selected from methyl, ethyl and propyl. In one embodiment, R11can be hydrogen, and R12can be hydrogen, stands, ethyl or propylene, preferably hydrogen.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R4denotes hydrogen, fluorine, chlorine, bromine, methyl, ethyl, cyano or trifluoromethyl.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R1and R2both represent hydrogen.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R1, R2and R11and R12if the neither are present, all are hydrogen.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R1, R2and R11and R12if they are present, are all hydrogen, R10denotes methyl, and R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R11and R12if they are present, are both hydrogen, R10denotes methyl or ethyl, R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano, and R4selected from hydrogen, fluorine, chlorine, bromine, methyl, cyano or trifloromethyl.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R11and R12if they are present, are both hydrogen, R10denotes methyl or ethyl, R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano, and R7denotes cyclopropylmethyl or C1-C5 alkyl, which mo is et to be optional galogenidov one or more radicals, selected from chlorine, bromine or preferably fluorine.

Another aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt as defined above in which R11and R12if they are present, are both hydrogen, R10denotes methyl or ethyl, R2, R5and R8denote hydrogen, R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano, and R7denotes a C1-C5 alkyl, which may be optional galogenidov one or more radicals selected from chlorine, bromine or preferably fluorine.

One preferred aspect of the present invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen, methyl or ethyl;

R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R6if it is present, is hydrogen, hydroxy, fluorine, bromine, chlorine, hydroxymethyl, C1-C5-alkyl, C1-C5 alkoxy, C2-C5-alkenyl, C2-C5-quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C2-C5, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) what Kilom, di(C1-C3 alkyl)amino, C1-C3-alkylpiperazine, piperidino, pyrrolidinyl, halogenfree, phenyl or morpholinyl, and R6preferably different from hydrogen;

R7denotes a C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, C2-C5 of alkenyl, and R7preferably represents halogen (C1-C4) alkyl;

R8and R9independently represent hydrogen, halogen or trifluoromethyl;

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and

R11and R12if they are present, are independently hydrogen or stands.

Another preferred embodiment of the invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt,

in which

R1, R2and R5denotes hydrogen;

R3denotes hydrogen, fluorine, chlorine, cyano, methyl, ethynyl, ethinyl or trifluoromethyl;

R4denotes hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;

R6if present, represents hydrogen, hydroxy, fluorine, bromine, chlorine, methyl, hydroxymethyl, methoxy, trifluoromethyl, diethylamino, piperidyl, pyrrolidinyl, tryptophanyl, phenyl or morpholinyl, and R6before occhialino is different from hydrogen;

R7denotes a methyl, isopropyl, tert-butyl, trifluoromethyl, chlorine, bromine, cyclopropyl, methylcyclopropyl, piperidyl, pyrrolidinyl or morpholinyl, and R7preferably represents trifluoromethyl;

R8denotes hydrogen;

R11and R12if they are present, are hydrogen;

R9denotes hydrogen or trifluoromethyl; and

R10denotes methyl.

Another preferred embodiment of the invention relates to the compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl;

R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;

R6if it is present, is hydrogen, fluorine, chlorine, bromine, stands, methoxy, piperidino or morpholino;

R7represents isopropyl, tert-butyl or, preferably, trifluoromethyl;

R8denotes hydrogen;

R11and R12if they are present, are hydrogen;

R9denotes hydrogen or trifluoromethyl; and

R10denotes methyl.

Another preferred variant of the invention, the relative is raised to the compound of formula (I) or (III), to its isomer or pharmaceutically acceptable salt,

in which

X represents-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH3)=C(CH3)-, -C(C2H5)=CH-, -CH=C(C2H5)-, -CF=CH-, -CH=CF -, or C≡C;

R1denotes hydrogen, fluorine, methyl or ethyl;

R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R6denotes hydrogen, hydroxy, fluorine, bromine, chlorine, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 of alkenyl, C2-C6 quinil, halogen (C1-C6) alkyl, halo (C1-C6) alkoxy, C2-C6, alkenylacyl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, di(C1-C6 alkyl)amino, C1-C6, alkylamino, C1-C3 alkoxy (C1-C5) alkylamino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cyclooctylamine, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cycloalkane, C3-C6, oxacyclobutane, N-(C1-C2)alkoxy(C1-C3)alkyl-N(C1-C3)alkylamino, N-(C3-C6)cycloalkyl-N-(C1-C3)alkylamino, C1-C3 alkylpiperazine, piperidyl, pyrrolidinyl, halogenfree, phenyl, phenoxy, pyridyloxy, phenylamino, halogenfree or morpholinyl;

R7denotes a C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl which could to be unsubstituted or substituted by one or more methyl groups, C2-C5 of alkenyl;

R8and R9independently represent hydrogen, halogen or trifluoromethyl; and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1, R2and R5represent hydrogen;

R3denotes hydrogen, fluorine, chlorine, cyano, methyl, ethynyl, ethinyl or trifluoromethyl;

R4denotes hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;

R6denotes hydrogen, hydroxy, fluorine, bromine, chlorine, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentox, methoxyethoxy, ethoxyethoxy, methoxypropane, trifluoromethyl, diethylamino, methoxyethylamine, methoxyethylamine, methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, ethylamine, Propylamine, butylamine, pentylamine, N,N-dimethylamino, N-methyl-N-ethylamine N,N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-methyl-N-methoxyethylamine, N-methyl-N-methoxyethylamine, N-methyl-N-methoxypropylamine, N-methyl-N-cyclobutylamine, N-methyl-N-cyclopentylamine, N-methyl-N-cyclohexylamino, phenoxy, halogenfree, piperidyl, pyrrolidinyl, trifter Anil, phenyl or morpholinyl, and R6preferably different from hydrogen;

R7denotes a methyl, isopropyl, tert-butyl, trifluoromethyl, chlorine, bromine, cyclopropyl, methylcyclopropyl, piperidyl, pyrrolidinyl or morpholinyl, and preferably represents trifluoromethyl;

R8denotes hydrogen;

R11and R12represent hydrogen;

R9denotes hydrogen or trifluoromethyl; and

R10denotes methyl.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl;

R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;

R6denotes hydrogen, fluorine, chlorine, bromine, methyl, n-butyl, methoxy, n-Butylochka, isobutoxy, sec-Butylochka, methoxyethoxy, methoxyethylamine, diethylamino, n-butylamino, cyclopentylamine, phenoxy, N-pyrrolidinyl, N-piperidyl or N-morpholinyl, and in one aspect, R6different from hydrogen;

R7represents isopropyl, tert-butyl or, preferably trifluoromethyl;

R8denotes hydrogen;

R11 and R12represent hydrogen;

R9denotes hydrogen or trifluoromethyl; and

R10denotes methyl.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, ethynyl or ethinyl;

R4denotes hydrogen or fluorine;

R5denotes hydrogen;

R6denotes hydrogen, hydroxy, fluorine, bromine, chlorine, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentox, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxyethoxy, trifluoromethyl, N,N-dimethylamino, N-methyl-N-ethylamine N,N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, methoxyethylamine, methoxyethylamine, methoxypropylamine, N-methyl-N-methoxyethylamine, N-methyl-N-methoxyethylamine, N-methyl-N-methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, N-methyl-N-cyclobutylamine, N-methyl-N-cyclopentylamine, N-methyl-N-cyclohexylamino, ethylamino, propylamino, butylamino, pentylamine, phenoxy, halogenfree, N-piperidyl, N-pyrrolidinyl, tryptophanyl, phenyl or N-morpholinyl,

and R6in one aspect which differentiates itself here from hydrogen;

R7represents isopropyl, tert-butyl or, preferably trifluoromethyl;

R8denotes hydrogen;

R9denotes hydrogen or trifluoromethyl;

R10denotes methyl; and

R11and R12denotes hydrogen.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen;

R2denotes hydrogen;

R3denotes hydrogen, ethynyl or ethinyl;

R4denotes hydrogen or fluorine;

R5denotes hydrogen;

R6denotes hydrogen, bromine, chlorine, n-butyl, methoxy, isobutoxy, sec-Butylochka, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamine, n-butylamino, phenoxy, n-Butylochka, methoxyethylamine, and R6in one aspect is different from hydrogen;

R7represents isopropyl, tert-butyl or, preferably trifluoromethyl;

R8denotes hydrogen;

R9denotes hydrogen or trifluoromethyl;

R10denotes methyl; and

R11and R12denote hydrogen.

Another aspect of the present invention relates to the compound of formula (III), as described below, to its isomer or pharmaceutically acceptable salts, in which

R1the convoy is achet hydrogen or methyl, moreover, if R1denotes methyl, the compound can be a pure enantiomer or may be a mixture of (R)- and (S)enantiomers; and the C-atom that is attached to R1is preferably in the (R)-configuration;

one of R2and R5denotes hydrogen and the other denotes hydrogen, methyl or halogen, preferably fluorine;

R3selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifloromethyl, Attila, ethinyl and cyano, preferably hydrogen, fluorine, chlorine, methyl, ethyl, Attila, ethinyl and cyano;

R4denotes hydrogen, fluorine, chlorine, cyano, methyl or ethyl;

R6matter described in different variants of implementation in the framework of this application;

R7denotes a C1-C5 alkyl or more preferably C1-C4 alkyl or C1-C3 alkyl, which galogenidov one or more radicals selected from chlorine, bromine or preferably fluorine, and R7particularly preferably denotes CF3;

one of R8and R9denotes hydrogen and the other denotes halogen, CF3or preferably hydrogen;

R10denotes methyl, ethyl or ethynyl, and preferably methyl;

R11denotes hydrogen;

R12denotes hydrogen, methyl, ethyl or propyl, and preferably hydrogen.

Another aspect of the present disclosure relates to soedineniya (III), as described herein, to its isomer or pharmaceutically acceptable salts, in which

R6denotes halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8 oxocyclohexyl-hydroxy, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, thienyl, heteroallyl, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl, provided that R6doesn't mean substituted by hydroxyl, alkylamino, preferably

R6denotes chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethinyl, methoxypropanol, diethylaminopropyl, phenyl, halogenfree, methoxyphenyl, thienyl, methoxy, ethoxy, propoxy, butoxy, pentox, triptoreline, cyclopentane, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenfree, benzyloxy, this is LTI, propylthio, butylthio, pentylthio, methylamino, ethylamino, propylamino, butylamino, pentylamine, methoxyethylamine, amoxicillin, methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, benzylamine, phenylamino, N,N-dimethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-pyrrolidinyl, N-piperidyl, etoxycarbonyl-N-piperidyl or N-morpholinyl, preferably

R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, forfinal, thienyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3 methylbutoxy, 2,2,2-triptoreline, cyclopentane, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, methoxyethylamine, amoxicillin, cyclopentylamine, benzylamine, phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or etoxycarbonyl-N-piperidyl, and more preferably

R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, is isobutoxy, Deut-butoxy, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino or N-methyl-N-phenylamino, and more preferably

R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, benzylamino or N-methyl-N-phenylamino, and even more preferably

R6denotes a C2-C5 alkyl, C1-C4, alkylamino or methoxyethylamine, particularly preferably

R6denotes a C3-C5 alkyl or C2-C4, alkylamino, particularly preferably

R6represents C2-C4 alkyl or C1-C3 alkylamino, particularly preferably

R6denotes a linear or branched C3 alkyl, C4 linear alkyl or a linear (C2-C3) alkylamino.

Preferred examples of compounds according to the invention is selected from the group consisting of the following compounds:

3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonyl the amino-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6-methoxy-4-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-2-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-hydroxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butoxy-6-Tr is formetal-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(pyridine-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-fluoro-phenoxy)-6-t is iformity-pyridine-3-yl]-acrylamide.

Preferred examples of compounds according to the invention is selected from the group consisting of the following compounds:

3-(6-tert-butyl-pyridin-3-yl)-N-(3-chloro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-vinyl-benzyl)-acrylamide,

N-(3-Fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-acrylamide,

3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl)-acrylamide,

3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide and

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(6'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl)-acrylamide.

Particularly preferred compounds according to the present invention are

3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-2-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butoxy-trifloromethyl-pyridine-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide and

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-fluoro-phenoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide.

Especially preferred compounds is tions according to the present invention are

3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-vinyl-benzyl)-acrylamide,

N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-acrylamide,

3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl)-acrylamide,

3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide and

3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide.

Another preferred embodiment of the invention relates to soedinenii formula (I) or (III), to its isomer or pharmaceutically acceptable salt,

in which

X represents-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH3)=C(CH3)-, -C(C2H5)=CH-, -CH=C(C2H5)-, -CF=CH-, -CH=CF -, or C≡C;

R1denotes hydrogen, fluorine, methyl or ethyl;

R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R6denotes a C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkyl, di(C1-C3)alkylaminocarbonyl, (C1-C3) alkoxyphenyl, thienyl, pyridinyl, halogenopyrimidines, (C3-C6) cycloalkyl (C1-C3) alkoxy, phenyl (C1-C3) alkoxy, C1-C5, alkylthio, phenylthio, phenyl (C1-C3) alkylamino, arylamino, N-phenyl-N-(C1-C3)alkylamino, hydroxy(C1-C3)alkyl-N-pyrrolidinyl, C1-C2 alkoxy-N-pyrrolidinyl, (C1-C3) alkoxycarbonyl piperidyl, piperazinil or C1-C3 alkylpiperazine, and R6in one embodiment, is different from hydrogen;

R7denotes a C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, C2-C5 of alkenyl, and R7preferably represents halogen (C1-C4) alkyl;

R8and R9independently represent hydrogen, halogen or trifluoromethyl; and

R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, methyl, ethyl, cyano, ethynyl, ethinyl or trifluoromethyl;

R4denotes hydrogen, fluorine, chlorine or methyl;

R5denotes hydrogen;

R6denotes fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethinyl, methoxypropanol, diethylaminopropyl, phenyl, halogenfree, methoxyphenyl, thienyl, pyridinyl, halogenopyrimidines, methoxy, ethoxy, propoxy, butoxy, pentox, triptoreline, cyclopentane, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenfree, benzyloxy, pyridyloxy, ethylthio, propylthio, butylthio, pentylthio, phenylthio, ethylamino, propylamino, butylamino, pentylamine, methoxyethylamine, amoxicillin, methoxypropylamine, cyclobutylamine, cyclopentylamine cyclohexylamino, benzylamino, phenylamino, N,N-dimethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-phenylamino, N-methyl-phenylamino, N-pyrrolidinyl, methoxy N-pyrrolidinyl, hydroxymethyl, N-pyrrolidinyl, N-piperidyl, etoxycarbonyl N-piperidyl, piperazinil or N-morpholinyl;

R7represents isopropyl, tert-butyl or trifluoromethyl;

R8denotes hydrogen;

R9denotes hydrogen or trifluoromethyl;

R10denotes methyl; and

R11and R12denote hydrogen.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl;

R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl or ethyl;

R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, phenylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R7represents isopropyl, tert-butyl or trifluoromethyl;

R8denotes hydrogen or chlorine;

R9denotes hydrogen or trifluoromethyl;

R10 denotes methyl; and

R11and R12denote hydrogen.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R4denotes hydrogen, fluorine, chlorine or methyl;

R3denotes hydrogen, fluorine, methyl, cyano, ethynyl, ethinyl or trifluoromethyl;

R5denotes hydrogen;

R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, forfinal, thienyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3 methylbutoxy, 2,2,2-triptoreline, cyclopentane, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, phenylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, methoxyethylamine, amoxicillin, cyclopentylamine, benzylamine, phenylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, methoxy N-pyrrolidinyl, N-piperidyl or etoxycarbonyl-N-piperidyl;

R7represents isopropyl, tert-butyl or trifluoromethyl;

R8denotes hydrogen or chlorine;

R9denotes hydrogen and trifluoromethyl;

R10denotes methyl; and

R11and R12denote hydrogen.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, methyl, cyano, ethynyl or ethinyl;

R4denotes hydrogen, fluorine or methyl;

R5denotes hydrogen;

R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R7represents isopropyl, tert-butyl or trifluoromethyl;

R8and R9denotes hydrogen;

R10denotes methyl; and

R11and R12denote hydrogen.

Another preferred embodiment of the invention relates to the compound of formula (III), its isomer or pharmaceutically acceptable salt,

in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

when R4denotes fluorine, R3denotes hydrogen, fluorine, shall ethyl or ethinyl, or when R4denotes hydrogen,

R3denotes methyl;

R5denotes hydrogen;

R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R7represents isopropyl, tert-butyl or trifluoromethyl;

R8and R9represent hydrogen;

R10denotes methyl; and

R11and R12denote hydrogen.

In a preferred aspect of the present invention in the compounds of formula III, as described herein, R7refers to a group of CF3. Another variant of implementation of the present disclosure relates to compounds having formula III, as described herein, in which R7means CF2Cl or CF2CF3.

Preferred examples of compounds according to the invention is selected from the group consisting of the following compounds:

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butylamino-6-three is tormentil-pyridine-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-Deut-butylamino-6-triform the Teal-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methyl-butoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic is,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

N-(3-cyano-5-fluoro-4-IU is unsulfonated-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

(R)-3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-f the PR-4-methanesulfonamido-5-methyl-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-3-(2-benzylamino-6-trifter ethyl-pyridine-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-triptime the Il-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-3(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide and

(S)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

including their isomers, racemic mixtures and pharmaceutically acceptable salts.

Preferred examples of compounds according to the invention is selected from the group consisting of the following compounds:

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-Tr is formetal-pyridine-3-yl)-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,

(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

3-(2-butyl-6-trifter ethyl-pyridine-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-3-(2-Deut-butylamino-6-trifluoromethyl-pyridine-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,

(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-the feast of the DIN-3-yl)-acrylamide,

(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,

(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide and

(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

including their isomers, racemic mixtures and pharmaceutically acceptable salts.

Preferred examples of compounds according to the invention is selected from the group consisting of the following compounds:

(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(R)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,

3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylic is,

N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,

N-(4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3,5-debtor-4-methanesulfonamido-benzylated 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid,

[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid,

N-(4-methanesulfonamido-benzyl)-3-(-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

N-(4-atenololonline-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,

3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,

[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,

[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid and

N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,

including their isomers, racemic mixtures and pharmaceutically acceptable salts.

Another aspect of the present invention relates to compounds of formula III, their isomers or pharmaceutically acceptable salts, in which

R1denotes hydrogen or methyl;

R2denotes hydrogen;

R3denotes hydrogen, fluorine, chlorine, methyl, cyano, ethynyl or ethinyl;

R4denotes hydrogen;

R5denotes a fluorine, chlorine or methyl, preferably fluorine;

R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, forfinal, thienyl, n-prop is XI, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3 methylbutoxy, 2,2,2-triptoreline, cyclopentane, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, methoxyethylamine, amoxicillin, cyclopentylamine, benzylamine, phenylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or etoxycarbonyl N-piperidyl, and R6preferably denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R7denotes halogen (C1-C3) alkyl, preferably-CF3;

R8and R9independently represent hydrogen, halogen or trifluoromethyl, and R8preferably represents hydrogen or chlorine, and R9denotes hydrogen;

R10denotes methyl; and

R11and R12denote hydrogen.

Another aspect of the present invention refers to the compound having formula IV, its isomer or pharmaceutically acceptable salt:

formula IV,

in which

R1denotes hydrogen, methyl or ethyl;

R12denotes hydrogen or C1-C3 alkyl, preferably hydrogen or propyl;

R6denotes a C2-C6 alkyl, di(C1-C6 alkyl)amino, C1-C6 alkoxy, 2,2,2-trifter(C1-C3)alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6, alkylamino, C3-C6, cyclooctylamine, phenoxy, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl, N-phenyl-N-(C1-C5)alkylamino, methoxy-N-pyrrolidinyl or C1-C6, alkylthio;

R7means CF3, CF2Cl or CF2CF3;

and

R8and R9independently represent hydrogen, CF3or halogen.

In a particular aspect of the present disclosure, the compound of formula IV is the same as described above, in which

R1denotes hydrogen or methyl;

R6denotes a C2-C5 alkyl, C1-C4, alkylamino, methoxy or methoxyethylamine;

R7means CF3;

R8and R9represent hydrogen; and

R12denotes hydrogen.

Another aspect of the present invention refers to the compound having formula V, to its isomer or pharmaceutically acceptable salt:

formula V,

in which

R1denotes hydrogen, methyl or ethyl;

R3denotes hydrogen, fluorine or chlorine;

R6denotes a C2-C6 alkyl, di(C1-C6 alkyl)amino, C1-C6 alkoxy, 2,2,2-trifter(C1-C3)alkoxy, C1-C3 al is hydroxy (C1-C5) alkylamino, C1-C6, alkylamino, C3-C6, cyclooctylamine, phenoxy, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N-(C1-C5)alkylamino;

R7means CF3, CF2Cl or CF2CF3;

R8and R9independently represent hydrogen, CF3or halogen; and

R12denotes hydrogen or C1-C3 alkyl, preferably hydrogen or propyl.

In one particular aspect of the invention the compound of formula V is as described above, in which

R1denotes hydrogen or methyl;

R3denotes hydrogen or fluorine;

R6denotes a C2-C5 alkyl, C1-C4, alkylamino, methoxy or methoxyethylamine;

R7means CF3;

R8and R9both represent hydrogen; and

R12denotes hydrogen.

Another aspect of the present invention refers to the compound having formula VI, its isomer or pharmaceutically acceptable salt:

,

in which

W denotes hydrogen or fluorine;

X represents-CR11=CR12- or-C≡C-;

R1selected from hydrogen and C1-C3 alkyl;

R6denotes hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C10 alkoxycarbonyl, C2-C10 alkenylamine, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, PI is uridil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8 oxocyclohexyl-hydroxy, N-(C1-C5)alkoxy(C1-C5)alkyl-N-(C1-C5)alkylamino, N-(C3-C8)cycloalkyl-N-(C1-C5)alkylamino, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, heteroaryl, preferably thienyl, heteroallyl, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl;

R11and R12if they are present, are independently selected from hydrogen and C1-C3 alkyl, preferably hydrogen or propyl;

R7means CF2CF3,CF2Cl or preferably CF3;

R8and R9independently selected from hydrogen, halogen or CF3,

and

each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarboxylic, alkylamino or alkenylamine may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted who passed or substituted one or more substituents, selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,

each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy, heteroaromatic or heteroarenes may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,

every cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

each piperidyl or morpholinyl may be unsubstituted or substituted by one or more unsubstituted or substituted by halogen C1-C3-alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl.

One aspect of the present invention relates to compounds of General formula VI, as described above, in which

• R8and R9are both hydrogen, and/or

• X represents-CH=CH-, and/or

• X represents-CH=CH-, and W, R8and R9are hydrogen, and/or

• R1denotes hydrogen or methyl; and/or

• R6selected from C2-C6 alkyl, di(C1-C6 alkyl)amino, 2,2,2-trifter(C1-C3)Alcock and, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6, alkylamino, C3-C6, cycloalkenyl, phenyl, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N-(C1-C5)alkylamino, each phenyl can be substituted by one or more halogen; and/or

• R7means CF3.

Another aspect of the present invention relates to compounds of General formula VI, as described herein, in which

• R1denotes hydrogen or methyl; and/or

• R6selected from C2-C5 alkyl, C1-C4, alkylamino or methoxyethylamine, preferably R6denotes-NH-(C1-C4) alkyl or linear or branched C2-C5 alkyl; and/or

• R7means CF3; and/or

• R12denotes hydrogen.

Another preferred embodiment of the invention relates to the compound of formula VI, as described above, in which

• W, R8and R9represent hydrogen;

• X represents-CH=CH-;

• R6selected from C2-C5 alkyl, C1-C4, alkylamino or methoxyethylamine, preferably R6denotes-NH-(C1-C4) alkyl or linear or branched C2-C5 alkyl;

• R1denotes hydrogen or methyl; and

• R7means CF3.

Another aspect of the present invention relates to compounds of formula I, III, IV, V or VI, as described herein, in which R1denotes hydrogen, methyl or ethyl, preferably hydrogen or met the L. In more particular embodiments, the implementation, if R1denotes methyl or ethyl, the atom that is attached to R1is preferably in the (R)-configuration.

The compounds of formula (I), (II), (III), (IV), (V) and (VI) according to the present invention can be chemically synthesized in accordance with the following reaction schemes. However, they provided only to illustrate the invention and are not intended to limit its scope.

[Diagram 1]

Scheme 1 shows a method of synthesis acrylamide compounds with different substituents. Substituted benzylamine(1)enter into reaction with pyridinylamino acid(2)receiving benzylpenicillin(3)using DMTMM {4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium} (Tetrahedron Lett.,1999, 40, 5327).

[Scheme 2]

Scheme 2 shows a method of synthesis pyridinylamino acid(9)with different substituents. Substituted pyridinecarboxylic(7)receive by known methods. Substituted nicotinic acid(4)or ester of nicotinic acid(5)turn to the appropriate pyridinecarboxamide(7)through pyridinylmethyl alcohol(6). Pyridinylmethyl alcohol into pyridinecarboxamide(7)through oxidation under Swern. Piri is intervocalic (7)turn on air metilprednisolona acid(8)the Wittig reaction. Ether metilprednisolona acid(8)hydrolyzing potassium hydroxide, getting pyridinylamino acid(9).

[Scheme 3]

Scheme 3 shows a method of synthesis of amide pyridinylamino acid(16)with tert-butilkoi group. Substituted pyridinecarboxylic with tert-butilkoi group(12)get recovery, followed by a radical way of substitution (J. Heterocyclic Chem., 1989, 25, 45-48). Substituted ester of nicotinic acid(10)converted into the corresponding pyridine-3-methanol(11). Pyridinyl-3-methanol is introduced into reaction with trimethylhexanoic acid and silver nitrate, getting pyridinecarboxamide(12)through radical substitution by Tada. Connection(14)synthesized from compound(12)in a manner similar to that specified for the scheme 2. 4-tert-Butylpyridinium acid(14)enter into reaction with the compound(15)receiving the connection(16).

[Map 4]

Scheme 4 shows a method of synthesis of amide pyridinylamino acid(22)with triptorelin group on the pyridine. Ether 2-chloro-6-trifluoromethyl-nicotinic acid(17)enter into reaction with a cyclic secondary amine, receiving the connection(18). Connection(18) make the connection(21)a reaction similar to reaction scheme 2. Connection(21)enter into reaction with the compound(15)receiving the connection(22).

[Map 5]

Scheme 5 shows a method of synthesis of pyridinesulfonamide(28). 2-Chloro-nicotinic acid(23)enter into reaction with N,O-dimethylhydroxylamine, receiving the connection(24). Connection(24)restore'lah, receiving the connection(25)that turned into the ether metilprednisolona acid(26)the Wittig reaction. Connection(26)hydrolized using LiOH, getting pyridinylamino acid(27)which is then injected into the reaction with the compound(15)receiving the connection(28).

[6]

Scheme 6 shows a method of synthesis of ether pyridinylamino acid or pyridinylamino acid(30)or(31)2-alkylamino-group or 2-alkoxy group on the pyridine respectively. Connection(29)enter into reaction with various amines or alcohols, receiving the connection(30)or connection(31)with or without using a base, such as K2CO3or NaH.

[Diagram 7]

Scheme 7 shows a method of synthesis of pyridinesulfonamide(32)or(33)with alkylamino- (what does arylamino-) group or alkoxy group on the pyridine respectively. Connection(28)enter into reaction with various amines or alcohols, receiving the connection(32)or connection(33)with or without using a base, such as K2CO3or NaH.

[Map 8]

Scheme 8 shows a method of synthesis of pyridinesulfonamide(40)2-alkyl group on the pyridine. Complex ketoester(34)enter into reaction with the compound(35)getting alkilany ether 2-alkyl-6-trifluoromethyl-nicotinic acid(36)which is reduced to an alcohol compound(37)lithium-aluminohydrides. Oxidation under Swern connection(37)subsequent Wittig reaction receive the methyl ester of 3-(2-alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid(38). 3-(2-Alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid(39)obtained by hydrolysis of compounds(38)using LiOH, enter into reaction with the amine compound(1)receiving peridiniaceae(40)2-alkyl group on the pyridine.

[Diagram 9]

Scheme 9 shows a method of synthesis of pyridinesulfonamide(44)2-aryl or 2-heteroaryl on the pyridine. Connection(42)obtained by the reaction mix by Suzuki from the connection(41)with different baronowie acids using microwave irradiation, hydrolyzing LiOH, produces the acrylic acid (43). Acrylic acid(43)then injected into the reaction with the compound(1)receiving peridiniaceae(44)2-aryl or 2-heteroaryl group on the pyridine.

[Map 10]

Scheme 10 shows another method of synthesis of pyridinesulfonamide(49)2-alkyl group on the pyridine. Connection(46)obtained by Sonogashira reaction mix from the connection(45)with various alkynes using microwave irradiation, restore the hydrogenation getting amide Weireb(47). This amide(47)reduced to the aldehyde, and the aldehyde is subjected to the Wittig reaction, followed by hydrolysis using LiOH, getting acrylic acid(48). Acrylic acid(48)then injected into the reaction with the compound(1)receiving peridiniaceae(49)2-alkyl group on the pyridine.

[11]

Scheme 11 shows a method of synthesis of pyridinesulfonamide(53)2-alkylsulfonyl or 2-arylsulfonyl group on the pyridine. Connection(50)obtained by reaction of the compound(45)with different alkylsilane or arylthiols using NaH, restore lithium-aluminohydrides, receiving the aldehyde, and the aldehyde is subjected to the Wittig reaction, receiving the connection(51). Connection(51)hydrolysat LiOH, receiving acrylic acid(54). Acrylic acid(54)then injected into the reaction with the compound(1)receiving peridiniaceae(55)2-alkylthio or 2-aaltio group on the pyridine.

[Chart 12]

Scheme 12 shows a method of synthesis of pyridinesulfonamide(56)2-alkylsulfonyl or 2-arylsulfonyl group on the pyridine. Connection(55)oxidize mCPBA, getting peridiniaceae(56)2-alkylsulfonyl or 2-arylsulfonyl group on the pyridine.

[Diagram 13]

Scheme 13 shows a method of synthesis of pyridinesulfonamide(59)2-steriley group on the pyridine. Connection(57)received by the Heck reaction of a compound(41)using microwave irradiation, hydrolized using LiOH, getting acrylic acid(58). Acrylic acid(58)then injected into the reaction with the compound(1)receiving peridiniaceae(59)2-steriley group on the pyridine.

[Diagram 14]

Diagram 14 shows a method of synthesis of pyridinesulfonamide(64). The compound 2-chloro-nicotinic acid(23)enter into reaction with various amines, receiving nicotinic acid(60)2-alkylamino-, 2-dialkylamino-, 2-arylamino - or 2-N-alkyl-N-aryl-amino group, which subject shall indicate the reactions similar to those of scheme 5, receiving pyridinylamino acid(63). Peridiniaceae(64)then get a reaction pyridinylamino acid(63)connection Amin(1).

[Chart 15]

Scheme 15 shows another method of synthesis Olkiluoto ether 2-alkyl-6-trifluoromethyl-nicotinic acid(36). Alkilany ester 3-Amino-Ala-2-ene acid(65)enter into reaction with the compound(66)getting alkilany ether 2-alkyl-6-trifluoromethyl-nicotinic acid(36).

[Chart 16]

Scheme 16 shows another method of synthesis of methyl ester of 3-(2-alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid(38). Alkilany ether 2-alkyl-6-trifluoromethyl-nicotinic acid(36)is treated with a base, such as LiOH, getting the corresponding acid, which is injected into reaction with N,O-dimethylhydroxylamine hydrochloride, receiving the connection amide(67). Connection(67)restore using LAH, receiving the corresponding aldehyde, which is transformed into methyl ester 3-(2-alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid(38)the Wittig reaction.

[Map 17]

Scheme 17 shows a method of synthesis of benzylamine 3-pyridin-3-yl-propanolol acid(71). Weinreb amide(67)vosstanavlivayutsa using LAH, receiving the corresponding aldehyde, which in turn dibromide(68). Connection(68)treated with BuLi, then methylchloroform, receiving methyl ether 3-pyridin-3-yl-propanolol acid(69)which is then converted into 3-pyridin-3-yl-propanolol acid(70)using LiOH. Benzylated 3-pyridin-3-yl-propanolol acid(71)get response propanolol acid(70)connection Amin(1).

[Chart 18]

Scheme 18 shows a method of synthesis of pyridinesulfonamide(76). Diketone(72)enter into reaction with the compound(35)receiving pyridinylamino(73)that turned into pyridineacetonitrile(74)the reaction with diethyl ether cyanomethylphosphonate acid and NaH. 3-(2-Alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid(75)obtained by hydrolysis of pyridineacetonitrile(74)with KOH, enter into reaction with the amine compound(1)receiving peridiniaceae(76).

[Figure 19]

Scheme 19 shows a method of synthesis of acrylamide with different substituents. Substituted benzylamine(77)enter into reaction with pyridinylamino acid(2)receiving benzylpenicillin(78)using DMTMM.

The present invention also relates to the compound of formula (I), (II), (III), (IV), (V) or (VI), e is of the isomer, or its pharmaceutically acceptable salts for the prevention or treatment of disease, associated with pathological excitation and/or aberrant expression vanilloideae receptor, and this composition contains a compound of the formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

In one preferred aspect the present invention relates to the compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salts for the treatment of a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth in the Los, such as effluvium, alopecia, rhinitis, pancreatitis, vulvodynia, hemorrhagic shock, and psychiatric disorders such as anxiety or fears.

In a particularly preferred aspect the present invention relates to the compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt, where the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, other types of headaches, pain in bone cancer, mastalgia and visceral pain.

The present invention also relates to pharmaceutical compositions containing a compound of the formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt as an active ingredient together with a pharmaceutically acceptable carrier.

The present invention also relates to pharmaceutical compositions for the prevention or treatment of diseases associated with pathological excitation and/or aberrant expression vanilloideae receptor, and this composition contains a compound of the formula (I), (II), (III), (IV), (V) or (VI), and the Omer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

In one preferred aspect the present invention relates to pharmaceutical compositions containing a compound of the formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt for the treatment of a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis, vulvodynia, hemorrhagic shock, and psychiatric disorders, such as anxiety or fears.

In a particularly preferred aspect the present invention relates to FA the pharmaceutical composition, containing the compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt for the treatment of pain, as described above, and the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, other types of headache, pain associated with bone cancer, mastalgia and visceral pain.

The present invention also relates to pharmaceutical compositions containing a compound of the formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt, which differs in that it is adapted for oral administration.

In another aspect, the present invention relates to a method of inhibiting the binding vanilloideae ligand with vanilloid receptor in a patient, comprising introducing cells expressing vanilloideae receptor in the patient's body in contact with the compound of the formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt.

In another aspect, the present invention also relates to a method for prevention or treatment of a condition selected from the group consisting of the C pain, inflammatory diseases of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis, vulvodynia, hemorrhagic shock, and psychiatric disorders such as anxiety or fears, which includes the introduction of a mammal, including human, a therapeutically effective amount of the compounds of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt.

In a particularly preferred aspect the present invention relates to a method of treating pain by introducing the compounds of formula (I), (II), (III), (IV), (V) or (I), its isomer or its pharmaceutically acceptable salt, as described above, and the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, other types of headache, pain in bone cancer, mastalgia and visceral pain.

In another aspect, the present invention relates to the use of compounds of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt to obtain drugs for prevention or treatment of a condition that is associated with aberrant expression and/or aberrant activation vanilloideae receptor.

In another aspect, the present invention relates to the use of compounds of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt in obtaining drugs for prevention or treatment of a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis, vulvodynia, hemorrhagic shock, and psychiatric disorders such as anxiety or fears.

In a particularly preferred aspect the present invention relates to the use of compounds of formula (I), (II), (III), (IV), (V) or (VI), its isomer to obtain drugs for prevention or treatment of pain, as described above, and the condition is a pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (on the tea fibromyalgia, myofascial pain syndrome and back pain), migraine, other types of headache, pain in bone cancer, mastalgia and visceral pain.

The present invention also relates to a method for producing compounds represented by formula (III):

,

(III)

which includes the introduction in the reaction of the compound represented by the formula (IIIa):

(IIIa),

with a compound represented by the formula (IIIb):

(IIIb),

in which

R1,R2, R3, R4, R5R6, R7, R8, R9, R10,R11and R12are as described in any of the previous embodiments.

One preferred aspect of the present invention relates to a method for obtaining compounds of formula (III), in which the reaction is carried out in the presence of the agent combinations.

Another preferred aspect of the present invention relates to a method for obtaining compounds of formula (III), in which the agent combinations selected from the group consisting of DCC (N,N-dicyclohexylcarbodiimide), EDCI {1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)} and DMTMM {4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride}.

The present invention also relates to a method for obtaining compounds of formula (IIIc):

(IIIc),

which includes a step of recovery of the compounds of formula (III).

One preferred aspect of the present invention relates to a method for obtaining compounds of formula (IIIc)in which stage of recovery is carried out in the presence of hydrogen gas and palladium on carbon.

Another preferred aspect of the present invention relates to a method for obtaining compounds of formula (III) or (IIIc)in which R1, R11and R12denote hydrogen.

Another preferred aspect of the present invention relates to a method for obtaining compounds of formula (III) or (IIIc)in which R1, R2, R8, R11and R12denote hydrogen; R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl; R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl; R6denotes hydrogen, fluorine, chlorine, bromine, methyl, methoxy, diethylamino, pyrrolidinyl, piperidyl or morpholinyl; R7represents isopropyl, tert-butyl or trifluoromethyl; R9denotes hydrogen or trifluoromethyl; and R10denotes methyl.

The present invention also relates to a new compound of the formula (IIId):

Formula (IIId),

in which

W denotes hydrogen or fluorine;

R1means in Gorod or C1-C3 alkyl, preferably methyl; and

R10denotes a C1-C3 alkyl, C2-C3 of alkenyl or halo C1-C3 alkyl, preferably methyl;

provided that if R1denotes hydrogen and R10denotes methyl, then W denotes fluorine.

Particular examples of compounds of formula (IIId) are:

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt,

(R)-N-[4-(1-amino-propyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt,

N-(4-aminomethyl-2,3,6-Cryptor-phenyl)-methanesulfonamide, HCl salt,

(R)-N-[4-(1-amino-ethyl)-2,3,6-Cryptor-phenyl]-methanesulfonamide, HCl salt,

(R)-N-[4-(1-amino-propyl)-2,3,6-Cryptor-phenyl]-methanesulfonamide, HCl salt,

N-(4-aminomethyl-2,6-debtor-phenyl)-tinsulanond, HCl salt,

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-tinsulanond, HCl salt,

(R)-N-[4-(1-amino-propyl)-2,6-debtor-phenyl]-tinsulanond, HCl salt,

N-(4-aminomethyl-2,3,6-Cryptor-phenyl)-tinsulanond, HCl salt,

(R)-N-[4-(1-amino-ethyl)-2,3,6-Cryptor-phenyl]-tinsulanond, salt HCl or

(R)-N-[4-(1-amino-propyl)-2,3,6-Cryptor-phenyl]-tinsulanond, HCl salt.

Another aspect of the present invention relates to the use of compounds of formula (IIId), as described above, as an intermediate connection in the connection of VR1 ligand, preferably the General formula I, III or most preferably VI, as described in this application, in which W denotes hydrogen or fluorine.

1denotes a C1-C3 alkyl, preferably methyl,

including:

(a) introducing the compound of formula (IIIe)

Formula (IIIe),

in which W has the meaning given above,

in the reaction with the compound of the formula (IIIf)

Formula (IIIf),

in which A represents I or Br, in the presence of acid in the solvent, to obtain the compounds of formula (IIIg)

Formula (IIIg),

where W and A are as defined above;

(b) introducing the compound of Formula (IIIg) in the reaction with the compound of the formula (IIIh)

Formula (IIIh),

in which R13denotes hydrogen or C1-C2 alkyl, preferably hydrogen, in the presence of a catalyst and a ligand in a solvent, to obtain the compounds of formula (IIIi)

Formula (IIIi),

in which W and R1are as defined above;

(c) introducing the compound of formula (IIIi) in the reaction with the compound of Formula (IIIj)

Formula (IIIj),

in which R10is the same as defined above, in the presence of a base in a solvent, then NaOH in a solvent, to obtain the compounds of formula (IIIk)

Formula (IIIk),

in which W, R1and R10are as defined above;

(d) introducing the compound of the Formula (IIIk) in the reaction with (R)-(+)-2-methyl-2-propanesulfinamide in the presence of acid in the solvent, then NaBH4in solvent and then HCl in a solvent, to obtain the compounds of Formula (IIId)in which W and R10are as defined above, and R1denotes a C1-C3 alkyl, preferably methyl.

Another variant of implementation of the present invention relates to a method for obtaining compounds of formula (IIId)in which R1denotes hydrogen,

including:

(a) introducing the compound of formula (IIIg)

Formula (IIIg),

where W and A are as defined above, in a reaction with CuCN in a solvent to obtain compounds of formula (IIIm)

Formula (IIIm),

in which W is as defined above;

(b) introducing the compound of formula (IIIm) in the reaction with the compound of formula (IIIj)

Formula (IIIj),

in which R10is the same as defined above, in the presence of a base in a solvent, then NaOH in a solvent, to obtain the compounds of formula (IIIn)

Formula (IIIn),

in which W and R10are as defined above;

c) introducing the compound of formula (IIIn) in the reaction with hydrogen in the presence of a catalyst and an acid in a solvent to obtain compounds of Formula (IIId)

Formula (IIId),

in which W and R10are such as is defined above, and R1denotes hydrogen.

Next will be described how to construct and types of excipients, but the present invention is not limited.

The compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt according to the present invention can be obtained in the form of a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like, for Example, the compounds according to the present invention can be dissolved in oils, propylene glycol or other solvents that are typically used to obtain compositions for injection. Suitable examples of carriers include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropylmyristate etc. For topical introduction of the compounds according to the present invention can be made in the form of ointment or cream.

The connection according to the present invention can also be used in the form of pharmaceutically acceptable salts and can be used individually or in combination, or in a mixture with other pharmaceutically active compounds.

Compounds according to the present invention can be prepared in injectable formulations by dissolution, suspension or emulsification in water-soluble solvent, t is lump as saline and 5%dextrose, or water-insoluble solvents, such as vegetable oil, synthetic fatty acid glycerides, esters of higher fatty acids and propylene glycol. The compositions according to the invention can include any of the conventional additives, such as solvents, isotonic means suspendresume agents, emulsifying agents, stabilizers and preservatives.

The preferred dose level of the compounds according to the present invention depends on various factors, including the condition and body weight of the patient, the severity of the particular disease, dosage form, route and period of administration, but may accordingly be selected by a specialist. Compounds according to the present invention is preferably introduced in an amount of from 0.001 to 100 mg/kg of body weight per day and more preferably from 0.01 to 30 mg/kg of body weight per day. Dose can be administered once a day or several times a day split dose. Compounds according to the present invention used in the pharmaceutical composition in amounts of 0.0001~10% by weight and preferably about 0.001 to about 1% by weight in relation to the total amount of the composition.

The pharmaceutical composition according to the present invention can be administered to a mammal such as rat, mouse, Pets, people and the like, in various ways. Methods of administration include oral and rect the aspects of the introduction; intravenous, intramuscular, subcutaneous, intrauterine, dural and intracerebroventricular injection.

Detailed description of the definition of invention

When describing the compounds, pharmaceutical compositions containing such compounds, methods of using such compounds and compositions and use of such compounds and compositions, all terms used in this application have the meanings commonly used by specialists, for example, pharmchemical, pharmacologists or physicians. As an example, some definitions of specific groups are given below:

"Alkyl" includes monovalent saturated aliphatic hydrocarbon group. The hydrocarbon chain may be straight or branched. "Alkyl" is preferably 1-15 carbon atoms (“C1-C15 alkyl”), more preferably 1-10 carbon atoms (“C1-C10 alkyl”), more preferably 1-8 carbon atoms (“C1-C8 alkyl), or 1-6 carbon atoms (“C1-C6 alkyl”), and in some cases, even more preferably 1-5 carbon atoms (“C1-C5 alkyl”), 1-4 carbon atoms (“C1-C4 alkyl), or only 1-3 carbon atoms (“C1-C3 alkyl”). This term is illustrated by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tert-amyl, etc.

"Alkoxy" includes the group-OR where R refers to "alkyl"as defined above. Private p is emery alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentox, 1,2-Dimethylbutane etc.

“Alkoxyalkyl” refers to the group-OROR', in which R and R' are the same or different alkyl" groups as defined above.

“Alkoxyalkyl” refers to the group-ROR'OR"in which R, R' and R" are the same or different alkyl" groups as defined above.

“Alkoxyalkyl” refers to the group-NH(ROR'), where R and R' are the same or different alkyl" groups as defined above.

"N-Alkoxyalkyl-N-alkylamino" refers to the group-NR(R'OR"), in which R, R' and R" are the same or different alkyl" groups as defined above.

“Alkoxyalkyl” refers to the groupin which n denotes an integer from 0 to 8, and R stands for "alkyl" group as defined above.

“Dialkylaminoalkyl” refers to the groupin which n denotes an integer from 0 to 8, and R and R' are the same or different alkyl" groups as defined above.

“Alkoxycarbonyl” refers to the radical-C(=O)-O-R, in which R stands for "alkyl" group as defined above.

"Alkenyl" includes monovalent alafinova unsaturated hydrocarbon group which is straight or branched and is Elsie at least 1 double bond. "Alkenyl" is preferably 2-15 carbon atoms (“C2-C15 of alkenyl”), more preferably 2-10 carbon atoms (“C2-C10 of alkenyl”), even more preferably 2-8 carbon atoms (“C2-C8 of alkenyl”) or 2 to 6 carbon atoms (“C2-C6 of alkenyl”), and in some cases even more preferably 2-5 carbon atoms (“C1-C5 of alkenyl”), 2-4 carbon atoms (“C2-C4 of alkenyl”) or only 2-3 carbon atoms (“C2-C3 of alkenyl”). Examples alkenyl groups include ethynyl (-CH=CH2), n-propenyl (-CH2CH=CH2), Isopropenyl (C(CH3)=CH2), etc. Preferred "alkenylphenol" group is ethynyl (vinyl).

"Quinil includes acetylene unsaturated hydrocarbon group which is straight or branched and having at least 1 triple bond. “Quinil” is preferably 2-15 carbon atoms (“C2-C15 quinil”), more preferably 2-10 carbon atoms (“C2-C10 quinil”), even more preferably 2-8 carbon atoms (“C2-C8 quinil”) or 2 to 6 carbon atoms (“C2-C6 quinil”), and in some cases even more preferably 2-5 carbon atoms (“C1-C5 quinil”), 2-4 carbon atoms (“C2-C4 quinil”) or only 2-3 carbon atoms (“C2-C3 quinil”). Preferred alkenylphenol group is ethinyl (acetylenyl).

"Alkylamino" includes the group-other', in which R' is the alkyl groups defined here.

"Dealkylase what about" includes the group-NR'r R", in which R' and R" are alkyl groups defined here.

"Alkylsulfonyl" includes a radical-S(O)2R, in which R denotes alkyl groups defined here. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.

"Alkylthio" includes a radical-S-R, in which R denotes an alkyl group, defined herein, which may be substituted, as defined here. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio etc.

"Amino" refers to the radical-NH2.

"Aryl" refers to aromatic hydrocarbon radical. Examples of "aryl" radicals are phenyl, naphthyl, indenyl, azulene, fluorine or anthracene, and phenyl is preferred.

"Arylamino" refers to the group-NHAr, in which Ar represents "aryl" group as defined above.

"Aryloxy" refers to the group-OAr, in which Ar represents "aryl" group as defined above.

"Carboxy" refers to the radical-C(=O)HE.

"Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon groups. The number of C-atoms specified in this cycloalkyl group corresponds to the number of forming a ring of carbon atoms, for example, “C3-C6 cycloalkyl” refers to cycloalkyl with Chi is scrap forming the ring C-atoms from three to six. Examples of "cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. If marked, "cycloalkyl" group can be unsubstituted or substituted by one or more alkyl groups, for example, C1-C6 alkyl groups, preferably C1-C3 alkyl groups, particularly preferably methyl groups. If "cycloalkyl" bears more than one alkyl substituent, these substituents may be attached to the same or different forming ring carbon atoms.

"Cycloalkane" refers to the group-OR, in which R stands for "cycloalkyl" groups defined above.

“Cycloalkenyl” refers to the group-other, in which R stands for "cycloalkyl" groups defined above.

"N-Cyclooctylamino-N-alkylamino" refers to the group-NRR'where R are identical or different alkyl" groups as defined above, and R' are cycloalkenyl" groups defined above.

"N-aryl-N-alkylamino" refers to the group-NRAr, in which Ar represents "aryl" group as defined above, and R stands for "alkyl" group as defined above.

“Oxocyclohexyl” refers to a cyclic saturated aliphatic hydrocarbon groups with one oxygen atom in any position in the ring. The number of C-atoms specified in this oxocyclohexyl group, ACC is tstuat number forming ring carbon atoms, for example, “C3-C6 oxocyclohexyl” refers to oxocyclohexyl with those forming the ring C-atoms from three to six and one atom of O. Examples of “oxocyclohexyl are oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl etc. If marked, “oxocyclohexyl” group can be unsubstituted or substituted by one or more alkyl groups, for example, C1-C6 alkyl groups, preferably C1-C3 alkyl groups, particularly preferably methyl groups. If “oxocyclohexyl” bears more than one alkyl substituent, these substituents may be attached to the same or different forming ring carbon atoms.

"Oxocyclohexyl-hydroxy" refers to the group-OR, in which R stands for “oxocyclohexyl” groups defined above.

"Cyano" refers to the radical-C≡N.

"Ethynyl" refers to-CH=CH2that is also defined in this application as "vinyl".

"Ethinyl" refers to-C≡CH.

"Halogen" refers to fluorine, chlorine, bromine and iodine. A preferred group of halogen are fluorine or chlorine.

“Halogenated” includes "alkyl" group as defined above, substituted by one or more halogen, which may be the same, for example, trifluoromethyl or pentaborate, or may be different.

"Heteroaryl" refers to the Aro is eticheskoi ring system, containing at least one heteroatom such as O, S or N. Examples of heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazines, indolinyl, indolyl, isoindolyl, benzofuranyl, benzothiophene, benzoimidazole, benzothiazole, purinol, hintline, chinoline, ethenolysis, hemolysins, pteridinyl, carbazolyl, and adnakolava system, and in particular pyridinyl and imidazolyl, are preferred.

“Heteroarenes” refers to the group-NHAr', where Ar' is a "heteroaryl" group, as defined above.

“Heteroaromatic” refers to the group-OAr', where Ar' is a "heteroaryl" group, as defined above.

"Hydroxy" refers to-IT.

"Hydroxyalkyl" includes "alkyl" group as defined above, substituted by one or more hydroxyl groups.

"Nitro" refers to the radical-NO2.

“Alkylpiperazine” refers to the piperazine ring, which is "alkyl" as Deputy, and piperazinilnom ring preferably is associated with "alkyl", and with the second position of the accession through the nitrogen atoms.

“Piperazinil includes piperazinilnom ring, which can b is to be connected via any C-atom, and through the nitrogen atom, and preferred is a binding through one of the nitrogen atoms.

“Pyrrolidinyl” includes ring pyrrolidine, which may be connected via any C-atom, as well as through the nitrogen atom, and preferred is a binding via its nitrogen atom.

“Morpholinyl includes morpholino ring, which may be connected via any C-atom, as well as through the nitrogen atom, and preferred is a binding via its nitrogen atom.

“Pyridinyl” includes ring {kernel} pyridine, which may be connected to any C-atom as well as its nitrogen atom.

Any "alkyl", "alkenyl", “quinil”, "aryl", "heteroaryl", "cycloalkyl", “piperazinil”, “piperidyl”, “morpholinyl” or “pyrrolidinyl”, also as part of larger groups, such as "alkoxy", “alkylsulfonyl”, “alkenylacyl”, “aryloxy”, “heteroaromatic”, “cycloalkenyl”, etc. may be unsubstituted or substituted by one or more groups. Suitable substituents are, for example, halogen, hydroxyl, unsubstituted or substituted by halogen C1-C5 alkoxy, unsubstituted or substituted one or more times with stands and/or halogen, C3-C8 cycloalkyl, C1-C5 alkyl, halogen (C1-C5) alkyl, amino, cyano or nitro. Unless explicitly stated otherwise, any "alkyl", "alkenyl", “quinil”, "aryl", "heteroaryl", "cycloalkyl", “PI is arsenil”, “piperidyl”, “morpholinyl” or “pyrrolidinyl” (as part of a larger group) is preferably unsubstituted.

"Isomer" includes especially optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers and their mixtures), as well as conformational isomers (isomers that differ only in their corners of the at least one chemical bond), isomers provisions (especially the tautomers and geometric isomers (for example, the isomers CIS-TRANS).

“Essentially pure”, for example, in respect of the enantiomers or diastereomers, means at least about 90%, preferably at least about 95%, more preferably at least about 97, or at least about 98%, even more preferably at least about 99%, and especially preferably at least approximately 99,5% (weight/weight) of the compounds, for example, a particular enantiomer or diastereoisomer.

"Pharmaceutically acceptable" means not shown significant toxic effects when used in doses commonly used in medical purposes, and in a way that can be tested or preferably may be approved by the regulatory authority of the Federal government or the state government, or which is first included in the U.S. Pharmacopoeia or other generally recognized Pharmacopoeia for use in animals, and more specifically on the person.

"Pharmaceutically acceptable salt" refers to salts of the compounds according to the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compounds. Such salts include: (1) salt accession acid, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethane-desulfonema acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tertiary Butylochka KIS the PTA, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or (2) salts formed by the replacement of a proton acid, present in the parent connection.

"Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or media, which enter the connection according to the invention.

"Preventing" or "prevention" refer to the reduction of the risk of acquiring diseases or disorders (i.e., the prevention of the development of the person who may be exposed to or predisposed to the disease but have yet to experience or do not show symptoms of the disease, at least one of the clinical symptoms of the disease to disease, but have yet to experience or shows symptoms of the disease).

"Patient" includes humans. The terms "person," "patient" and "person" are used interchangeably.

"Therapeutically effective amount" means an amount of compound that, when administered to a patient for treating a disease, is sufficient to effect the treatment of the disease. "Therapeutically effective amount" can vary depending on the compound, the disease and its severity and the age, body weight, etc. of the patient.

Treatment of disease or disorders of the worn, in one embodiment, the improvement in the disease or disorder (i.e. stop or weaken the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to the improvement in at least one physical parameter, which may not be discernible by the patient. In yet another embodiment, "treatment" refers to the correction of diseases or disorders physically (for example, stabilization of discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treatment" refers to delaying the onset of diseases or disorders.

The method of carrying out the invention

The present invention is more specific due to the following examples and experimental examples. However, it should be understood that the scope of the present invention is not limited to the following examples and experimental examples.

Example 1: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: Synthesis of 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid

To a solution of 6-tert-butyl-pyridine-3-carboxaldehyde (1,34 g is 8.75 mmol), obtained in accordance with known procedure, in toluene was added meth is l(triphenylphosphonium)acetate (2,93 g), and the resulting mixture was heated at 90°C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=4/1)to give the ester product (1.56 g, 81%). The obtained ester was dissolved in 1,4-dioxane, treated with water and KOH were stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed simple ether. The aqueous phase was acidified using 1N. HCl and then was extracted with CHCl3, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (1.00 g, 68%).

1H NMR (300 MHz, CDCl3): δ 8,78 (d, 1H, J=2.1 Hz), to 7.84 (DD, 1H, J=2.1 and 8.4 Hz), 7,78 (d, 1H, J=16.2 Hz), 7,42 (d, 1H, J=8,4 Hz), 6,53 (d, 1H, J=16.2 Hz), 1,40 (c, 9H).

Stage 2: Synthesis of 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (50 mg, 0.20 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (40 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-meanswhen is a melamine-benzyl)-acrylamide (75 mg, 92%).

1H NMR (300 MHz, CDCl3): δ to 8.70 (d, 1H, J=2.1 Hz), to 7.77 (DD, 1H, J=2.1 and 8.1 Hz), to 7.64 (d, 1H, J=15.6 Hz), of 7.48 (m, 1H), 7,38 (d, 1H, J=8,4 Hz), 7,13 (m, 2H), 6,77 (c, 1H), 6,51 (d, 1H, J=15.6 Hz), to 6.43 (t, 1H), 4,54 (d, 2H, J=6,0 Hz), to 3.02 (c, 3H), 1,38 (c, 9H).

ESI [M+H]+: 406,2.

Example 2: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-chloro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-chloro-phenyl)-methanesulfonamide, HCl salt (100 mg, 0.35 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (70 mg)to give 3-(6-tert-butyl-pyridin-3-yl)-N-(3-chloro-4-methanesulfonamido-benzyl)-acrylamide (110 mg, 74%) after purification by chromatography on columns (Hex/EtOAc=1/2).

1H NMR (300 MHz, CDCl3): δ 8,66 (d, 1H, J=2.1 Hz), 7,74 (DD, 1H, J=2.1 and 8.1 Hz), to 7.64 (d, 1H, J=15.6 Hz), EUR 7.57 (d, 1H, J=8.7 Hz), 7,41 (d, 1H, J=2.1 Hz), was 7.36 (d, 1H, J=8.1 Hz), 7.24 to (DD, 1H, J=2.1 and 8.7 Hz), 6,82 (c, 1H), 6.48 in (d, 1H, J=15.6 Hz), 6.42 per (t, 1H), 4.53-in (d, 2H, J=6.0 Hz), 3.00 and (c, 3H), 1,37 (c, 9H).

ESI [M+H]+: 422,2.

Example 3: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (70 mg, 0.25 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (52 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) 3-(6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (63 mg, 64%).

1H NMR (300 MHz, CDCl3): δ 871 (d, 1H, J=2.4 Hz), 7,76 (DD, 1H, J=2.4 and 8.4 Hz), 7,63 (d, 1H, J=16.0 Hz), 7,39 (d, 1H, J=8,4 Hz), 7,28 (c, 1H), 7,16 (DD, 1H, J=2,1 and 11.0 Hz), 6,64 (c, 1H), of 6.52 (d, 1H, J=16.0 Hz), 6,47 (t, 1H), 4,51 (d, 2H, J=6,0 Hz), 3.45 points (c, 1H), 3,24 (c, 3H), 1,38 (c, 9H).

ESI [M+H]+: 430,1.

Example 4: 3-(6-tert-butyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-vinyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-vinyl-phenyl)-methanesulfonamide, HCl salt (70 mg, 0.28 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (52 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) 3-(6-tert-butyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-vinyl-benzyl)-acrylamide (62 mg, 54%).

1H NMR (300 MHz, CDCl3): δ 8,66 (d, 1H, J=1.8 Hz), 7,74 (DD, 1H, J=2.1 and 8.4 Hz), 7,63 (d, 1H, J=16.0 Hz), 7,44 (d, 1H, J=2.1 Hz), was 7.36 (m, 2H), 7.23 percent (m, 2H), 6.90 to (DD, 1H, J=11.0 and of 17.0 Hz), 6,70 (c, 1H), 6.48 in (d, 1H, J=16.0 Hz), 6,40 (t, 1H), 5,70 (d, 1H, J=17,0 Hz), 5,43 (d, 1H, J=11.0 in Hz)of 4.54 (d, 2H, J=5.7 Hz), 2,98 (c, 3H), 1,37 (c, 9H).

ESI [M+H]+: level of 414.2.

Example 5: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (100 mg, 0.40 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (121 mg)obtained in accordance with known procedure, getting after purification by chromatography on columns (CH2Cl2/MeOH=20/1) N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (118 mg, 66%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ 9,13 (c, 1H), 8,32 (t, 1H), of 7.96 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=15,9 Hz), 7,56 (t, 1H, J=8,4 Hz), 7,38 (d, 1H, J=7.8 Hz), 7,26 (m, 2H), 6,80 (d, 1H, J=15,9 Hz), 4,63 (d, 2H, J=5.7 Hz), 3,98 (m, 4H), 3.46 in (m, 4H), 3,13 (c, 3H).

ESI [M+H]+: 503,1.

Example 6: N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-vinyl-phenyl)-methanesulfonamide, HCl salt (70 mg, 0.27 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (81 mg)to give after purification by chromatography on columns (CH2Cl2/MeOH=20/1) N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (55 mg, 45%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ 8,92 (c, 1H), 8,18 (c, 1H), of 7.97 (d, 1H, J=7.8 Hz), 7,83 (d, 1H, J=16.0 Hz), 7,73 (c, 1H), 7,44 (m, 3H), 7,33 (DD, 1H, J=11.0 and of 17.0 Hz), 6,83 (d, 1H, J=16.0 Hz), to 5.93 (d, 1H, J=17,0 Hz), 6,55 (d, 1H, J=to 11.0 Hz), 4,69 (d, 2H, J=5,1 Hz)to 4.01 (m, 4H), to 3.50 (m, 4H), 3,09 (c, 3H).

ESI [M+H]+: 511,1.

Example 7: N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-chloro-phenyl)-methanesulfonamide, HCl salt (62 mg, 0.22 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg)to give after purification by chromatography on columns (CH2Cl2/MeOH=20/1) N-(3-chloro-4-m is consultonline-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (93 mg, 91%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ of 8.37 (c, 1H), 8,27 (t, 1H), to 7.99 (d, 1H, J=7.8 Hz), 7,86 (d, 1H, J=15,9 Hz), 7,72 (d, 1H, J=8,4 Hz), a 7.62 (m, 1H), 7,44 (m, 2H), at 6.84 (d, 1H, J=15,9 Hz), and 4.68 (d, 2H, J=5.7 Hz), Android 4.04 (m, 4H), 3,52 (m, 4H), 3,19 (c, 3H).

ESI [M+H]+: 519,1.

Example 8: N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (100 mg, 0.35 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (116 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (120 mg, 74%).

1H NMR (300 MHz, CDCl3): δ 7,76 (d, 1H, J=7.8 Hz), 7,71 (d, 1H, J=15.6 Hz), 7,24 (m, 3H), 6.42 per (d, 1H, J=15.6 Hz), 6,32 (c, 1H), the 6.06 (t, 1H), 4,59 (d, 2H, J=6.3 Hz), 3,85 (m, 4H), to 3.34 (m, 4H), 3,05 (c, 3H), of 2.25 (d, 3H, J=2.1 Hz).

ESI [M+H]+: 517,1.

Example 9: 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (17,8 mg, 0,052 mmol) were introduced in the reaction with 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-acrylic acid (12 mg), DMTMM (1.1 EQ., 16 mg) and NMP (1.2 EQ., 90 μl) in THF (THF)to give after purification by chromatography on columns (Hex/EtOAc=3/2) of the target compound (14 mg, 61.8 percent).

1H NMR (300 MHz, CDCl 3): δ of 7.70 (d, 1H, J=15.6 Hz), to 7.61 (d, 1H, J=9.3 Hz), 7,51 (m, 1H), 7,13 (m, 2H), 6.90 to (d, 1H, J=7.8 Hz), at 6.84 (d, 1H, J=15.6 Hz), 6,61 (c OSiR., 1H), 6,10 (c OSiR., 1H), 4,54 (d, 2H, J=6 Hz), 4,01 (c, 3H), 3,02 (c, 3H), 1,33 (c, 9H).

ESI [M+H]+: 436,1.

Example 10: 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt (84 mg, 0.30 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (62 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) 3-(6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-acrylamide (34 mg, 26%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ 8,68 (d, 1H, J=2.4 Hz), 8,09 (c, 1H), 7,78 (DD, 1H, J=2.1 and 8.4 Hz), to 7.61 (c, 1H), 7,56 (d, 1H, J=15,9 Hz), 7,35 (d, 1H, J=8,4 Hz), 7,33 (c, 1H), 7,12 (DD, 1H, J=14,8 and of 18.0 Hz), 7,01 (DD, 1H, J=1.8 and 10,2 Hz), 6,60 (d, 1H, J=15,9 Hz), 5,73 (d, 1H, J=18,0 Hz), 5,33 (d, 1H, J=11,4 Hz), 4,46 (d, 2H, J=6.0 Hz), 2,97 (d, 3H, J=0.9 Hz), 1,34 (c, 9H).

ESI [M+H]+: 432,2.

Example 11: 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (to 82.4 mg, 0.30 mmol) were introduced in the reaction with 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-acrylic acid (66 mg), DMTMM (1.1 EQ., 90 mg) and NMP (1.2 EQ., 40 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (51,2 mg, 37.6 per cent).

p> 1H NMR (300 MHz, CDCl3): δ of 7.70 (d, 1H, J=15,9 Hz), a 7.62 (d, 1H, J=8,4 Hz), 7,30 (c, 1H), 7,17 (m, 1H), 6,91 (d, 1H, J=7.8 Hz), 6,69 (d, 1H, J=15.6 Hz), 6,41 (c, 1H). of 6.02 (c OSiR., 1H), 4.53-in (d, 2H, J=6 Hz), was 4.02 (c, 3H), 3,47 (c, 1H), 3,26 (c, 3H), 1,34 (c, 9H).

ESI [M+H]+: 460,1.

Example 12: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (100 mg, 0.22 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (108 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (190 mg, 100%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ 9,31 (c, 1H), 8,73 (t, 1H), 7,92 (d, 1H, J=7.8 Hz), 7,49 (d, 1H, J=15.6 Hz), 7,31 (d, 1H, J=7.8 Hz), 7,25 (c, 1H), 7,18 (d, 1H, J=10,8 Hz), of 6.71 (d, 1H, J=15.6 Hz), to 4.38 (d, 2H, J=5.7 Hz), 4,14 (c, 1H), 3,76 (m, 4H), up 3.22 (m, 4H), 3.04 from (c, 3H).

ESI [M+H]+: 527,2.

Example 13: 2-(2-piperid-1-yl-6-chloro-pyridinyl-3-yloxy)-N-(3-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide, HCl salt (32 mg, 0.12 mmol) and NMP (0.05 ml) was added in 20 ml of THF. The mixture was stirred for 10 minutes. To the mixture was added DMTMM (51 mg, 0.18 mmol) and 2-(2-piperid-1-yl-6-chloro-pyridine-3-yloxy)-acetic acid (20 mg, 0,092 mmol). The reaction mixture was peremeshivayu throughout the night. The reaction solvent was removed in vacuum. The residue was extracted with ethyl acetate (30 ml × 3) and H2O (30 ml). The combined organic layer was washed a feast upon. NaHCO3(30 ml) and brine (30 ml), dried using MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns, receiving solid white (11 mg).

1H NMR (CDCl3, 300 MHz) δ 7,87 (d, J=15,9 Hz, 1H), 7.62mm (d, J=9.0 Hz, 1H), 7,51 (t, J=7.8 Hz, 1H), 7,12 (m, 2H), 6,39 (user., 1H), 6,51 (d, J=9.0 Hz, 1H), 6,20 (d, J=15.6 Hz), 6,00 (user., 1H), of 5.53 (d, J=6.3 Hz, 2H), 3,60 (m, 4H), 3,01 (c, 3H), of 1.65 (m, 6H).

ESI [M+H]+: 467,1.

Example 14: 3-(6-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: methyl ester of 3-(6-chloro-pyridine-3-yl)-acrylic acid

To 6-chloro-pyridine-3-carboxaldehyde (300 mg, 2,12 mmol) in toluene was added methyl(triphenylphosphonium)acetate (708 mg, 2,12 mmol) and the solution was heated under reflux for 6 hours. The reaction mixture was diluted with EtOAc and then washed three times H2O, brine, dried Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was chromatographically on the column, getting the methyl ester of 3-(6-chloro-pyridine-3-yl)-acrylic acid (380 mg, 90%).

1H NMR (300 MHz, CDCl3): δ 8,51 (d, 1H, J=2.7 Hz), 7,80 (DD, 1H, J=8,1, 2.4 Hz), 7,65 d, 1H, J=15,9 Hz), was 7.36 (d, 1H, J=8,4 Hz), 6.48 in (d, 1H, J=15,9 Hz), 3,83 (c, 3H).

Stage 2: 3-(6-chloro-pyridine-3-yl)-acrylic acid

Methyl ester of 3-(6-chloro-pyridine-3-yl)-acrylic acid (107 mg, 0,541 mmol) in THF was added to a solution of 0,5h. LiOH (2 EQ.), and the mixture was stirred for 3 hours at room temperature. The obtained residue was dissolved in H2O and then washed three times Et2O, neutralize 1H. HCl to pH 5~7. The obtained solid was filtered and washed with H2O, and then dried in vacuum, obtaining 3-(6-chloro-pyridine-3-yl)-acrylic acid (80 mg, 80%).

1H NMR (300 MHz, DMSO-d6): δ 8,64 (c, 1H), 8,16 (d, 1H, J=8.1 Hz), 7,54 (d, 1H, J=16,8 Hz), 7,50 (d, 1H, J=9.9 Hz), 6,63 (d, 1H, J=15,9 Hz).

Stage 3: 3-(6-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (to 78.3 mg, 0,272 mmol) suspended in THF and treated with triethylamine (30 mg, 0,299 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 3-(6-chloro-pyridine-3-yl)-acrylic acid (50 mg, 0,272 mmol), then after 10 minutes, DMTMM (82 mg, 0,299 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(x2), brine and then dried over Bezbog. Na2SO4,2Cl2), obtaining the target compound (26 mg, 23%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c, 1H), total of 8.74 (t, 1H, J=6.0 Hz), 8,61 (d, 1H, J=2.4 Hz), 8,07 (DD, 1H, J=8,4, 2.4 Hz), 7,56 (d, 1H, J=8,4 Hz), 7,51 (d, 1H, J=15,9 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=12.0 Hz), 7,12 (d, 1H, J=8,4 Hz), 6,79 (d, 1H, J=15,9 Hz), 4,39 (d, 2H, J=5.7 Hz), 3.00 and (c, 3H).

ESI [M+H]+: 408,0.

Example 15: 3-(6-bromo-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: methyl ester of 3-(6-bromo-pyridin-3-yl)-acrylic acid

To 6-bromo-pyridine-3-carboxaldehyde (300 mg, of 1.61 mmol) in toluene was added methyl(triphenylphosphonium)acetate (647 mg, 1.94 mmol) and the solution was heated under reflux for 6 hours. The reaction mixture was diluted with EtOAc and then washed three times H2O, brine, dried Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was chromatographically on the column, getting the methyl ester of 3-(6-bromo-pyridin-3-yl)-acrylic acid (380 mg, 97%).

1H NMR (300 MHz, CDCl3): δ of 8.47 (d, 1H, J=2.4 Hz), to 7.68 (DD, 1H, J=8,4, 2.4 Hz), 7,60 (d, 1H, J=15,9 Hz), 7,51 (d, 1H, J=8,4 Hz), of 6.49 (d, 1H, J=15,9 Hz), 3,81 (c, 3H).

Stage 2: 3-(6-bromo-pyridin-3-yl)-acrylic acid

To methyl ether 3-(6-bromo-pyridin-3-yl)-acrylic acid (120 mg, 0,495 mmol) in THF was added 0,5h. a solution of LiOH (2 EQ.) and the mixture peremeci the Ali for 3 hours at room temperature. The obtained residue was dissolved in H2O, then washed three times Et2O and neutralize 1H. HCl to pH 5~7. The obtained solid was filtered and washed with H2O, and then dried in vacuum, obtaining 3-(6-bromo-pyridin-3-yl)-acrylic acid (100 mg, 88%).

1H NMR (300 MHz, DMSO-d6): δ 8,67 (d, 1H, J=2.1 Hz), 8,11 (DD, 1H, J=8,4, and 2.1 Hz), 7,69 (d, 1H, J=8,4 Hz), to 7.59 (d, 1H, J=15,9 Hz), of 6.71 (d, 1H, J=15,9 Hz).

Stage 3: 3-(6-bromo-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (63 mg, 0,219 mmol) suspended in THF and treated with triethylamine (25 mg, 0,241 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 3-(6-bromo-pyridin-3-yl)-acrylic acid (50 mg, 0,219 mmol), then after 10 minutes, DMTMM (66 mg, 0,241 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(×2) and brine and then dried over Bezbog. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (EtOAc/n-hexane)to give the target compound (71 mg, 72%).

1H NMR (300 MHz, DMSO-d6): δ 9,42 (c, 1H), 8,77 (t, 1H, J=6.0 Hz), at 8.60 (d, 1H, J=2.4 Hz), of 7.96 (DD, 1H, J=8,1, 1.8 Hz), of 7.70 (d, 1H, J=8.1 Hz), of 7.48 (d, 1H, J=15,GC), 7,28 (c, 1H), 7,27 (d, 1H, J=8.7 Hz), for 6.81 (d, 1H, J=15,9 Hz), 4,50 (c, 1H), 4,39 (d, 2H, J=5.7 Hz), 3,06 (c, 3H).

ESI [M+H]+: 452,0.

Example 16: 3-(6-chloro-pyridine-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (51 mg, 0,201 mmol) suspended in THF and treated with triethylamine (23 mg, 0.22 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 3-(6-chloro-pyridine-3-yl)-acrylic acid (37 mg, 0,201 mmol), then after 10 minutes, DMTMM (61 mg, 0.22 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(x2), brine and then dried over Bezbog. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, obtaining the target compound (74 mg, 96%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c, 1H), total of 8.74 (t, 1H, J=6.0 Hz), to 8.62 (d, 1H, J=2.4 Hz), 8,07 (DD, 1H, J=6,0, 2.4 Hz), EUR 7.57 (d, 1H, J=8,4 Hz), 7,51 (d, 1H, J=15,9 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=12.0 Hz), 7,12 (d, 1H, J=8,4 Hz), 6,79 (d, 1H, J=15,9 Hz), 4,39 (d, 2H, J=5.7 Hz), 3.00 and (c, 3H).

ESI [M+H]+: 384,0.

Example 17: 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonyl is inbaseline (41,2 mg, rate £ 0.162 mmol) were introduced in the reaction with 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.0 EQ., a 44.2 mg), DMTMM (1.0 EQ., 44,8 mg) and NMP (1.2 EQ., 22 ml) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (48 mg, 62.6 per cent).

1H NMR (300 MHz, CDCl3): δ 8,84 (c, 1H), to 7.93 (d, 1H, J=15.3 Hz), EUR 7.57 (c, 1H), 7,52 (t, 1H), 7,14 (m, 1H), 6,60 (c OSiR., 1H), 6,45 (d, 1H, J=15.6 Hz), 6,24 (c OSiR., 1H), 6,50 (c OSiR., 1H), 4,54 (d, 2H, J=6.0 Hz), 3,03 (c, 3H), 1.39 in (c, 9H).

ESI [M+H]+: 474,2.

Example 18: 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (11.2 mg, 0.04 mmol) were introduced in the reaction with 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.0 EQ., 11.0 mg), DMTMM (1.0 EQ., 11,1 mg) and NMP (1.2 EQ., 6 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=3/2) of the target compound (6 mg, 30.2 percent).

1H NMR (300 MHz, CDCl3): δ cent to 8.85 (c, 1H), 7,95 (d, 1H, J=13.5 Hz), 7,58 (c, 1H), 7,32 (c OSiR., 1H). then 7.20 (d, 1H, J=12,6 Hz), 6,05 (c OSiR., 1H), 4,54 (d, 1H, J=6.0 Hz), 3,49 (c, 1H), 3.27 to (c, 3H), 1,40 (c, 9H).

ESI [M+H]+: 498,2.

Example 19: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(6-piperid-1-yl-pyridinyl-3-yl)-acrylamide

Stage 1: methyl ester of 3-(6-piperid-1-yl-pyridinyl-3-yl)-acrylic acid

Methyl ester of 3-(6-bromo-pyridin-3-yl)-acrylic acid (180 mg, of 0.74 mmol)was added to piperidine (1 ml), and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed three times H2O, brine, dried Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was chromatographically on the column, getting the methyl ester of 3-(6-piperid-1-yl-pyridinyl-3-yl)-acrylic acid (60 mg, 33%).

1H NMR (300 MHz, CDCl3): δ of 8.25 (d, 1H, J=2.1 Hz), 7,63 (DD, 1H, J=6,0, 2.4 Hz), 7,58 (d, 1H, J=15,9 Hz), 6,62 (d, 1H, J=9.3 Hz), 6,21 (d, 1H, J=15,9 Hz), 3,78 (c, 3H), 3,64-3,61 (m, 4H), 1,66-to 1.60 (m, 6H).

Stage 2: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(6-piperid-1-yl-pyridinyl-3-yl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl of 25.2 mg, 0,099 mmol) suspended in THF and treated with triethylamine (11 mg, to 0.108 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 3-(6-piperid-1-yl-pyridinyl-3-yl)-acrylic acid (23 mg, 0,099 mmol), then after 10 minutes, DMTMM (30 mg, to 0.108 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(×2), brine and then dried over Bezbog. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2), receiving the target issue for lighting the e compound (15 mg, 35%).

1H NMR (300 MHz, CDCl3): δ of 8.25 (d, 1H, J=2.7 Hz), to 7.59 (DD, 1H, J=6,0, 2.7 Hz), 7,52 (d, 1H, J=15,9 Hz), to 7.15 (t, 1H, J=6.0 Hz), 6,62 (d, 1H, J=9.0 Hz), 6,21 (d, 1H, J=15.3 Hz), 6,01 (c, 1H, usher.), a 4.53 (d, 2H, J=6.0 Hz), 3,62-3,59 (m, 4H), 3,01 (c, 3H), 1,65-of 1.64 (m, 6H).

ESI [M+H]+: 433,2.

Example 20: 3-(6-bromo-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (183 mg, 0,719 mmol) suspended in THF and treated with triethylamine (80 mg, 0,791 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 6-chloro-pyridine-3-yloxy)-acetic acid (164 mg, 0,719 mmol), then after 10 minutes, DMTMM (218 mg, 0,791 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(×2), brine and then dried over Bezbog. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2), obtaining the target compound (225 mg, 65%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c, 1H), up 8.75 (t, 1H, J=6.0 Hz), 8,59 (d, 1H, J=2.1 Hz), 7,95 (DD, 1H, J=8,4, 2.4 Hz), 7,71 (d, 1H, J=8,4 Hz), 7,49 (d, 1H, J=15,9 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=12.0 Hz), 7,12 (d, 1H, J=8,4 Hz), 6,79 (d, 1H, J=15,9 Hz), 4,39 (d, 2H, J=5.7 Hz), 3.00 and (c, 3H).

ESI [M+H]+: 428,0.

Example 21: N-(3,5-debtor-4-methanol is phenylamino-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (50 mg, 0.22 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridine-3-yl)-acrylamide (37 mg, 39%).

1H NMR (300 MHz, CDCl3): δ for 7.78 (d, 1H, J=8.1 Hz), of 7.75 (d, 1H, J=15.3 Hz), 7,25 (d, 1H, J=8.1 Hz), 6,98 (d, 2H, J=8,4 Hz), 6,46 (d, 1H, J=15.3 Hz), 6,15 (c, 1H), 6,10 (t, 1H), to 4.38 (d, 2H, J=6.6 Hz), 3,85 (m, 4H), to 3.35 (m, 4H), 3,21 (c, 3H).

ESI [M+H]+: 521,1.

Example 22: N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl)-methanesulfonamide, HCl salt (80 mg, 0.25 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (76 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (56 mg, 39%).

1H NMR (300 MHz, CDCl3): δ 8,71 (c, 1H), 8,21 (t, 1H), 7,65 (d, 1H, J=7.8 Hz), 7,49 (d, 1H, J=15.6 Hz), 7,29 (c, 1H), 7,22 (d, 1H, J=9.9 Hz), 7,07 (d, 1H, J=7.8 Hz), 6.48 in (d, 1H, J=15.6 Hz), 4,36 (d, 2H, J=6.0 Hz), to 3.67 (m, 4H), 3,18 (m, 4H), to 3.02 (c, 3H).

ESI [M+H]+: 571.

Example 23: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6-morpholin-yl-pyridine-3-yl)-acrylamide

Stage 1: methyl ester of 3-(6-morpholine-4-yl-pyridine-3-yl)-acrylic acid

Methyl ester of 3-(6-bromo-pyridin-3-yl)-acrylic acid (100 mg, 0,413 mmol) was added to piperidine (1 ml)and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed three times H2O, brine, dried Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was chromatographically on the column, getting the methyl ester of 3-(6-morpholine-4-yl-pyridine-3-yl)-acrylic acid (40 mg, 21%).

1H NMR (300 MHz, CDCl3): δ of 8.27 (d, 1H, J=2.4 Hz), to 7.68 (DD, 1H, J=6,0, 2.4 Hz), to 7.59 (d, 1H, J=15,9 Hz), 6,62 (d, 1H, J=9.3 Hz), and 6.25 (d, 1H, J=15.3 Hz), 3,82-of 3.78 (m, 7H), 3,61 is 3.57 (m, 4H).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6-morpholine-4-yl-pyridine-3-yl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (20 mg, 0,072 mmol) suspended in THF and treated with triethylamine (11 mg, to 0.108 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 3-(6-morpholine-4-yl-pyridine-3-yl)-acrylic acid (17 mg, 0,072 mmol), then after 10 minutes, DMTMM (22 mg, 0.08 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, us the Sch. NaHCO3(×2), brine and then dried over Bezbog. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2), obtaining the target compound (8 mg, 24%).

1H NMR (300 MHz, DMSO-d6): δ 9,39 (c, 1H), charged 8.52 (t, 1H, J=5.4 Hz), 8,24 (c, 1H), 7,74 (d, 1H, J=8.7 Hz), 7,34 (d, 1H, J=15,9 Hz), 7,22-7,19 (m, 2H), at 6.84 (d, 1H, J=9.3 Hz), 6,45 (d, 1H, J=15,9 Hz), 4,46 (c, 1H), or 4.31 (d, 2H, J=5.7 Hz), 3,63-3,62 (m, 4H), 3,48-3,47 (m, 4H), 3,01 (c, 3 H).

ESI [M+H]+: 459.

Example 24: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide

Stage 1: Synthesis of 3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylic acid

3-(2-Piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylic acid (720 mg) was obtained according to a procedure similar to that described in the previous examples, from 2-chloro-6-triftormetilfosfinov acid with a total yield of 54%.

1H NMR (300 MHz, CDCl3): δ 7,81 (m, 2H), 7,18 (d, 1H, J=7.5 Hz), 6,45 (d, 1H, J=16.2 Hz), and 3.31 (m, 4H), 1,72 (m, 6H).

Stage 2: Synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (139 mg, 0.50 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylic acid (150 mg)to give after purification chromatogra what s in columns (Hex/EtOAc=1/1) N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide (132 mg, 50%).

1H NMR (300 MHz, CDCl3): δ 7,72 (m, 2H), 7,30 (c, 1H), 7,16 (m, 2H), 6,44 (c, 1H), gold 6.43 (d, 1H, J=15.6 Hz), 6,10 (c, 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,30 (m, 4H), 3,26 (c, 3H), of 1.65 (m, 6H).

ESI [M+H]+: 525.

Example 25: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(6-pyrrolidin-1-yl-pyridine-3-yl)-acrylamide

3-(6-Chloro-pyridine-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (15 mg, 0,413 mmol) was added to pyrrolidine (0.5 ml)and the mixture was stirred for 12 hours at 90°C. the Obtained residue was dissolved in EtOAc, then washed three times H2O and neutralize 1 N. HCl to pH 5~7. The resulting solution was washed with saline and then dried over Bezbog. Na2SO4,was filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2), obtaining the target compound (4 mg, 24%).

1H NMR (300 MHz, DMSO-d6): δ, to 8.41 (t, 1H, J=6.0 Hz), 8,15 (c, 1H), 7,65 (d, 1H, J=8.7 Hz), 7,29 (d, 1H, J=16,8 Hz), 7,26 (d, 1H, J=16.5 Hz), 7,10 (d, 1H, J=11.7 Hz), 7,02 (d, 1H, J=7.5 Hz), to 6.43 (d, 1H, J=9.3 Hz), 6,36 (d, 1H, J=15.6 Hz), the 4.29 (d, 2H, J=5.7 Hz), 3,85 of 3.75 (m, 4H), 2,92 (c, 3H), 3,48-3,47 (m, 4H).

ESI [M+H]+: 419.

Example 26: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (127 mg, 0.50 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl-acrylic acid (150 mg), getting after purification by chromatography on columns (Hex/EtOAc=1/1) N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide (175 mg, 70%).

1H NMR (300 MHz, CDCl3): δ of 7.70 (m, 2H), 7,50 (t, 1H, J=8.1 Hz), 7,12 (m, 3H), 6,65 (c, 1H), 6,45 (d, 1H, J=15.6 Hz), 6,14 (t, 1H), 4,54 (d, 2H, J=6.0 Hz), 3,29 (m, 4H), to 3.02 (c, 3H), of 1.70 (m, 6H).

ESI [M+H]+: 501.

Example 27: N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide

A suspension of N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (32 mg, 0,069 mmol) and 10% Pd/C (3 mg) in MeOH was injected into the reaction under hydrogen pressure of 40 psi. The reaction mixture was filtered through celite and then concentrated under reduced pressure, obtaining N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide (22 mg, 69%).

1H NMR (300 MHz, CDCl3): δ to 7.61 (d, 1H, J=6.9 Hz), 7,27 (d, 1H, J=8,4 Hz), 7,10 (m, 2H), 6,51 (c, 1H), 6,21 (c, 1H), 4,42 (d, 2H, J=5,1 Hz), 3,86 (m, 4H), 3,20 (m, 4H), of 3.07 (m, 2H), 3,03 (c, 3H), 2.63 in (m, 2H), 2,22 (d, 3H, J=2,4 Hz).

ESI [M+H]+: 519.

Example 28: 2-(2-bromo-6-tert-butyl-pyridine-3-yloxy)-N-(3-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (72 mg, 0.25 mmol) were introduced in the reaction with (2-bromo-6-tert-butyl-pyridine-3-yloxy)-vinegar is Oh acid (64 mg), DMTMM (1.2 EQ., 83 mg) and NEt3(2.5 EQ., 90 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (71 mg, 58.2 per cent).

1H NMR (300 MHz, CDCl3): δ 7,56 (m, 1H), 7,24 (m, 2H), 7,11 (m, 3H), 6.48 in (c OSiR., 1H), 4,58 (c, 2H), 4,55 (d, 2H, J=6 Hz), 3,03 (c, 3H), 1,33 (c, 9H).

ESI [M+H]+: 488.

Example 29: 2-(6-tert-butyl-pyridine-3-yloxy)-N-(3-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (158 mg, of 0.62 mmol) were introduced in the reaction with (6-tert-butyl-pyridine-3-yloxy)-acetic acid (130 mg), DMTMM (1.2 EQ., 206 mg) and NEt3(2.5 EQ., 220 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/3) of the target compound (165 mg, 65%).

1H NMR (300 MHz, CDCl3): δ with 8.33 (d, 1H, J=0.6 Hz), 7,38 (m, 1H), 7,21 (c OSiR., 1H), of 6.96 (m, 2H), to 6.88 (m, 2H), 4,71 (c, 2H), to 4.52 (d, 2H, J=6 Hz), 2,99 (c, 3H), 1,47 (c, 9H).

ESI [M+H]+: 409.

Example 30: 2-(6-tert-butyl-2-chloro-pyridine-3-yloxy)-N-(3-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (21 mg, 0.08 mmol) were introduced in the reaction with (6-tert-butyl-2-chloro-pyridine-3-yloxy)-acetic acid (1.0 EQ., 20 mg), DMTMM (1.2 EQ., 27 mg) and NMM (1.5 EQ., 14 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (10 mg, 28.2 per cent).

1H NMR (300 MHz, CDCl3): δ at 7.55 (m, 1H), 7.23 percent (c, 1H), 7,16 (c, 1H), 7,13 (m, 2H), 7,10 (c the Shire., 1H), 6,50 (c OSiR., 1H), 4,59 (c, 2H), 4,54 (d, 2H, J=6.3 Hz), 3,03 (c, 3H), 1,33 (c, 9H).

ESI [M+H]+: 444.

Example 31: N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(2-hydroxymethyl-6-methyl-pyridine-3-yloxy)-ndimethylacetamide

Stage 1: Synthesis of (2-hydroxymethyl-6-methyl-pyridine-3-yloxy)-acetic acid

(2-Hydroxymethyl-6-methyl-pyridine-3-yloxy)-acetic acid (200 mg) was obtained according to a procedure similar to that described above, from 2,6-lutidine-α2,3-diol with a total yield of 51%.

1H NMR (300 MHz, DMSO-d6): δ 7.24 to (d, 1H, J=8.1 Hz), 7,10 (d, 1H, J=8.1 Hz), 4,73 (c, 2H), 4,54 (c, 2H), 2.40 a (c, 3H).

Stage 2: Synthesis of N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(2-hydroxymethyl-6-methyl-pyridine-3-yloxy)-ndimethylacetamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (270 mg, 1.00 mmol) were introduced in the reaction with (2-hydroxymethyl-6-methyl-pyridine-3-yloxy)-acetic acid (200 mg)to give after purification by chromatography on columns (Hex/EtOAc=10/1) N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(2-hydroxymethyl-6-methyl-pyridine-3-yloxy)-ndimethylacetamide (350 mg, 88%).

1H NMR (300 MHz, DMSO-d6): δ 8,69 (t, 1H), 7,29 (m, 2H), to 7.09 (m, 3H), 5,10 (t, 1H), 4,66 (c, 2H), 4,60 (d, 2H, J=5.4 Hz), or 4.31 (d, 2H, J=6.3 Hz), 2,99 (c, 3H), 2.40 a (c, 3H).

ESI [M+H]+: 398.

Example 32: N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(6-trifluoromethyl-pyridine-3-yloxy)-ndimethylacetamide

Stage 1: Synthesis of (6-trifluoromethyl-pyridine-3-yloxy)-susei acid

(6-Trifluoromethyl-pyridine-3-yloxy)-acetic acid (410 mg) was obtained according to a procedure similar to that described above from 2-trifluoromethyl-5-hydroxypyridine with a total yield of 93%.

1H NMR (300 MHz, DMSO-d6): δ 8,29 (d, 1H, J=2.7 Hz), of 7.75 (d, 1H, J=8.7 Hz), 7,34 (DD, 1H, J=2.7 and 8.7 Hz), 4,33 (c, 2H).

Stage 2: Synthesis of N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(6-trifluoromethyl-pyridine-3-yloxy)-ndimethylacetamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (270 mg, 1.00 mmol) were introduced in the reaction with (6-trifluoromethyl-pyridine-3-yloxy)-acetic acid (221 mg)to give after recrystallization from Hex/EtOAc N-(3-fluoro-4-methanesulfonamido-benzyl)-2-(6-trifluoromethyl-pyridine-3-yloxy)-ndimethylacetamide (54 mg, 88%).

1H NMR (300 MHz, DMSO-d6): δ 9,52 (c, 1H), 8,80 (t, 1H), 8,49 (d, 1H, J=2.7 Hz), 7,87 (d, 1H, J=9.0 Hz), 7,60 (DD, 1H, J=2.7 and 9.0 Hz), 7,32 (m, 1H), 7,11 (m, 2H), 4,80 (c, 2H), 4,33 (d, 2H, J=6.3 Hz), 2,99 (c, 3H).

ESI [M+H]+: 422.

Example 33: 2-(6-tert-butyl-5-chloro-pyridine-3-yloxy)-N-(3-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (192 mg, 0,751 mmol) were introduced in the reaction with (6-tert-butyl-5-chloro-pyridine-3-yloxy)-acetic acid (183 mg), DMTMM (1.1 EQ., 229 mg) and NMM (1.2 EQ., 100 μl) in THF, obtaining the target compound (102 mg, 30,6%) after purification by chromatography on columns (Hex/EtOAc=1/1).

1H NMR (300 MHz, CDCl3): δ 8,18 (d, 1H, J=1.8 Hz), 7,56 (t, 1H), 7,10 (m, 2H), ,07 (m, 1H), of 6.71 (c OSiR., H)6,50 (c OSiR., 1H), 4,60 (c, 2H), 4,54 (d, 2H, J=6 Hz), 3,03 (c, 3H), 1,38 (c, 9H).

ESI [M+H]+: 444.

Example 34: 2-(6-tert-butyl-pyridine-3-yloxy)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (120 mg, 0.43 mmol) were introduced in the reaction with (6-tert-butyl-pyridine-3-yloxy)-acetic acid (90 mg), DMTMM (1.1 EQ., 131 mg) and NMP (1.2 EQ., 60 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (62 mg, 33.3%)of them.

1H NMR (300 MHz, CDCl3): δ at 8.36 (d, 1H, J=1.8 Hz), 7,22 (c OSiR., 1H), 7,18 (m, 1H), 7,06 (m, 1H), 6.89 in (TC, 1H), 6,64 (c, 1H), 4,68 (c, 2H), 4,51 (d, 2H, J=6 Hz), 3.46 in (c, 1H), 3,23 (c, 3H), 1,47 (c, 9H).

ESI [M+H]+: 434.

Example 35: 2-(6-chloro-pyridine-3-yloxy)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

Stage 1: ethyl ether (6-chloro-pyridine-3-yloxy)-acetic acid

To a suspension of 6-chloro-pyridine-3-ol (1000 mg, 7,72 mmol) and bromacil acetate (1933 mg, 11,57 mmol) in CH3CN was added Cs2CO3(3772 mg, 11,57 mmol). The mixture was stirred over night at room temperature. The reaction mixture was diluted with EtOAc, then washed three times H2O and brine and then dried MgSO4, filtered and concentrated under reduced pressure. The obtained residue was chromatographically on the column, getting ethyl ester(6-chloro-pyridine-3-yloxy)-acetic acid (1.5 g, 90%).

1H NMR (300 MHz, CDCl3): δ 8,07 (DD, 1H, J=2.7, and 0.9 Hz), 7,27-of 7.23 (m, 2H), 4,65 (c, 2H), 4,28 (q, 2H, J=7,2 Hz), of 1.30 (t, 3H, J=7.2 Hz).

Stage 2: (6-chloro-pyridine-3-yloxy)-acetic acid

Ethyl ester (6-chloro-pyridine-3-yloxy)-acetic acid (800 mg, 3,71 mmol) in THF was added to a solution of 0.5 N. LiOH (2 EQ.), and the mixture was stirred for 1.5 hours at room temperature. The obtained residue was dissolved in H2O, then washed three times Et2O and neutralize 1 N. HCl to pH 5~7. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4, and concentrated in vacuum, obtaining (6-chloro-pyridine-3-yloxy)-acetic acid (300 mg, 36%).

1H NMR (300 MHz, CDCl3): δ with 8.05 (d, 1H, J=3.3 Hz), 7,43-7,35 (m, 2H), 4,74 (c, 2H).

Stage 3: 2-(6-chloro-pyridine-3-yloxy)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-ndimethylacetamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide (74,3 mg, 0,266 mmol) suspended in THF and treated with triethylamine (27 mg, 0,266 mmol), and then the resulting mixture was stirred for 10 minutes To the reaction mixture were added 6-chloro-pyridine-3-yloxy)-acetic acid (50 mg, 0,266 mmol), then after 10 minutes, DMTMM (62.5 mg, 0,266 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, feast upon. NaHCO3(×3) and the sole is th solution and then dried over Bezbog. MgSO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2), obtaining the target compound (25 mg, 25%).

1H NMR (300 MHz, CDCl3): δ 8,13 (DD, 1H, J=3,0, 0.9 Hz), 7,34-7,24 (m, 3H), 7,14 (DD, 1H, J=10,5, and 2.1 Hz), 6.90 to (c, 1H, usher.), 6,44 (c, 1H), 4,58 (c, 2H), 4.53-in (c, 1H), 4,50 (d, 2H, J=6.3 Hz), 3,26 (c, 3H).

ESI [M+H]+: 412.

Example 36: 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Hydrochloride 3-fluoro-4-methanesulfonylaminoethyl (116 mg, 0,454 mmol) were introduced in the reaction with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 EQ., 129 mg), DMTMM (1.0 EQ., 126 mg) and NMP (1.2 EQ., 60 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (72 mg, 32.8 per cent).

1H NMR (300 MHz, CDCl3): δ 7,89 (d, 1H, J=12.9 Hz), 7,72 (d, 1H, J=7.8 Hz), 7,56 (m, 1H), 7,29 (d, 1H, J=8,4 Hz), to 7.15 (m, 2H), 6,46 (c OSiR., 1H), 6,36 (d, 1H, J=15.3 Hz), 6,01 (c OSiR., 1H), 4,56 (d, 2H, J=6.3 Hz), 3,03 (c, 3H), 1,35 (c, 9H).

Example 37: 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (41,2 mg, 0,148 mmol) were introduced in the reaction with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 EQ., 42 mg), DMTMM (1.0 EQ., 41 mg) and NMP (1.2 EQ., 20 μl) in THF, getting after purification by chromatography on columns (Hex/EtOAc=3/2) CE is Evoe compound (42 mg, 55,8%).

1H NMR (300 MHz, CDCl3): δ of 7.90 (d, 1H, J=15,9 Hz), 7,73 (d, 1H, J=7.5 Hz), 7,31 (m, 1H), 7,28 (c, 1H), 7,17 (DD, 1H, J=2.1 Hz and 1.5 Hz), 6,41 (c, 1H), 6,37 (d, 1H, J=15.7 Hz), 6,09 (c OSiR., 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3.27 to (c, 3H), 1,35 (c, 9H).

Example 38: 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of 2-chloro-6-trifluoromethyl-nicotinic acid (200 mg, 0.88 mmol) and N,O-dimethylhydroxylamine (95 mg, 0.97 mmol) in CH2Cl2(3 ml) was added N-methylmorpholine (0,106 ml, 0.97 mmol). The mixture was stirred for 5 minutes, then was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (185 mg, 0.97 mmol). The mixture was stirred for 3 hours at room temperature and then diluted with EtOAc and water. The organic layer was washed 1 N. HCl, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was dried in vacuum, obtaining 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (220 mg, 92%).

1H NMR (300 MHz, CDCl3): δ 7,86 (d, 1H, J=7.8 Hz), 7,69 (d, 1H, J=7.8 Hz), 3,52 (c, 3H), 3.42 points (c, 3H).

Stage 2: 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicoti the amide (400 mg, 1,489 mmol) and diethylamine (0,773 ml, 7,44 mmol) in DMF (4 ml) was added K2CO3(1,02 g, 7,44 mmol). The mixture was stirred for 4 hours at 110°C. the Reaction mixture was diluted with EtOAc (30 ml) and then washed two times 1 N. HCl (30 ml) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically, getting 2 diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 88%).

1H NMR (300 MHz, CDCl3): δ 7,50 (d, 1H, J=7.5 Hz), 6.90 to (d, 1H, J=7.5 Hz), 3,54-to 3.41 (m, 7H), 3,29 (c, 3H), 1,71 (t, 6H, J=7.2 Hz).

Stage 3: 2-diethylamino-6-trifluoromethyl-pyridine-3-carbaldehyde

To a suspension of 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (66 mg, 0,216 mmol) in THF (2 ml) was added dropwise a 1.0 M LiAlH4(to 0.108 ml, to 0.108 mmol) at -78°C. the Mixture was heated to -20°C for 30 minutes the Reaction mixture was diluted with Et2O and washed twice 1 N. KHSO4and brine, dried over Bezbog. MgSO4,was filtered and concentrated under reduced pressure. The product was dried in vacuum, obtaining 2-diethylamino-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (43 mg, 75%).

1H NMR (300 MHz, CDCl3): δ 9,98 (c, 1H), 8,07 (d, 1H, J=7.5 Hz), 7,05 (d, 1H, J=7.5 Hz), 3,54 (q, 4H, J=7,2 Hz), of 1.27 (t, 6H, J=7.2 Hz).

Stage 4: methyl ester 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a solution of 2-diethylamino-6-triptime the Il-pyridin-3-yl-carbaldehyde (39 mg, 0.147 mmol) in toluene was added methyl(triphenylphosphonium)acetate (73,8 mg, 0,221 mmol)and the resulting mixture was heated at 90°C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=10/1)to give methyl ester 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 90%).

1H NMR (300 MHz, CDCl3): δ 7,73 (d, 1H, J=16.2 Hz), 7,72 (d, 1H, J=8.1 Hz), 6,36 (d, 1H, J=16.2 Hz), 3,82 (c, 3H), 3,38 (q, 4H, J=7,2 Hz), 1,78 (t, 6H, J=7.2 Hz).

Stage 5: 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a suspension of methyl ester 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0,132 mmol) in THF (1 ml) was added a solution of 0.5 N. LiOH (0.3 ml)and the mixture was stirred for 3 hours at room temperature. The obtained residue was dissolved in H2O and then washed three times with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4, and concentrated in vacuum, obtaining 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (33 mg, 87%).

1H NMR (300 MHz, CDCl3): δ 7,79 (d, 1H, J=18,0 Hz), 7,74 (d, 1H, J=8.1 Hz), to 7.09 (d, 1H, J=7.5 Hz), 6,37 (d, 1H, J=15.6 Hz), to 3.38 (q, 4H, J=7,2 Hz), 1,22 (t, 6H, J=7.2 G is).

Step 6: 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

To a suspension of N-(4-aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (476 mg, of 1.66 mmol) in THF (5 ml) was added N-methylmorpholine (0,365 ml of 3.32 mmol). The mixture was stirred for 5 minutes, then was added 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (434 mg and 1.51 mmol) and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM, 459 mg of 1.66 mmol). The mixture was stirred over night at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1 N. HCl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2receiving the target compound (645 mg, 83%).

1H NMR (300 MHz, CDCl3): δ 7,73 (d, 1H, J=16.5 Hz), 7,69 (d, 1H, J=8,4 Hz), 7,28 (d, 1H, J=7.8 Hz), 7,16 (d, 1H, J=11,1 Hz), 7,07 (d, 1H, J=7.8 Hz), 6,44 (c, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6,10 (c, 1H), 4,51 (d, 2H, J=5.7 Hz), 3,47 (c, 1H), 3,38 (q, 4H, J=7,2 Hz), 3,26 (c, 1H), 1,19 (t, 6H, J=7.2 Hz).

ESI [M+H]+: 513.

Example 39: 3-(6-tert-butyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid

RA is Toru 6-tert-butyl-pyridin-3-yl-carbaldehyde (1,34 g, is 8.75 mmol), obtained in accordance with known procedure, in toluene was added methyl(triphenylphosphonium)acetate (2,93 g)and the resulting mixture was heated at 90°C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=4/1)to give the ester product (1.56 g, 81%). The obtained ester was dissolved in 1,4-dioxane, treated with water and KOH were stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed simple ether. The aqueous phase was acidified using 1 N. HCl and then was extracted with CHCl3, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (1,00 g, 68%).

1H NMR (300 MHz, CDCl3): δ 8,78 (d, 1H, J=2.1 Hz), to 7.84 (DD, 1H, J=2.1 and 8.4 Hz), 7,78 (d, 1H, J=16.2 Hz), 7,42 (d, 1H, J=8,4 Hz), 6,53 (d, 1H, J=16.2 Hz), 1,40 (c, 9H).

Stage 2: 3-(6-tert-butyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (50 mg, 0.18 mmol) were introduced in the reaction with 3-(6-tert-butyl-pyridin-3-yl)-acrylic is acid (37 mg), getting after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (60 mg, 79%).

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ 8,69 (d, 1H, J=2.4 Hz), 7,98 (7, 1H, J=6.0 Hz), 7,76 (DD, 1H, J=2.4 and 8.4 Hz), 7,63 (d, 1H, J=15.6 Hz), 7,37 (d, 1H, J=8,4 Hz), of 6.99 (d, 2H, J=8.1 Hz), 6,63 (d, 1H, J=15.6 Hz), 4,50 (d, 2H, J=6.0 Hz), 3,11 (c, 3H), 1,37 (c, 9H).

ESI [M+H]+: 424.

Example 40: 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 2-chloro-6-trifluoromethyl-pyridin-3-yl-carbaldehyde

The target compound was obtained according to the General procedure described in example 38 (stage 3).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1,109 mg, 4,128 mmol) were introduced in the reaction with 1.0 M LiAlH4(0.5 equiv.) getting 2-chloro-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (844 mg, 97%).

1H NMR (300 MHz, CDCl3): δ 10,49 (c, 1H), to 8.41 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=7,8 Hz).

Stage 2: methyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

The target compound was obtained according to the General procedure described in example 38 (stage 4).

2-Chloro-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (844 mg, 4,027 mmol) were introduced in the reaction with methyl(triphenylphosphonium)acetate (1,62 g of 4.83 mmol)to give methyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (900 mg, 84%).

1H NMR (300 MHz, CDCl3): δ 8,08 (d, 1H, J=8.1 Hz), to 7.99 (d, 1H, J=15,9 Hz), to 7.67 (d 1H, J=8.1 Hz), 6,53 (d, 1H, J=15,9 Hz), 3,86 (c, 3H).

Stage 3: 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

The target compound was obtained according to the General procedure described in example 38 (stage 5).

Methyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, 0,753 mmol) were introduced in the reaction with 0.5 N. LiOH (2 EQ.), getting 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (189 mg, 99%).

1H NMR (300 MHz, DMSO-d6): δ 8,56 (d, 1H, J=8.1 Hz), to 7.93 (d, 1H, J=8.1 Hz), to 7.68 (d, 1H, J=15,9 Hz), 6,77 (d, 1H, J=15,9 Hz).

Stage 4: 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (228 mg, 0,795 mmol) were introduced in the reaction with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, 0,795 mmol)to give the target compound (340 mg, 90%).

1H NMR (300 MHz, DMSO-d6): δ for 9.47 (c, 1H), 8,96 (t, 1H, J=6.0 Hz), 8,43 (d, 1H, J=7.8 Hz), 8,02 (d, 1H, J=8.1 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,31-7,27 (m, 2H), 6.90 to (d, 1H, J=15.6 Hz), to 4.52 (c, 1H), to 4.41 (d, 2H, J=5.7 Hz), 3,07 (c, 3H).

ESI [M+H]+: 476.

Example 41: N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(6-methoxy-4-triptorelin-3-yl)acrylamide

Stage 1: synthesis of methyl-6-methoxy-4-triftoratsetofenona

To a solution of 6-hydroxy-4-trifluoromethyl who ikodinovic acid (400 mg, of 1.93 mmol) in chloroform (25 ml) was added silver carbonate (1.06 g, of 3.84 mmol) and methyliodide (2.4 ml, of 3.84 mmol). The mixture was stirred in the dark at room temperature overnight, filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography on columns (EtOAc/hexane=from 1/10 to 1/1)to give methyl-6-methoxy-4-triftorperasin (300 mg, 69.9 per cent) in the form of solids.

1H NMR (300 MHz, CDCl3): δ 8,79 (c, 1 H), was 7.08 (m, 1 H), 4.04 the (c, 3 H), 3,93 (c, 3 H).

Stage 2: synthesis of 6-methoxy-4-trifluoromethyl-3-pyridinemethanol

To a cooled (-78°C) solution of methyl-6-methoxy-4-triftoratsetofenona (300 mg, 1.35 mmol) in toluene (10 ml) was added diisobutylaluminium (DIBAL, 1M/toluene, to 1.35 ml). The mixture was slowly heated to room temperature and was stirred for 2 days. Added additional DIBAL (1M/toluene, 2 ml)to complete the reaction. After stirring for 4 hours the mixture was suppressed saturated aqueous ammonium chloride (1 ml), dried over anhydrous magnesium sulfate, filtered through celite and concentrated under reduced pressure, obtaining 6-methoxy-4-trifluoromethyl-3-pyridinemethanol (220 mg, 78.6 per cent). The crude product was used directly in the following oxidation under Swern.

1H NMR (300 MHz, CDCl3): to 8.41 δ (c, 1H), 7,00 (c, 1H), 4,80 (c, 2 H), 3,98 (c, 3H).

Stage 3: synthesis of 6-methoxy-4-trifluoromethyl-3-pyridine is localdevice

To a cooled (-78°C) solution of dimethyl sulfoxide (DMSO) (0.15 ml, 2,13 mmol) in dichloromethane (2 ml) was added oxalicacid (0,14 ml of 1.60 mmol)and the mixture was stirred for 10 minutes. To the reaction mixture was added 6-methoxy-4-trifluoromethyl-3-pyridinemethanol (220 mg, 1.06 mmol) in dichloromethane (4 ml). After stirring at -40°C for 50 minutes, the mixture was treated with triethylamine (of 0.44 ml, and 3.16 mmol), was stirred for 90 minutes, was heated to room temperature and extinguished with water. The organic layer was washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 6-methoxy-4-trifluoromethyl-3-pyridinecarboxamide (162 mg, 74.4 per cent) in the form of solids. The crude product was used directly in the following oxidation under Swern.

1H NMR (300 MHz, CDCl3): δ of 10.25~10,23 (m, 1H), 8,91 (c, 1H), 7,07 (c, 1H), 4,08 (c, 3H).

Stage 4: synthesis of methyl ester of 3-(6-methoxy-4-triptorelin-3-yl)-acrylic acid

To a solution of 6-methoxy-4-trifluoromethyl-3-pyridinecarboxamide (150 mg, 0.73 mmol) in toluene (8 ml) was added methyl(triphenylphosphonium)acetate (270 mg, 0.81 mmol). The mixture was heated at 110°C overnight, cooled to room temperature and was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under pengendali. The residue was purified by chromatography on columns (EtOAc/hexane=1/4)to give methyl ester of 3-(6-methoxy-4-triptorelin-3-yl)-acrylic acid (140 mg, 73,3%) as a mixture of CIS - and TRANS-isomers (CIS/TRANS=1/10). The TRANS-isomer was then isolated by recrystallization from hexanol, receiving 60 mg in the form of solids.

1H NMR (300 MHz, CDCl3): δ charged 8.52 (c, 1H), of 7.90~to 7.84 (m, 1H), 7,03 (c, 1H), 6,38 (d, 1H, J=15,9 Hz), 4,01 (c, 3H), 3,83 (c, 3H).

Stage 5: synthesis of 3-(6-methoxy-4-triptorelin-3-yl)-acrylic acid

To a solution of methyl ester of 3-(6-methoxy-4-triptorelin-3-yl)-acrylic acid (TRANS-isomer, 59 mg, 0.23 mmol) in THF (2 ml) was added 1 N. LiOH (2 ml). The mixture was stirred at room temperature for 2 hours, acidified to pH 5 using 3 N. HCl and was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining 3-(6-methoxy-4-triptorelin-3-yl)-acrylic acid (50 mg, 89.6 per cent) in the form of solids.

1H NMR (300 MHz, CDCl3): δ 8,57 (c, 1H), 7,80~7,94 (m, 1H), 7,05 (c, 1H), 6,41 (d, 1H, J=15,9 Hz), was 4.02 (c, 3H).

Step 6: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(6-methoxy-4-triptorelin-3-yl)acrylamide

To a suspension of 3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl (67 mg, 0.24 mmol) in THF (2 ml) was added N-methylmorpholine (40 μl, 0.36 mmol). After peremeci the project within 5 minutes was added 3-(6-methoxy-4-triptorelin-3-yl)acrylic acid (50 mg, 0.20 mmol)dissolved in THF (3 ml)and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM 67 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by recrystallization from a mixture of EtOAc/hexane, obtaining N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(6-methoxy-4-triptorelin-3-yl)acrylamide (75 mg, 66.2 per cent) in the form of solids.

1H NMR (300 MHz, DMSO-d6): δ 8,83 (t, 1H, J=6 Hz), to 8.70 (d, 1H, J=0.6 Hz), to 7.59~rate of 7.54 (m, 1H), 7,28~of 7.24 (m, 3H), of 6.71 (d, 1H, J=15.6 Hz), 4,49 (c, 1H), to 4.38 (d, 2H, J=5.7 Hz), 3.96 points (c, 3H), 3,05 (c, 3H).

ESI [M+H]+: 472

Example 42: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (50 mg, 0,105 mmol) in CH3OH (1 ml) was added dropwise at 0°C 30% NaOCH3in CH3OH (3 EQ.). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and washed twice 1 N. HCl and brine, dried over Bezbog. MgSO4,was filtered and concentrated under reduced pressure is. The obtained residue was purified by chromatography on columns, obtaining the target compound (10 mg, 20%).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c, 1H), 8,86 (c, 1H, usher.), 8,19 (d, 1H, J=7.5 Hz), 7,60-rate of 7.54 (m, 2H), 7,29-7,26 (m, 2H), of 6.96 (d, 1H, J=15,9 Hz), 4,51 (c, 1H), and 4.40 (d, 2H, J=5.7 Hz), 4,01 (c, 3H), of 3.07 (c, 3H).

ESI [M+H]+: 472.

Example 43: N-(3-fluoro-4-methanesulfonylaminoethyl)-3-(6-methoxy-4-triptorelin-3-yl)acrylamide

To a suspension of 3-fluoro-4-methanesulfonylaminoethyl (40 mg, 0.16 mmol) in THF (4 ml) was added N-methylmorpholine (26 μl, 0.24 mmol). After stirring for 5 minutes was added 3-[6-methoxy-4-(trifluoromethyl)pyridin-3-yl]acrylic acid (32 mg, 0.13 mmol)dissolved in THF (3 ml)and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM 43 mg, 0.16 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by recrystallization from a mixture of EtOAc/hexane, obtaining N-(3-fluoro-4-methanesulfonylaminoethyl)-3-(6-methoxy-4-triptorelin-3-yl)acrylamide (30 mg, 42.7 percent) in the form of solids.

1H NMR (300 MHz, DMSO-d6): δ 8,80 (t, 1H, J=5.7 Hz), 8,68 (c, 1H), to 7.59~7,53 (m, 1H), 7,35 (t, 1H, J=8,4 Hz), 7,24 (c, 1H), 7,22~to 7.18 (m, H), 7,14~7,11 (m, 1H), 6,70 (d, 1H, J=15.6 Hz), to 4.38 (d, 2H, J=5.7 Hz), 3.96 points (c, 3H), 3.00 and (c, 3H).

ESI [M+H]+: 448.

Example 44: 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (467 mg, of 1.84 mmol) were introduced in the reaction with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (420 mg, 1,67 mmol)to give the target compound (737 mg, 98%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c, 1H), 8,92 (t, 1H, J=5.7 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,02 (d, 1H, J=8.1 Hz), to 7.67 (d, 1H, J=15,9 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,20 (d, 1H, J=11,4 Hz), 7,13 (d, 1H, J=8.1 Hz), 6.89 in (d, 1H, J=15,9 Hz), and 4.40 (d, 2H, J=5.4 Hz), 3.00 and (c, 3H).

ESI [M+H]+: 452.

Example 45: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (35 mg, 0,077 mmol) and methoxyethylamine (5 EQ.) in DMF (0.5 ml) was added K2CO3(5 EQ.). The mixture was stirred for 12 hours at 110°C. the Reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, receiving CE is Evoe compound (10 mg, 26%).

1H NMR (300 MHz, CDCl3): δ to 7.67 (m, 3H), 7,13 (t, 2H, J=9,3 Hz), 6,92 (d, 1H, J=7.8 Hz), 6,57 (c, 1H), 6,37 (d, 1H, J=15.3 Hz), 6,11 (c, 1H, usher.), the 5.25 (c, 1H, usher.), 4,55 (d, 2H, J=6.0 Hz), 3,74 at 3.69 (m, 2H), 3,65-to 3.58 (m, 2H), 3,38 (c, 3H), 3,01 (c, 3H).

ESI [M+H]+: 491.

Example 46: missing

Example 47: 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

The target compound was obtained according to the General procedure described in example 45 (stage 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (27 mg, 0.06 mmol) were introduced in the reaction with diethylamine (5 equiv.) receiving the target compound (14 mg, 48%).

1H NMR (300 MHz, CDCl3): δ of 7.75 (d, 1H, J=15,9 Hz), to 7.68 (d, 1H, J=7.8 Hz), 7,52 (t, 1H, J=7.8 Hz), 7,17-7,11 (m, 2H), 7,06 (d, 1H, J=7.8 Hz), 6,57 (c, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6,04 (t, 1H, J=5.7 Hz), 4,55 (d, 2H, J=6,0 Hz), to 3.38 (q, 4H, J=7,2 Hz), to 3.02 (c, 3H), 1,19 (t, 6H, J=7.2 Hz).

ESI [M+H]+: 489.

Example 48: missing

Example 49: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-pyridine-3-yl)-acrylamide

Stage 1: synthesis of 2-morpholine-4-yl-pyridine-3-carbaldehyde

To a solution of 2-chloro-pyridine-3-yl-carbaldehyde (0.5 g, of 3.53 mmol) in DMF was added morpholine (from 0.37 ml, 1.2 EQ.), and the reaction mixture was stirred at 90°C for 6 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. Organically the layer was dried over anhydrous MgSO 4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=4/1)to give the product (0,38 g, 56.1 per cent).

1H NMR (300 MHz, CDCl3): δ 10,04 (c, 1H), 8,40 (m, 1H), 8,01 (m, 1H), of 6.96 (m, 1H), 3,88 (m, 4H), 3,47 (m, 4H).

Stage 2: synthesis of 3-(2-morpholine-4-yl-pyridine-3-yl)-acrylic acid

To a solution of 2-morpholine-4-yl-pyridine-3-yl-carbaldehyde (0,38 g of 1.98 mmol) in toluene was added methyl(triphenylphosphonium)acetate (0.793 g, 1.2 EQ.), and the resulting mixture was heated at 90°C for 4 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=4/1)to give the ester product (0.35 g, 71.2 percent). The obtained ester was dissolved in 1,4-dioxane, treated with water and KOH were stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed simple ether. The aqueous phase was acidified using 1 N. HCl and then was extracted with EtOAc, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (0.25 g, 75.7 percent).

1H NMR (300 MHz, CDCl3): δ 8,33(m, 1H), of 7.90 (d, 1H, J=15,9 Hz), to 7.77 (m, 1H), 6,97 (m, 1H), 6.42 per (d, 1H, J=15,9 Hz), 3,86 (m, 4H), of 3.27 (m, 4H).

Stage 3: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-pyridine-3-yl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (96 mg, 0.35 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-pyridine-3-yl)-acrylic acid (81 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=1/10) N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-pyridine-3-yl)-acrylamide (105 mg, 63.6 per cent).

1H NMR (300 MHz, CDCl3): δ 8,29 (m, 1H), 7,80 (d, 1H, J=15.3 Hz), 7,30 (c OSiR., 1H), 7,18 (m, 1H), 6,94 (m, 1H), gold 6.43 (c OSiR., 1H), 6,40 (d, 1H, J=15.3 Hz), 5,99 (c OSiR., 1H), 4,54 (d, 1H, J=6.0 Hz), 3,88 (m, 4H), 3,49 (c, 1H), 3.27 to (c, 3H), 3,26 (m, 4H).

ESI [M+H]+: 459.

Example 50: N-(5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-pyridine-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (57 mg, 0.22 mmol) were introduced in the reaction with 3-(2-morpholine-4-yl-pyridine-3-yl)-acrylic acid (52 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=1/7) N-(5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-pyridine-3-yl)-acrylamide (67 mg, 69.5 per cent).

1H NMR (300 MHz, CDCl3): δ 8,29 (m, 1H), 7,81 (d, 1H, J=15.6 Hz), 7,69 (m, 1H), 7,55 (m, 1H), 7,17 (m, 1H), 6,93 (m, 1H), 6,46 (c OSiR., 1H), 6,40 (d, 1H, J=15.6 Hz), of 5.92 (c OSiR., 1H), 4,56 (d, 1H, J=6.0 Hz), 3,88 (m, 4H), 3,26 (m, 4H), 3,03 (c, 3H).

ESI [M+H]+: 435.

Prima is 51: 3-(6-tert-butyl-2-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (30 mg, 0.11 mmol), was introduced in the reaction with 3-(6-tert-butyl-2-chloro-pyridine-3-yl)-acrylic acid (30 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=2/3) 3-(6-tert-butyl-2-chloro-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (19 mg, 37.9 per cent).

1H NMR (300 MHz, CDCl3): δ to 7.93 (d, 1H, J=15.6 Hz), 7.23 percent (m, 3H), 7,00 (m, 1H), 6.42 per (c OSiR., 1H), 6,41 (d, 1H, J=15.6 Hz), between 6.08 (c OSiR., 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,26 (c, 3H), 1,36 (c, 9H).

ESI [M+H]+: 464.

Example 52: 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: synthesis of N-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-O,N-dimethyl-hydroxylamine

To a solution of 6-chloro-4-trifluoromethyl-nicotinic acid (0.9 g, 3,99 mmol) in methylene chloride at 0°C was added N,O-dimethylhydroxylamine HCl (0.39 g, 1.0 EQ.), NMM (of 0.44 ml) and EDC (0,768 g)and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was extracted with methylene chloride and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=4/1)to give the product (0,824 g, 76,9%).

1H NMR (300 MHz, CDCl3): δ 8,53 (c, 1H), 7,63 (c, 1H), 3,47 (c, 3H), 3,38 (c, H).

Stage 2: synthesis of 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid

N-(6-Chloro-4-trifluoromethyl-pyridin-3-yl)-O,N-dimethyl-hydroxylamine (0,824 g of 3.07 mmol) was dissolved in anhydrous THF and cooled to -78°C and added to the syringe to 1.0 M LAH (1,54 ml), and then the resulting mixture was stirred for 30 minutes. To the reaction mixture was carefully added 1 M NaOH (2 ml) and H2O (2 ml), and then the resulting solution was stirred for 30 minutes. The mixture was dried anhydrous MgSO4, filtered and concentrated in vacuum, obtaining 6-chloro-4-trifluoromethyl-pyridin-3-yl-carbaldehyde in the form of a light yellow oil (0,643 g, 100%). To a solution of 6-chloro-4-trifluoromethyl-pyridin-3-yl-carbaldehyde (0,643 g of 3.07 mmol) in toluene was added methyl(triphenylphosphonium)acetate (1.13 g, 1.1 equiv.) and the resulting mixture was heated at 90°C for 4 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=8/1)to give the ester product (0.56 g, 68,4%). The obtained ester was dissolved in 1,4-dioxane, treated with water and KOH were stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed simple ether. Vadouvan acidified 1 N. HCl and then was extracted with EtOAc, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (0,43 g, 81.4 per cent).

1H NMR (300 MHz, CDCl3): δ 8,77 (c, 1H), 7,97 (m, 1H), 7,65 (c, 1H), of 6.52 (d, 1H, J=15,9 Hz).

Stage 3: synthesis of 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (123 mg, 0.40 mmol) were introduced in the reaction with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (105 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=3/2) 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (136 mg, 73.3 per cent).

1H NMR (300 MHz, CDCl3): δ 8,70 (c, 1H), of 7.90 (m, 1H), 7.62mm (c, 1H), 7,30 (c, 1H), 7,18 (m, 1H), 6,46 (d, 1H, J=15.3 Hz), 6,14 (c OSiR., 1H), 4,54 (d, 2H, J=6.0 Hz), 3,49 (c, 1H), 3.27 to (c, 3H).

ESI [M+H]+: 476.

Example 53: 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (56 mg, 0.22 mmol) were introduced in the reaction with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (54 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=3/2) 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(5-fluoro-4-meth is sulfonylamino-benzyl)-acrylamide (66 mg, 65,7%).

1H NMR (300 MHz, CDCl3): δ 8,69 (c, 1H), 7,89 (m, 1H), EUR 7.57 (d, 1H, J=15.3 Hz), 7,54 (m, 1H), 7,15 (m, 2H), 6,53 (c OSiR., 1H), 6,46 (d, 1H, J=15.3 Hz), 6,13 (c OSiR., 1H), 4,56 (d, 2H, J=5.7 Hz), 3,03 (c, 3H).

ESI [M+H]+: 452.

Example 54: missing

Example 55: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (40 mg, 0,088 mmol) in pyrrolidine (0.4 ml) was added DMF (0.5 ml). The mixture was stirred for 12 hours at 110°C. the Reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, obtaining the target compound (40 mg, 93%).

1H NMR (300 MHz, DMSO-d6): δ 9,95 (c, 1H), 8,72 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7.5 Hz), 7,69 (d, 1H, J=15.3 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=11,4 Hz), 7,13-was 7.08 (m, 2H), to 6.43 (d, 1H, J=15.3 Hz), 4,37 (d, 1H, J=6,0 Hz), 3,48-to 3.41 (m, 4H), 3.00 and (c, 3H), 1,88 is 1.86 (m, 4H).

ESI [M+H]+: 487.

Example 56: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-hydroxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (40 mg, 0,088 mmol) in pyrrolidin-3-Ola (0.4 ml) was added DMF (0.5 to the l). The mixture was stirred for 12 hours at 110°C. the Reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, obtaining the target compound (40 mg, 91%).

1H NMR (300 MHz, DMSO-d6): δ 8,72 (t, 1H, J=5.7 Hz), 7,80 (d, 1H, J=7.5 Hz), to 7.68 (d, 1H, J=15.3 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=11,1 Hz), 7,12-was 7.08 (m, 2H), to 4.98 (d, 1H, J=2.7 Hz), 4,37 (d, 2H, J=6.0 Hz), or 4.31 (c, 1H, usher.), 3,74-to 3.64 (m, 4H), 3.00 and (c, 3H), 1,98-of 1.84 (m, 2H).

ESI [M+H]+: 503.

Example 57: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (137 mg, 0.49 mmol) were introduced in the reaction with 3-(6-trifluoromethyl-pyridin-3-yl)-acrylic acid (107 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=2/3) N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide (105 mg, 48.5 percent).

1H NMR (300 MHz, DMSO-d6): δ 9,44 (c OSiR., 1H), 8,97 (c, 1H), 8,84 (m, 1H), 8,28 (m, 1H), of 7.96 (m, 1H), 7,60 (d, 1H, J=16.2 Hz), 7,25 (m, 2H), 6,92 (d, 1H, J=15,9 Hz), 4,39 (d, 2H, J=6.0 Hz), 3.33 and (c, 1H), 3,02 (c, 3H).

ESI [M+H]+: 442.

Example 58 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (59 mg, 0.23 mmol) were introduced in the reaction with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 1.0 EQ.), getting after purification by chromatography on columns (Hex/EtOAc=4/5) 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (47 mg, 49,0%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c OSiR., 1H), 8,97 (c, 1H), 8,83 (m, 1H), 8,28 (m, 1H), of 7.96 (m, 1H), 7,60 (d, 1H, J=15,9 Hz), 7,35 (m, 1H), 7,17 (m, 2H), 6,92 (d, 1H, J=16.2 Hz), to 4.41 (d, 2H, J=6.0 Hz), 3.00 and (c, 3H).

ESI [M+H]+: 418.

Example 59: 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: synthesis of 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-acrylic acid

Methyl ester of 3-(6-tert-butyl-2-chloro-pyridine-3-yl)-acrylic acid (0,281 g, 1.11 mmol) was dissolved in DMF and Paladino was added morpholine (0.15 ml), NEt3(0,31 ml) and reagent palladium (48 mg), and then the reaction mixture was stirred at 80°C for 18 hours. The resulting mixture was extracted with EtOAc, and the organic phase was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=8/1)to give methyl ester of 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-acrylic acid (76 mg, 0.25 mmol, 22.5 per cent). Methyl ester was dissolved in 1,4-dioxane, treated with water and KOH were mixed and heated to the reflux condenser is m for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed simple ether. The aqueous phase was acidified using 1 N. HCl and then was extracted with EtOAc, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure, obtaining 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-acrylic acid (67 mg, 92%).

1H NMR (300 MHz, CDCl3): δ 7,88 (d, 1H, J=15,9 Hz), to 7.68 (d, 1H, J=8.1 Hz), 6,97 (d, 1H, J=8.1 Hz), 6,38 (d, 1H, J=15,9 Hz), a 3.87 (m, 4H), 3,30 (m, 4H), 1,33 (c, 9H).

Stage 2: synthesis of 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (59 mg, 0.23 mmol) were introduced in the reaction with 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-acrylic acid (67 mg)to give after purification by chromatography on columns (Hex/EtOAc=3/2) 3-(6-tert-butyl-2-morpholine-4-yl-pyridine-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (60 mg, 92%).

1H NMR (300 MHz, CDCl3): δ for 7.78 (d, 1H, J=15,9 Hz), to 7.61 (m, 1H), 7,25 (m, 2H), 6,93 (m, 1H), 6,41 (c OSiR., 1H), 6.35mm (d, 1H, J=15,9 Hz), 5,91 (c OSiR., 1H), 4.53-in (d, 2H, J=6.3 Hz), 3,86 (m, 4H), 3,48 (c, 1H), 3,29 (m, 4H), 3,26 (c, 3H), 1.32 to (c, 9H).

ESI [M+H]+: 515.

Example 60: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

The target compound was obtained with the according to the General procedure described in example 42 (stage 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (40 mg, 0,088 mmol) were introduced in the reaction with 30%NaOCH3in CH3OH, obtaining the target compound (39 mg, 98%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c, 1H), 8,82 (c, 1H, usher.), 8,17 (d, 1H, J=7.5 Hz), to 7.59-rate of 7.54 (m, 2H), 7,34 (t, 1H, J=7.8 Hz), 7,19 (d, 1H, J=11,4 Hz), 7,12 (d, 1H, J=7.8 Hz), to 6.95 (d, 1H, J=15,9 Hz), 4,39 (d, 2H, J=5.4 Hz), 4.00 points (c, 3H), 3.00 and (c, 3H).

ESI [M+H]+: 448.

Example 61: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-hydroxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

The target compound was obtained according to the General procedure described in example 56 (stage 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (40 mg, 0,088 mmol) were introduced in the reaction with 2-aminoethanol (excess), obtaining the target compound (10 mg, 24%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c, 1H), 8,72 (c, 1H), 7,78 (d, 1H, J=7.5 Hz), 7,60 (d, 1H, J=15,0 Hz), 7,34 (t, 1H, J=7.5 Hz), 7,19 (d, 1H, J=10,8 Hz), 7,13 (d, 1H, J=8.1 Hz),? 7.04 baby mortality (c, 1H), 6,98 (d, 1H, J=7,2 Hz), 6,63 (d, 1H, J=15.3 Hz), 4,68 (c, 1H), and 4.40 (d, 2H, J=4.5 Hz), 3,55-of 3.54 (m, 2H), 3,42 is 3.40 (m, 2H), 3.00 and (c, 3H).

ESI [M+H]+: 477.

Example 62: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

It is Uspenie 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0,397 mmol) in pyrrolidine (1.0 ml) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, getting the 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 91%).

1H NMR (300 MHz, CDCl3): δ with 8.05 (d, 1H, J=15,9 Hz), 7,69 (d, 1H, J=10,8 Hz), 6,97 (d, 1H, J=10,8 Hz), 6,21 (d, 1H, J=15,9 Hz), 3,64-of 3.60 (m, 4H), 1,96-of 1.92 (m, 4H).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (94 mg, 0,327 mmol) were introduced in the reaction with 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (78 mg, 0,272 mmol)to give the target compound (110 mg, 80%).

1H NMR (300 MHz, DMSO-d6): δ 9,44 (c, 1H), 8,73 (t, 1H, J=9.0 Hz), 7,82 (d, 1H, J=7.5 Hz), 7,69 (d, 1H, J=15.3 Hz), 7,29-7,26 (m, 2H), 7,10 (d, 1H, J=7.8 Hz), to 6.43 (d, 1H, J=15,9 Hz)to 4.52 (c, 1H), to 4.38 (d, 2H, J=5.7 Hz), 3,51-3,47 (m, 4H), of 3.07 (c, 3H), 1,88 is 1.86 (m, 4H).

ESI [M+H]+: 511.

Example 63: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

To a suspension of 3-(chlor-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (40 mg, 0,088 mmol) in 1-butanol (0.5 ml) was added K2CO3(5 EQ.). The mixture was stirred for 12 hours at 110°C. the Reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized from a mixture of CH2Cl2/n-hexane, obtaining the target compound (40 mg, 93%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c, 1H), 8,83 (t, 1H, J=5.7 Hz), 8,16 (d, 1H, J=7.8 Hz), 7,58 (d, 1H, J=15,9 Hz), 7,52 (d, 1H, J=7.5 Hz), 7,35 (t, 1H, J=8.1 Hz), 7,19 (d, 1H, J=11,4 Hz), 7,12 (d, 1H, J=8.1 Hz), 6,92 (d, 1H, J=15,9 Hz), 4,42-to 4.38 (m, 4H), 3.00 and (c, 3H), 1,83-of 1.73 (m, 2H), 1,47-of 1.40 (m, 2H), were 0.94 (d, 3H, J=7.5 Hz).

ESI [M+H]+: 490.

Example 64: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-methyl-piperazine-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (70 mg, 0,057 mmol) were introduced in the reaction with N-methylpiperazine (30 ml)as in example 46, receiving after recrystallization from a mixture of Hex/EtOAc target compound (13 mg, 15%).

1H NMR (300 MHz, CDCl3): δ of 7.75 (d, 1H, J=7,2 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,29 (c, 1H), 7,18 (m, 2H), 6,44 (d, 1H, J=15.3 Hz), 6,12 (t, 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,39 (m, 4H), 3,26 (c, 3H), at 2.59 (m, 4H), 2,35 (c, 3H).

ESI [M+H]+: 540.

Example 65: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-triptime the Il-pyridin-3-yl]-acrylamide

A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (30 mg, 0.28 mmol) and 2-methoxyethylamine (100 μl) was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with water and then acidified 2 N. HCl solution. The aqueous phase was extracted with EtOAc, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=2/3)to give the target compound (4.0 mg, 12%).

1H NMR (300 MHz, CDCl3): δ the 7.65 (d, 1H, J=15.6 Hz), to 7.59 (d, 1H, J=7,2 Hz), 7,21 (c, 1H), 7,11 (d, 1H, J=10.5 Hz), 6,92 (d, 1H, J=7,2 Hz), 6,33 (d, 1H, J=15.6 Hz), 6,33 (t, 1H), 5.40 to (c, 1H), 4,47 (d, 2H, J=5.7 Hz), 3,71 (m, 2H), 3,61 (m, 2H), 3,44 (c, 1H), 3,37 (c, 3H), 3,28 (c, 3H).

ESI [M+H]+: 515.

Example 66: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0,158 mmol) and 1-butanol (0,029 ml, 0,316 mmol) in DMF (2 ml) at 0°C was added NaH (19 mg, 0.47 mmol). The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed 1 N. HCl, saturated what astora sodium bicarbonate and brine, was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, getting the 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 92%).

1H NMR (300 MHz, CDCl3): δ 7,88 (d, 1H, J=16.2 Hz), 7,88 (d, 1H, J=7.8 Hz), 7,28 (d, 1H, J=7.8 Hz), 6.73 x (d, 1H, J=16.2 Hz), 4,49 (t, 2H, J=6.6 Hz), 1,86-to 1.79 (m, 2H), 1,53 to 1.47 (m, 2H), and 1.00 (t, 3H, J=7.5 Hz).

Stage 2: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (25 mg, 0,087 mmol) were introduced in the reaction with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 0.73 mmol)to give the target compound (24 mg, 54%).

1H NMR (300 MHz, DMSO-d6): δ 9,44 (c, 1H), cent to 8.85 (t, 1H, J=6.0 Hz), 8,18 (d, 1H, J=7.5 Hz), 7,58 (d, 1H, J=15,9 Hz), 7,52 (d, 1H, J=7.5 Hz), 7,29-7,25 (m, 2H), 6,93 (d, 1H, J=15,9 Hz), 4,50 (c, 1H), 4,42-4,37 (m, 2H), 3,06 (c, 3H)and 1.83-of 1.73 (m, 2H), 1,50-of 1.42 (m, 2H), were 0.94 (d, 3H, J=7.5 Hz).

ESI [M+H]+: 514.

Example 67 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

The target compound was obtained according to the General procedure described in example 63 (step 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylic is ID (70 mg, 0,155 mmol) were introduced in the reaction with methoxyethanol, obtaining the target compound (50 mg, 66%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c, 1H), 8,82 (t, 1H, J=5.7 Hz), 8,19 (d, 1H, J=7.5 Hz), to 7.61-7,53 (m, 2H), 7,34 (t, 1H, J=8,4 Hz), 7,21 (d, 1H, J=11,4 Hz), 7,12 (d, 1H, J=8,4 Hz), 6,92 (d, 1H, J=15,9 Hz)to 4.52 (t, 2H, J=4,5 Hz), and 4.40 (d, 2H, J=5.7 Hz), 3,74 (t, 2H, J=4.5 Hz), 3,31 (c, 3H), 3.00 and (c, 3H).

ESI [M+H]+: 492.

Example 68: N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide

To a solution of 2-methyl-6-triftormetilfosfinov acid (500 mg, of 2.44 mmol) and N,O-dimethylhydroxylamine (285 mg, of 2.92 mmol) in dichloromethane (10 ml) was added N-methylmorpholine (0,32 ml of 2.92 mmol) and N-(3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (EDC, 560 mg of 2.92 mmol). The mixture was stirred at room temperature for 2 hours and washed with 1 N. HCl and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide quantitatively in the form of oil. The crude product was used directly in the next reaction.

1H NMR (300 MHz, CDCl3): δ to 7.77 (d, 1H, J=7.5 Hz), 7,56 (d, 1H, J=7.8 Hz), 3,44 (c OSiR., 3H), 3,39 (c OSiR., 1H), 2.63 in (c, 3H).

Stage 2: synthesis of 2-methyl-6-trifluoromethyl-3-PI is idencebuild

To a cooled (-78°C) solution of N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide (615 mg, 2.48 mmol) in THF (10 ml) was added lithium-aluminiumhydride (LAH, 1M/THF, 1.23 ml). The mixture was stirred for 15 minutes and then was heated to -10°C. After additional stirring for 30 minutes, the mixture was suppressed with a saturated solution of potassium hydrosulfate (1 ml) and was extracted with simple diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 2-methyl-6-trifluoromethyl-3-pyridinecarboxamide quantitatively in the form of oil. The crude product was used directly in the next reaction.

1H NMR (300 MHz, CDCl3): δ the 10.40 (c, 1H), 8,29 (d, 1H, J=8.1 Hz), 7,71 (d, 1H, J=8.1 Hz), 2,61 (c, 3H).

Stage 3: synthesis of 3-(2-methyl-6-triptorelin-3-yl)acrylic acid

To a solution of 2-methyl-6-trifluoromethyl-3-pyridinecarboxamide (440 mg, 2.32 mmol) in toluene (10 ml) was added methyl(triphenylphosphonium)acetate (855 mg, 2.56 mmol). The mixture was heated at 110°C overnight, cooled to room temperature and was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on columns (EtOAc/hexane=1/4)to give methyl ester 3-(2-methyl-6-triptoreline the n-3-yl)acrylic acid (376 mg, 65,9%) in the form of a mixture of CIS - and TRANS-isomers (CIS/TRANS=1/10). To a solution of ester (376 mg, 1.53 mmol) in THF (5 ml) was added 1 N. LiOH (2.5 ml). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The aqueous layer was then separated, acidified to pH 4 with 3 N. HCl and was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from a mixture of EtOAc/hexane, getting 3-(2-methyl-6-triptorelin-3-yl)acrylic acid (TRANS-isomer, 200 mg, 56.4 per cent) in the form of solids.

1H NMR (300 MHz, CDCl3): δ 8,05~of 7.97 (m, 2H), 7,58 (d, 1H, J=8.1 Hz), 6,47 (d, 1H, J=15,9 Hz), 2,75 (c, 3H).

Stage 5: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide

To a suspension of 3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl (73 mg, 0.26 mmol) in THF (5 ml) was added N-methylmorpholine (43 μl, 0,39 mmol). After stirring for 5 minutes was added 3-(2-methyl-6-triptorelin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM 73 mg, 0.26 mmol). The mixture was stirred at room temperature overnight, concentrated under reduced pressure and diluted with EtOAc and water. Organizes the second layer was dried over anhydrous magnesium sulfate, was filtered and concentrated under reduced pressure. The crude product was purified by recrystallization from a mixture of EtOAc/hexane, obtaining N-(3-ethinyl-5-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide (89 mg, 75,5%) in the form of solids.

1H NMR (300 MHz, CDCl3+ DMSO-d6): δ by 8.22 (c, 1H), 8,16 (t, 1H, J=5.7 Hz), 7,94 (d, 1H, J=8.1 Hz), to 7.84 (d, 1H, J=15.6 Hz), 7,54 (d, 1H, J=8.1 Hz), 7,33 (c, 1H), 7,19 (DD, 1H, J=10,5, 1.8 Hz), is 6.61 (d, 1H, J=15.3 Hz), 4,50 (d, 2H, J=5,7 Hz), 3,18 (c, 3H), 2,72 (c, 3H).

ESI [M+H]+: 456.

Example 69 N-(3-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide

Stage 1: synthesis of N-(3-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide

To a suspension of 3-fluoro-4-methanesulfonylaminoethyl (67 mg, 0.26 mmol) in THF (5 ml) was added N-methylmorpholine (43 μl, 0,39 mmol). After stirring for 5 minutes was added 3-(2-methyl-6-triptorelin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM 73 mg, 0.26 mmol). The mixture was stirred at room temperature overnight, concentrated under reduced pressure and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified re what kristallizatsiei from a mixture of EtOAc/hexane, receiving N-(3-fluoro-4-methanesulfonylaminoethyl)-3-(2-methyl-6-triptorelin-3-yl)acrylamide (66 mg, 58.8 per cent) in the form of solids.

1H NMR (300 MHz, CDCl3): δ 7.95 is~7,88 (m, 2H), 7,56~7,51 (m, 2H), 7.18 in~7,11 (m, 2H), 6,51 (c OSiR., 1H), 6,41 (d, 1H, J=15.6 Hz), 6,07 (t OSiR., 1H), 4,57 (d, 2H, J=6 Hz), 3,03 (c, 3H), 2,72 (c, 3H.)

ESI [M+H]+: 432.

Example 70: 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: synthesis of 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

60%NaH (24 mg, 3.0 EQ.) was placed in a flask and was added to the syringe 2-propanol (30 μl) in DMF (1 ml), stirred for some time, and finally was added at room temperature, 3-(2-chloro-6-trifluoromethyl-4-yl-pyridine-3-yl)-acrylic acid (50 mg). The reaction mixture was stirred for 18 hours. After completion of the reaction according to the test results TLC, the mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure to give crude 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (23 mg, 42%).

1H NMR (300 MHz, CDCl3): δ 7,86 (m, 2H), 7,24 (m, 1H), of 6.71 (d, 1H, J=15,9 Hz), 5,49 (m, 1H), USD 1.43 (m, 6H).

Stage 2: synthesis of 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl the-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, the HCl salt (23 mg, 0,084 mmol) were introduced in the reaction with 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (23 mg)to give after purification by chromatography on columns (Hex/EtOAc=3/2) 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (19 mg, 45%).

1H NMR (300 MHz, CDCl3): δ 7,81 (m, 1H), of 7.75 (d, 1H, J=15,9 Hz), 7,29 (c, 1H), 7,20 (m, 2H), 6.73 x (d, 1H, J=15,9 Hz), 6,44 (c, 1H), 6,12 (c OSiR., 1H), 5,48 (m, 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,47 (c, 1H), 3,26 (c, 3H), USD 1.43 (m, 6H).

ESI [M+H]+: 500.

Example 71: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-benzyloxycarbonyl-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Hydrochloride benzyl ester of L-Proline (96 mg, 2.0 EQ.) in DMF were placed in a flask and added K2CO3(132 mg, 2.0 EQ.), was stirred for some time and was added at room temperature, 3-(2-chloro-6-trifluoromethyl-4-yl-pyridine-3-yl)-acrylic acid (50 mg). The reaction mixture was stirred for 18 hours. After completion of the reaction according to the test results TLC, the mixture was diluted with EtOAc, washed with 1 N. HCl solution. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure to give crude benzyl ester 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid (45 mg). N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (30 mg, 0.11 mmol) vvodili reaction with benzyl ester 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid (45 mg), getting benzyl ester 1-{3-[2-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzylcarbamoyl)-vinyl]-6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid (3.2 mg, and 4.5%) after purification by chromatography on columns (EtOAc/MeOH=10/1).

1H NMR (300 MHz, CDCl3): δ 7,81 (d, 1H, J=15.6 Hz), to 7.67 (m, 1H), 7,29 (c, 1H), 7,19 (m, 5H), 6,92 (m, 1H), 6,86 (c OSiR., 1H), 6,40 (m, 2H), 6,09 (d, 1H, J=15,0 Hz), 4,49 (d, 2H, J=5.7 Hz), 4,32 (d, 2H, J=5.7 Hz), 3,48 (c, 1H), 3,26 (c, 3H), of 2.38 (m, 2H, in), 2.25 (m, 2H), 2,02 (m, 3H).

Example 72: 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (30 mg, 0,057 mmol) were introduced in the reaction with n-butylamine (500 μl)as in example 65, receiving after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (3.6 mg, 12%).

1H NMR (300 MHz, CDCl3): δ 7,66 (d, 1H, J=15.3 Hz), EUR 7.57 (d, 1H, J=7.8 Hz), 7.23 percent (c, 1H), 7,12 (DD, 1H, J=1,8 and 10.8 Hz), 6.89 in (d, 1H, J=7.8 Hz), 6,64 (c, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6,24 (t, 1H), 5,04 (c, 1H), 4,48 (d, 2H, J=6,0 Hz), 3,50 (m, 2H), 3.46 in (c, 1H), 3.27 to (c, 3H), of 1.61 (m, 2H), 1,36 (m, 2H), of 0.95 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 513.

Example 73: 3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (30 mg, 0,057 mmol) was introduced by the reaction with cyclopentylamine (500 μl), as in example 65, receiving after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (2.5 mg, 8%).

1H NMR (300 MHz, CDCl3): δ the 7.65 (d, 1H, J=15,0 Hz), 7,58 (d, 1H, J=7.5 Hz), 7,29 (c, 1H), 7,17 (DD, 1H, J=2.1 and up 10.8 Hz), 6.90 to (d, 1H, J=7.5 Hz), 6,46 (c, 1H), 6.35mm (d, 1H, J=15,0 Hz), 6,07 (t, 1H), 4,82 (c, 1H), 4.53-in (d, 2H, J=6.3 Hz), to 4.41 (m, 1H), 3,49 (c, 1H), 3.27 to (c, 3H), 2,17 (m, 2H), 1.70 to of 1.30 (m, 6H).

ESI [M+H]+: 525.

Example 74 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (50 mg, 0.11 mmol), 2-methyl-1-propanol (20 μl, 0.22 mmol) and 60% NaH (13 mg, 0.33 mmol) in DMF was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and then acidified 2 N. HCl solution. The aqueous phase was extracted with EtOAc, and the combined organic phase was washed with saline, dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=1/2)to give the target compound (12 mg, 40%).

1H NMR (300 MHz, CDCl3): δ of 7.97 (d, 1H, J=7.8 Hz), 7,83 (m, 2H), 7,71 (c, 1H), 7,31 (m, 2H), 7,22 (DD, 1H, J=1.8 and 10.5 Hz), 6,94 (d, 1H, J=15,9 Hz), of 4.54 (d, 2H, J=6.0 Hz), 4,22 (d, 2H, J=6.6 Hz), 3,64 (c, 1H), 3,18 (c, 3H), to 2.18 (m, 1H), was 1.04 (d, 6H, J=6.6 Hz).

ESI [M+H]+: 514.

Example 75 N-(3-ethinyl-5-fluoro-4-methanesulfonyl the Ino-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid

The target compound was obtained according to the General procedure described in example 66 (stage 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (86,6 mg, 0,344 mmol) were introduced in the reaction with methoxyethanol, getting 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (100 mg, 99%).

1H NMR (300 MHz, CDCl3): δ of 7.90 (d, 1H, J=7.5 Hz), 7,88 (d, 1H, J=16.2 Hz), 7,30 (d, 1H, J=7.5 Hz), 4,66-4,63 (m, 2H), 3,86-3,82 (m, 2H), 3,47 (c, 3H).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (45 mg, 0,156 mmol) were introduced in the reaction with 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (38 mg, 0.13 mmol)to give the target compound (47 mg, 70%).

1H NMR (300 MHz, DMSO-d6): δ 9,44 (c, 1H), cent to 8.85 (t, 1H, J=6.0 Hz), to 8.20 (d, 1H, J=7.5 Hz), 7,58 (d, 1H, J=16,8 Hz), 7,54 (d, 1H, J=8.1 Hz), 7,29-7,26 (m, 2H), 6,93 (d, 1H, J=15,9 Hz), 4,54-4,51 (m, 2H), and 4.40 (d, 2H, J=6.0 Hz), 3,97 (c, 1H), 3,76-to 3.73 (m, 2H), 3,31 (c, 3H), of 3.07 (c, 3H).

ESI [M+H]+: 516.

Example 76: 3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 3-(2-BU the Il-5-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (78 mg, 0.31 mmol) in THF (2 ml) was added dropwise at -78°C 2.5 M n-utility (2 EQ.). The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed 1 N. HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographically on the column, getting the 3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (14 mg, 17%).

1H NMR (300 MHz, CDCl3): δ 7,83 (d, 1H, J=16.5 Hz), 7,51 (c, 1H), 6.35mm (d, 1H, J=16.5 Hz), 2,79-of 2.66 (m, 2H), 1,66 of 1.50 (m, 2H), 1,50-of 1.44 (m, 2H), and 0.98 (t, 3H, J=7.5 Hz).

Stage 2: 3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (13 mg, 0,044 mmol) were introduced in the reaction with 3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (14 mg, being 0.036 mmol)to give the target compound (18 mg, 86%).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c, 1H), 8,92 (t, 1H, J=6.0 Hz), 7,92 (c, 1H), 7,50 (d, 1H, J=15.6 Hz), 7,30-7,29 (m, 2H), 6,55 (d, 1H, J=15,9 Hz)to 4.52 (c, 1H), to 4.41 (d, 2H, J=5.7 Hz), to 3.02 (c, 3H), 2,80-of 2.75 (m, 2H), 1,59-1,49 (m, 2H), from 0.88 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 532.

Example 77: 3-(2-WTO is butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

2-Butanol (70.1 mg, 0,945 mmol) and sodium hydride (70 mg, 1.8 mmol) was added to DMF. The reaction mixture was stirred for 10 minutes and then the reaction mixture was added 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0,266 mmol). The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=1/1)to give the desired product (52 mg).

1H NMR (300 MHz, CDCl3): δ 7,89 (d, 1H, J=7,2), 7,86 (d, 1H, J=3.6 Hz), 7,25 (d, 1H, J=7.8 Hz), 6,72 (d, 1H, J=16.2 Hz), 5,35 (h, 1H, J=6.0 Hz), to 1.79 (m, 2H), 1.26 in (m, 3H), of 1.02 (m, 3H).

Stage 2: 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (35 mg, 0.13 mmol) were introduced in the reaction with 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (22 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (10 mg).

1H NMR (300 MHz, CDCl3): δ of 7.82 (d, 1H, J=7.8 Hz), of 7.75 (d, 1H, J=15.6 Hz), 7,27 (d, 1H, J=15,9 Hz), 7,21 (m, 3H), 6.73 x (d, 1H, J=15.6 Hz), 6,44 (c, 1H), 6,11 (t, 1H), 5,33 (h, 1H, J=6.3 Hz), a 4.53 (d, 2H, J=6.3 Hz), 3,48 (c, 1H), 3,26 (c, 3H), of 1.37 (d, 3H, J=6.0 Hz), and 0.98 (t, 3H, J=7.2 Hz).

ESI [M+] +: 514.

Example 78 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

Phenol (57 mg, of 0.60 mmol) and sodium hydride (32 mg, 0.8 mmol) was added to DMF (15 ml). The reaction mixture was stirred for 10 minutes and then the reaction mixture was added 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol). The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=1/1)to give the desired product (15 mg).

1H NMR (300 MHz, CDCl3): δ 8,07 (d, 1H, J=15,9 Hz), of 8.04 (d, 1H, J=7.5 Hz), the 7.43 (m, 3H), 7,21 (m, 2H), 6,79 (d, 1H, J=15,9 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (35 mg, 0.13 mmol) were introduced in the reaction with 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (17 mg), obtaining the target compound (22 mg, 75%) after purification by chromatography on columns (Hex/EtOAc=1/1).

1H NMR (300 MHz, CDCl3): δ of 7.90 (d, 1H, J=7.5 Hz), 7,80 (d, 1H, J=15.6 Hz), 7,33 (m, 3H), 7,21 (m, 2H), 7,03 (m, 2H), 6,80 (d, 1H, J=15.6 Hz), 6,45 (c, 1H), 6,37 (t, 1H), 4,43 (d, 2H, J=6.0 Hz),3,32 (c, 1H), 3,22 (c, 3H).

ESI [M+H]+: 534.

Example 79: 3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (50 mg, 0.11 mmol) and 3-hydroxymitragynine (18 μl, 0.22 mmol) was introduced into the reaction as in example 72, obtaining the target compound (23 mg, 21%).

1H NMR (300 MHz, CDCl3): δ a 7.85 (d, 1H, J=7.8 Hz), 7,71 (d, 1H, J=15,9 Hz), 7,30 (d, 1H, J=7.8 Hz), 7,29 (c, 1H), 7,18 (DD, 1H, J=2.1 and up 10.8 Hz), 6,77 (d, 1H, J=15,9 Hz), 6,51 (c, 1H), 6,41 (t, 1H), 5,74 (m, 1H), to 4.52 (d, 2H, J=6,0 Hz), of 4.05 (m, 3H), 3,91 (m, 1H), 3.46 in (c, 1H), 3,25 (c, 3H), 2,35 (m, 1H), 2,30 (m, 1H).

ESI [M+H]+: 528.

Example 80 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-pyrazole-1-yl-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: 3-(5-chloro-2-pyrazole-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

The target compound was obtained according to the General procedure described in example 66 (stage 1).

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0,397 mmol) were introduced in the reaction with pyrazole, getting 3-(5-chloro-2-pyrazole-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 99%).

1H NMR (300 MHz, CDCl3): δ 8,59 (d, 1H, J=15,9 Hz), 8,53 (d, 1H, J=2.7 Hz), 8,16 (d, 1H, J=8.1 Hz), to 7.84 (d, 1H, J=0.6 Hz), to 7.64 (d, 1H, J=8.1 Hz), 5,52 (d, 1H, J=2.7 Hz), 6.42 per (d, 1H, J=15,9 Hz).

Stage 2: N-(3-e is inil-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

The target compound was obtained according to the General procedure described in example 38 (stage 6).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (8.5 mg, 0,029 mmol) were introduced in the reaction with 3-(5-chloro-2-pyrazole-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (7 mg, of 0.025 mmol), obtaining the target compound (9 mg, 70%).

1H NMR (300 MHz, CDCl3): δ of 8.47 (d, 1H, J=2.7 Hz), 8,32 (d, 1H, J=15,9 Hz), 8,11 (d, 1H, J=7.8 Hz), 7,80 (d, 1H, J=0.6 Hz), 7,60 (d, 1H, J=7.8 Hz), 7.23 percent (c, 1H), 7,15-7,11 (m, 1H), 6,59-of 6.49 (m, 3H), 6,38 (d, 1H, J=15,9 Hz), to 4.46 (d, 2H, J=6.0 Hz), 3,44 (c, 1H), 3,24 (c, 3H).

ESI [M+H]+: 534.

Example 81: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(pyridine-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (48 mg, 0.11 mmol), 3-hydroxypyridine (97 mg) and potassium carbonate (421 mg) was added in 40 ml of DMF. The reaction mixture was stirred over night. The reaction mixture was extracted with ethyl acetate (30 ml × 2) and water (30 ml). The combined organic layer was washed H2O (30 ml × 4) and brine (40 ml), dried MgSO4and then concentrated in vacuum. The residue was purified by chromatography on columns (hexane/ethyl acetate=1/4)to give the target compound (46 mg, 82%).

1H NMR (300 MHz, acetone-d6): δ 8,53 (d, 1H, J=2.4 Hz), to 8.45 (DD, 1H, J=4,5, 1.2 Hz), 8,31 (d, 1H, J=7.8 Hz), 8,00 (t OSiR., 1H), 7,83 (d, 1H, J=15,9 Hz), and 7.7 (m, 1H), 7,60 (d, 1H, J=7.8 Hz), 7,44 (m, 1H), 7,20 (m, 1H), 7,12 (d, 1H, J=15,9 Hz), 4,50 (d, 2H, J=6.0 Hz), 2,98 (c, 3H).

Example 82 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: 3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid

4-Terfenol (116 mg, of 1.03 mmol) and sodium hydride (53 mg, 1.3 mmol) was added in DMF (7 ml). The reaction mixture was stirred for 10 minutes and then the reaction mixture was added 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (132 mg, 0.52 mmol). The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=1/1)to give the desired product (57 mg).

1H NMR (300 MHz, CDCl3): δ of 8.00 (d, 1H, J=15,9 Hz), to 7.99 (d, 1H, J=7.8 Hz), was 7.36 (d, 1H, J=7.8 Hz), was 7.08 (m, 3H), 6.73 x (d, 1H, J=15,9 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (32 mg, 0.13 mmol) were introduced in the reaction with 3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (25 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (42 mg, 67%).

1H NMR (300 MHz, CDCl3) δ of 7.90 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=15.6 Hz), 7,30 (d, 1H, J=7.5 Hz), 7,19 (c, 1H), 7,03 (m, 4H), 6,79 (d, 1H, J=15.6 Hz), 6,64 (t usher, 1H), 6,57 (c, 1H), to 4.41 (d, 2H, J=6.0 Hz), 3,37 (c, 1H), and 3.16 (c, 3H).

Example 83 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-hydroxymethyl-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (17 mg, 0.06 mmol) were introduced in the reaction with 2-(2-hydroxymethyl-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 0.06 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (15 mg, 46%).

1H NMR (300 MHz, CDCl3): δ 7,88 (d, 1H, J=15.6 Hz), to 7.68 (m, 1H), 7,30 (c, 1H), 7,18 (m, 1H), 7,03 (m, 1H), 6,44 (c, 1H), of 6.20 (d, 1H, J=15,0 Hz), 6,05 (c OSiR., 1H), to 4.52 (d, 1H, J=6.3 Hz), with 3.79 (m, 6H), to 3.41 (m, 3H), 3.27 to (c, 3H).

Example 84 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (69 mg, 0.25 mmol) were introduced in the reaction with 2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl-acrylic acid (78 mg, 0.26 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (73 mg, 54%).

1H NMR (300 MHz, CDCl3): δ a 7.92 (d, 1H, J=7.5 Hz), 7,73 (d, 1H, J=16,8 Hz), 7,42 (d, 1H, J=7.8 Hz), 7,20 (m, 2H), 6,77 (d, 1H, J=15.6 Hz), 6,41 (c, 1H), 6,03 (c OSiR., 1H), 4,90 (d, 2H, J=8.1 Hz), 4,55 (d, 2H, J=5.7 Hz), 3,89 (c, 1H) 3,26 (c, 3H).

Example 85 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-4-trifluoromethyl-phenyl]-acrylamide

Stage 1: synthesis of 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid.

To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0,198 mmol) in 3-ethoxypyrrolidine (40 mg, 0,396 mmol) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times 1 N. HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographically, getting 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (59 mg, 98%).

1H NMR (300 MHz, CDCl3): δ of 8.06 (d, 1H, J=15,9 Hz), 7,71 (d, 1H, J=7.5 Hz), 7,01 (d, 1H, J=7,50 Hz), 6,23 (d, 1H, J=15,9 Hz), of 4.05 (t, 1H, J=2.1 Hz), 3,89-to 3.58 (m, 2H), 3,69-to 3.58 (m, 2H), 3,37 (c, 3H), 2,18-2,11 (m, 1H), 2,05-1,94 (m, 1H).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-4-trifluoromethyl-phenyl]-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (16.6 mg, 0,057 mmol) were introduced in the reaction with 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (15.2 mg, 0,048 mmol)to give after purification of precrystallization is from a mixture of n-hexane/EtOAc N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (18 mg, 58%).

1H NMR (300 MHz, DMSO): δ 9,45 (c, 1H, usher.), is 8.75 (t, 1H, J=6.0 Hz), 7,83 (d, 1H, J=7.8 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,28 (c, 1H), 7,27 (d, 1H, J=7.8 Hz), 7,13 (d, 1H, J=7.8 Hz), 6,45 (d, 1H, J=15.6 Hz), 4,50 (c, 1H), to 4.38 (d, 2H, J=5.7 Hz), 4,00 (d, 1H, J=1.8 Hz), 3,71-of 3.12 (m, 7H), 3,06 (c, 3H), 2.00 in with 1.92 (m, 2H).

Example 86: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-propionamide.

To a suspension of 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide (19.3 mg, 0,039 mmol) in 5%om Pd/C (6 mg) was added CH3OH (1.0 ml). The mixture was purged three times with gaseous hydrogen (50 psi) and which for 40 minutes at room temperature. The reaction mixture was filtered through a layer of celite and concentrated under reduced pressure. The crude residue was chromatographically, getting 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-propionamide (19 mg, 98%).

1H NMR (300 MHz, DMSO): δ 9,49 (c, 1H, user), 8,43 (c, 1H), 7,71 (d, 1H, J=7.5 Hz), 7,35 (d, 1H, J=7,2 Hz), 7,28 (t, 1H, J=8.1 Hz), 6,70 (d, 1H, J=8,4 Hz), of 6.96 (d, 1H, J=9.0 Hz), or 4.31 (t, 2H, J=3.3 Hz), 4,21 (d, 2H, J=5.7 Hz), 2,87 (c, 3H), 2,85 (t, 2H, J=8,2 Hz), of 2.51-2,47 (m, 2H), 1.77 in by 1.68 (m, 2H), 1,50 to 1.37 (m, 2H), of 0.93 (t, 3H, J=7.5 Hz).

Example 87: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl (41 mg, 0.16 mmol) were introduced in the reaction with 2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl-acrylic acid (50 mg, 0.16 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (53 mg, 64%).

1H NMR (300 MHz, CDCl3): δ a 7.92 (d, 1H, J=8.1 Hz), 7,73 (d, 1H, J=15.3 Hz), 7,55 (t, 1H, J=8.7 Hz), 7,42 (d, 1H, J=7,42 Hz), to 7.15 (m, 2H), 6,78 (d, 1H, J=16.2 Hz), 6,50 (c OSiR., 1H), 6,03 (c OSiR., 1H), 4,90 (q, 2H, J=7.8 Hz), of 4.57 (d, 2H, J=5.7 Hz), 3,03 (c, 3H).

Example 88: 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (53 mg, 0,19 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (10 mg, being 0.036 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (12 mg, 69%).

1H NMR (300 MHz, CDCl3): δ to 7.68 (d, 1H, J=15,0 Hz), EUR 7.57 (d, 1H, J=7.5 Hz), of 7.48 (t, 1H, J=8,4 Hz), 7,10 (m, 2H), 6.89 in (d, 1H, J=7.5 Hz), 6,80 (c, 1H), 6,37 (d, 1H, J=15,0 Hz), 6,12 (t, 1H, J=6.0 Hz), to 6.95 (t, 1H, J=5.4 Hz), of 4.54 (d, 2H, J=6.0 Hz), 3,50 (m, 2H), 3,03 (c, 3H), of 1.61 (m, 2H), 1,40 (m, 2H), of 0.95 (t, 3H, J=7.5 Hz).

Example 89: 3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (53 mg, 0,19 mmol) were introduced in the reaction with 3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (10 mg, 0,034 mmol), olucha after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (6.3 mg, 38%).

1H NMR (300 MHz, CDCl3): δ the 7.65 (d, 1H, J=15.3 Hz), 7,56 (m, 2H), 7,13 (m, 2H), 6.89 in (d, 1H, J=7.8 Hz), 6,60 (c, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6,03 (t, 1H), 4,82 (d, 1H, J=6.3 Hz), 4,56 (d, 2H, J=6.0 Hz), and 4.40 (m, 1H), 3,03 (c, 3H), and 2.14 (m, 2H), 1,67 (m, 4H), of 1.44 (m, 2H).

Example 90 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (to 14.5 mg, 0,057 mmol) were introduced in the reaction with 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (15 mg, 0,047 mmol)to give after purification by recrystallization from a mixture of n-hexane/CH2Cl2N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (22 mg, 76%).

1H NMR (300 MHz, DMSO): δ of 9.55 (c, 1H, usher.), 8,71 (t, 1H, J=5.7 Hz), 7,81 (d, 1H, J=7.5 Hz), to 7.67 (d, 1H, J=15.3 Hz), 7,34 (t, 1H, J=8,4 Hz), 7,21-7,10 (m, 2H), 6,44 (d, 1H, J=15.6 Hz), to 4.38 (d, 1H, J=6.0 Hz), 4,01 (c, 1H), 3,71-and 3.16 (m, 7H), 2,99 (c, 3H), 2.00 in of 1.93 (m, 2H).

Example 91 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide

To a suspension of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (15 mg, 0,029 mmol) in 5%om Pd/C (5 mg) was added CH3OH (1.0 ml). The mixture was purged three times with gaseous hydrogen (50 psi) and C is the which was for 40 minutes at room temperature. The reaction mixture was filtered through a layer of celite and concentrated under reduced pressure. The crude residue was chromatographically, receiving N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide (15 mg, 98%).

1H NMR (300 MHz, CDCl3): δ 7,33 (d, 1H, J=7,2 Hz), 7,12 (c, 1H), of 6.96 (DD, 1H, J=10,5, 1.8 Hz), 6.89 in (d, 1H, J=7.8 Hz), 6,39 (c, 1H), 5,78 (c, 1H, usher.), 4,27 (d, 2H, J=6.0 Hz), 3,89 (c, 1H), 3,50-of 3.42 (m, 4H), 3,20 (c, 3H), 3,05 (t, 2H, J=7.5 Hz), is 2.41 (t, 2H, J=7.5 Hz), 1,91 is 1.86 (m, 4H).

Example 92: 3-(2-cyclopentyloxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (41 mg, 0.15 mmol) were introduced in the reaction with 3-(2-cyclopentyloxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0.13 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (50 mg, 73%).

1H NMR (300 MHz, CDCl3): δ 7,80 (d, 1H, J=7.5 Hz), 7,74 (d, 1H, J=15,9 Hz), 7,22 (m, 3H), 6,72 (d, 1H, J=15,9 Hz), 6,41 (c, 1H), 6,02 (t, 1H), 5,58 (m, 1H), 4,54 (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,26 (c, 3H), equal to 1.82 (m, 8H).

Example 93: 3-(2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (41 mg, 0.15 mmol) were introduced in the reaction with 3-(2-cyclopropylmethoxy-6-trifluoromethyl-pyridine-3-is)-acrylic acid (10 mg, being 0.036 mmol)to give after crystallization from a mixture of EtOAc/Hex the target compound (48 mg, 72%).

1H NMR (300 MHz, CDCl3): δ 7,81 (m, 2H), 7,26 (m, 3H), to 6.80 (d, 1H, J=15.6 Hz), 6,40 (c, 1H), 6,00 (t, 1H), 4,55 (d, 2H, J=6.3 Hz), or 4.31 (d, 2H, J=7.5 Hz), 3,48 (c, 1H), 3.27 to (c, 3H), 1.39 in (m, 1H), 0,63 (m, 2H), and 0.40 (m, 2H,).

Example 94: 3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (33 mg, 0.12 mmol) were introduced in the reaction with 3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (26 mg, 0.10 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (42 mg, 87%).

1H NMR (300 MHz, CDCl3): δ to 7.77 (d, 1H, J=15.6 Hz), of 7.70 (d, 1H, J=7.8 Hz), 7,30 (c, 1H), 7,18 (d, 1H, J=10,8 Hz), 7,10 (d, 1H, J=7.8 Hz), 6,41 (c, 1H), 6.35mm (d, 1H, J=15.6 Hz), 5,96 (t, 1H), 4,54 (d, 2H, J=6.0 Hz), 3.46 in (c, 1H), 3.27 to (c, 3H), 3,01 (c, 6H).

Example 95 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (60 mg, 0.24 mmol) were introduced in the reaction with 3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (34 mg, 25%).

1H NMR (300 MHz, CDCl3): δ 7,74 (d, 1H, J=7.8 Hz), 7,69 (d, 1H, J=1.6 Hz), rate of 7.54 (m, 1H), 7,18 (m, 2H), 6,51 (c, 1H), 6,47 (d, 1H, J=15,9 Hz), 6,04 (c OSiR., 1H), 4,57 (d, 2H, J=6.0 Hz), 4,16 (d, 2H, J=7,2 Hz), and 3.72 (m, 2H), 3,03 (c, 3H), 2,99 (m, 2H), 2,50 (m, 1H), 1,96 (m, 4H), of 1.28 (t, 3H, J=7.2 Hz).

Example 96 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-benzyloxy 6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(5-Ethinyl-4-aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (58 mg, 0.21 mmol) were introduced in the reaction with 3-(2-benzyloxy 6-trifluoromethyl-pyridin-3-yl)-acrylic acid (87 mg, 0.21 mmol)to give the target compound (75 mg, 66%) after purification by chromatography on columns (Hex/EtOAc=2/3).

1H NMR (300 MHz, CDCl3): δ 7,83 (m, 1H), of 7.75 (d, 1H, J=15,9 Hz), 7,49 (m, 2H), 7,35 (m, 5H), to 7.15 (m, 1H), 6,74 (d, 1H, J=15.6 Hz), 6,39 (c, 1H), 5,93 (c OSiR., 1H), 5,54 (c, 2H), 4,51 (d, 2H, J=6.3 Hz), 3,48 (c, 1H), 3,26 (c, 3H).

Example 97 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (33 mg, the amount of 0.118 mmol) were introduced in the reaction with 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (33 mg, the amount of 0.118 mmol)to give after purification by recrystallization from Et2O N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (33 mg, 55%).

1H NMR (300 MHz, DMSO): δ 10,07 (c, 1H, usher.), 8,77 (t, 1H, J=6.0 Hz), 7,82 (d, 1H, J=7.8 Hz), of 7.70 (d, 1H, J=15.6 Hz), 7,76-of 7.60 (m, 2H), 7,10 (d, 1H, J=7,8 Hz), 43 (d, 1H, J=15.6 Hz), of 4.44 (d, 1H, J=6.0 Hz), 3,51-to 3.34 (m, 4H), 3,11 (c, 3H), 1,88-of 1.84 (m, 4H).

Example 98: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (33 mg, the amount of 0.118 mmol) were introduced in the reaction with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (34 mg, the amount of 0.118 mmol)to give after purification by recrystallization from Et2O 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (32 mg, 53%).

1H NMR (300 MHz, DMSO): δ 10,07 (c, 1H, usher.), of 8.90 (t, 1H, J=6.0 Hz), 8,18 (d, 1H, J=7.5 Hz), 7,76-7,51 (m, 4H), 6,93 (d, 1H, J=15,9 Hz), of 4.45 (d, 2H, J=5.4 Hz), and 4.40 (t, 2H, J=6.3 Hz), 3,10 (c, 3H), 1,83-of 1.73 (m, 2H), 1,47-of 1.40 (m, 2H), were 0.94 (t, 3H, J=7.5 Hz).

Example 99 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (33 mg, the amount of 0.118 mmol) were introduced in the reaction with 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (34 mg, the amount of 0.118 mmol)to give after purification by recrystallization from Et2O N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (38 mg, 62%).

1H NMR (300 MHz, DMSO): δ 10,08 (c, 1H, usher.), 8,89 (t, 1H, J=5.4 Hz), to 8.20 (d, 1H, J=7.5 Hz), of 7.64-7,53 (m, 3H), 6,93 (d, 1H, J=15,9 Hz), 4,54-of 4.44 (m, 4H), 374 (t, 2H, J=4.5 Hz), 3,31 (c, 3H), to 3.09 (m, 4H).

Example 100 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (58 mg, 0.21 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 0.18 mmol)to give after purification by chromatography on columns (Hex/EtOAc=3/5) of the target compound (40 mg, 45%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 8,40 (c OSiR., 1H), to 8.20 (t, 1H, J=5.7 Hz), to 7.59 (m, 2H), 7,32 (c, 1H), 7,19 (DD, 1H, J=2.1 and 10.5 Hz), to 6.88 (d, 1H, J=7.8 Hz), 6,53 (d, 1H, J=15.3 Hz), free 5.01 (d, 1H, J=7,2 Hz), 4,48 (d, 2H, J=6.0 Hz), 4,33 (m, 1H), 3,48 (c, 1H), 3,17 (c, 3H), of 1.25 (d, 6H, J=6.3 Hz).

ESI [M+H]+: 499.

Example 101: N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-5-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (168 mg, of 0.60 mmol) were introduced in the reaction with 3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (145 mg, 0.50 mmol)to give after crystallization from a mixture of MeOH/EtOAc/Hex the target compound (189 mg, 73%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 9,90 (c OSiR., 1H), 8,63 (t, 1H, J=6.0 Hz), to 7.64 (d, 1H, J=7.8 Hz), 7,58 (d, 1H, J=15.3 Hz), 7,45 (c, 1H), 7,43 (DD, 1H, J=1,8 and 10.2 Hz), 6,83 (d, 1H, J=7.8 Hz), 6,24 (t, 1H, J=5,1 Hz), of 6.52 (d, 1H, J=15.3 Hz), 4,42 (d, 2H, J=6.0 Hz), 3,52 (m, 4H), 3.27 to (c, 3H), 3.04 from (c, 3H).

Example 102 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (130 mg, 0.46 mmol) were introduced in the reaction mixture (120 mg), 3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid and 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, getting after purification by chromatography on columns (Hex/EtOAc=1/1) followed by recrystallization from a mixture of EtOAc/hexane N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide (59 mg).

1H NMR (300 MHz, CDCl3): δ for 7.78 (d, 1H, J=15 Hz), 7,71 (d, 1H, J=7,2 Hz), 7,49~7,42 (m, 2H), 7,11 (d, 1H, J=7.8 Hz), 6,39~6,34 (m, 2H), equal to 6.05 (m, 1H), 4,59 (d, 2H, J=6.3 Hz), 3.33 and (c, 3H), 3,02 (c, 6H).

Example 103 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (130 mg, 0.46 mmol) were introduced in the reaction mixture (120 mg), 3-(2-dimethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid and 3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, getting after purification by chromatography on columns (Hex/EtOAc=1/1) followed by recrystallization from a mixture of EtOAc/hexane N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-triptime the Il-pyridin-3-yl)-acrylamide (7 mg).

1H NMR (300 MHz, CDCl3): δ 7,81 (d, 1H, J=7.5 Hz), 7,72 (d, 1H, J=15.6 Hz), 7,42~7,38 (m, 2H), 7.23 percent (d, 1H, J=7.8 Hz), 6.75 in (t, 1H, J=6 Hz), 6,55 (d, 1H, J=15.3 Hz), 4,56 (d, 2H, J=6 Hz), 3,85~is 3.82 (m, 4H), 3,35~of 3.32 (m, 4H), 3,23 (c, 3H).

Example 104: 3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (76 mg, 0.30 mmol) were introduced in the reaction with 3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (60 mg, 0.20 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (70 mg, 70%).

1H NMR (300 MHz, CDCl3): δ to 7.84 (d, 1H, J=7.8 Hz), 7,71 (d, 1H, J=15,9 Hz), 7,51 (t, 1H, J=8,4 Hz), 7,30 (d, 1H, J=7.8 Hz), 7,13 (m, 2H), 6,79 (d, 1H, J=15,9 Hz), 6.73 x (c, 1H), 6,46 (t, 1H, J=6.0 Hz), USD 5.76 (m, 1H), 4,54 (d, 2H, J=6.0 Hz), of 4.05 (m, 2H), 3,91 (m, 2H), 3,02 (c, 3H), 2,35 (m, 1H), measuring 2.20 (m, 1H).

Example 105 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-cyano-phenyl)-methanesulfonamide, HCl salt (to 48.5 mg, 0,173 mmol) were introduced in the reaction with NMM (0,07 ml), DMTMM (55 mg) and 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.16 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (66 mg, 76%).

1H NMR (300 MHz, CD3OD): δ to 8.20 (d, 1H, J=7.5 Hz), 7,83 (d, 1H, J=16.2 Hz), was 7.45 (m, 4H), to 7.15 (m, 2H), 6,99 (d, 1H, J=15.9 G is), 4,47 (c, 2H), 3,05 (c, 3H).

Example 106: 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-cyano-phenyl)-methanesulfonamide, HCl salt (46,1 mg, 0,165 mmol) were introduced in the reaction with NMM (0.2 ml), DMTMM (60.1 mg) and 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (43 mg, 0.15 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (57 mg, 75%).

1H NMR (300 MHz, CD3OD): δ 8,02 (d, 1H, J=7.8 Hz), 7,69 (d, 1H, J=15,9 Hz), 7,52 (m, 1H), 7,47 (DD, 1H, J=0.75 and 9.9 Hz), 7,30 (d, 1H, J=7.8 Hz), 6.87 in (d, 1H, J=15,9 Hz), m, 2H), 5,27 (m, 1H), 4,89 (c, 1H), 3,07 (c, 3H), 1,33 (d, 3H, J=6.0 Hz), of 0.95 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 515.

Example 107 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

In a microwave vial was loaded ethyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0,376 mmol), phenylboronic acid (2 equiv.) Cs2CO3(3 equiv.) Pd(PPh3)2Cl2(0.08 EQ.), DME (1 ml) and ethanol (0.25 ml). The vial was irradiated in a microwave synthesizer at 140°C for 20 minutes the Contents of the vial were filtered through celite, which was then thoroughly washed with methanol. F is ltrate was evaporated, and the residue was purified by chromatography on columns, obtaining the ethyl ester of 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (96 mg, 80%).

1H NMR (300 MHz, CDCl3): δ 8,07 (d, 1H, J=7.5 Hz), 7,73 (d, 1H, J=16.2 Hz), to 7.64 (d, 1H, J=8.1 Hz), EUR 7.57-7,53 (m, 2H), 7,47-the 7.43 (m, 3H), of 6.45 (d, 1H, J=16,3 Hz), is 4.21 (q, 2H, J=7.2 Hz), 1.26 in (t, 3H, J=7.2 Hz).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

To a suspension of ethyl ester of 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (20 mg, holding 0.062 mmol) in THF (1 ml) was added an aqueous solution of 0.5 N. LiOH (0.3 ml)and the mixture was stirred for 3 hours at room temperature. The obtained residue was dissolved in H2O and then washed three times with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4and concentrated in vacuum, obtaining 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 96%). To a suspension of N-(4-aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0,074 mmol) in THF (3 ml) was added N-methylmorpholine (of 0.015 ml, 0,148 mmol). The mixture was stirred for 5 minutes, then was added 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 0,065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM 19 mg, 0,068 mmol). The mixture was stirred over night at room themes is the temperature value and then concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1 N. HCl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by recrystallization from Et2O, receiving N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (18 mg, 56%).

1H NMR (300 MHz, DMSO): δ 9,46 (c, 1H, usher.), cent to 8.85 (t, 1H, J=5.7 Hz), 8,39 (d, 1H, J=8.1 Hz), 7,98 (d, 1H, J=8.1 Hz), to 7.61-rate of 7.54 (m, 5H), was 7.45 (d, 1H, J=15,9 Hz), 7,26 (m, 2H), at 6.84 (d, 1H, J=15,9 Hz)to 4.52 (c, 1H), 4,36 (d, 2H, J=5.7 Hz), 3,06 (c, 3H).

Example 108 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (46 mg, 0.18 mmol) were introduced in the reaction with 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.18 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/1) of the target compound (34 mg, 25%).

1H NMR (300 MHz, CDCl3): δ 7,81 (d, 1H, J=7.8 Hz), 7,76 (d, 1H, J=15.6 Hz), 7,54 (m, 1H), 7,19 (m, 3H), 6,72 (d, 1H, J=15.6 Hz), 6,51 (c, 1H), 6,03 (c OSiR., 1H), 5,48 (septet, 1H, J=6.0 Hz), of 4.57 (d, 2H, J=6.3 Hz), 3,03 (c, 3H), of 1.41 (d, 6H, J=7.2 Hz).

Example 109 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-cyano-2-fluoro-phenyl)-meth is sulfonamid, the HCl salt (51 mg, 0.18 mmol) were introduced in the reaction with 3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.18 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (44 mg, 51%).

1H NMR (300 MHz, DMSO-d6): δ 10,08 (c OSiR., 1H), 8,90 (m, 1H), 8,177 (d, 1H, J=7.8 Hz), 7,56 (m, 4H), 7,35 (septet, 1H, J=6.0 Hz), of 4.44 (d, 2H, J=5.7 Hz), is 3.08 (c, 3H), of 1.38 (d, 6H, J=6.0 Hz).

Example 110 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (75 mg, 0.27 mmol) were introduced in the reaction with 3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (100 mg, 0.27 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (111 mg, 69%).

1H NMR (300 MHz, CDCl3): δ 7,72 (m, 2H), 7,31 (c OSiR., 1H), 7,19 (m, 2H), 6,45 (d, 2H, J=15.6 Hz), 6,41 (c OSiR., 1H), 6,00 (c OSiR., 1H), 4,54 (d, 2H, J=6.3 Hz), is 4.15 (q, 2H, J=7,2 Hz), 3,71 (m, 2H), 3,49 (c, 1H), 3.27 to (c, 3H), 3,01 (m, 2H), of 2.51 (m, 1H), 1,96 (m, 4H), of 1.27 (t, 3H, J=7.2 Hz).

Example 111 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-5-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (39 mg, 0.14 mmol) were introduced in the reaction with 3-[2-(4-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridi the-3-yl]-acrylic acid (52 mg, 0.14 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (63 mg, 75%).

1H NMR (300 MHz, CDCl3): δ to 7.77 (m, 1H), of 7.70 (d, 1H, J=15,0 Hz), 7,46 (m, 2H), 7,21 (m, 1H), 6,50 (d, 1H, J=15.6 Hz), 6,44 (c OSiR., 1H), 4,59 (d, 2H, J=6.6 Hz), of 4.16 (q, 2H, J=7,2 Hz), and 3.72 (m, 2H), 3,32 (c, 3H), to 3.02 (m, 2H), 2,52 (m, 1H), 1,96 (m, 4H), of 1.28 (t, 3H, J=7.2 Hz).

Example 112: 3-(2-benzyloxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0,083 mmol) were introduced in the reaction with 3-(2-benzyloxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (35 mg, 0,083 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (18 mg, 41%).

1H NMR (300 MHz, CDCl3): δ to 7.84 (m, 1H), 7,76 (d, 1H, J=15,9 Hz), 7,49 (m, 3H), 7,35 (m, 4H), 7,12 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), 6,46 (c, 1H), of 5.92 (c OSiR., 1H), 5,54 (c, 2H), 4,54 (d, 2H, J=6.3 Hz), to 3.02 (c, 3H).

Example 113 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (31 mg, 0.11 mmol) were introduced in the reaction with 3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 0.06 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (10 mg, 17%).

1H NMR (300 MHz, CDCl3): δ EUR 7.57 (d, 1H, J=16.2 Hz), the 7.43 (m, 5H), of 7.23 (m, 3H), 7,06 m, 1H), of 6.49 (d, 1H, J=15,9 Hz), 6,45 (c OSiR., 1H), 6,29 (c OSiR., 1H), 4,34 (d, 2H, J=6.6 Hz), 3.46 in (c, 1H), 3,31 (c, 3H).

Example 114 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(5-Ethinyl-4-aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (75 mg, 0.27 mmol) were introduced in the reaction with 3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (100 mg, 0.27 mmol)to give after purification by chromatography on columns (Hex/EtOAc=4/5) of the target compound (75 mg, 46%).

1H NMR (300 MHz, CDCl3): δ 7,79 (d, 1H, J=7,2 Hz), to 7.67 (d, 1H, J=16.2 Hz), 7,32 (c OSiR., 1H), 7,21 (m, 2H), 6,82 (c OSiR., 1H), is 6.54 (d, 1H, J=16.2 Hz), 6,39 (c, 1H), 4,54 (t, 2H, J=6.6 Hz), 4,10 (m, 2H), 3,48 (c, 1H), 3.43 points (m, 4H), 3,26 (c, 3H), 3,19 (m, 2H), 2,75 (m, 1H), 1,92 (m, 2H), 1,24 (t, 3H, J=7.2 Hz).

Example 115 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-3-cyano-5-fluoro-phenyl)-methanesulfonamide, HCl salt (23 mg, of 0.081 mmol) was introduced into the reaction with 3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (30 mg, of 0.081 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (35 mg, 72%).

1H NMR (300 MHz, DMSO-d6): δ 10,10 (c OSiR., 1H), cent to 8.85 (m, 1H), 8,03 (d, 1H, J=7.5 Hz), 7,63 (m, 2H), 7,43 (m, 2H), 6,76 (d, 1H, J=16.2 Hz), of 4.45 (d, 2H, J=5.7 Hz), a 4.03 (q, 2H, J=6,9 Hz, and 3.72 (m, 1H), 3,09 (c, 3H), equal to 2.94 (m, 4H), of 1.81 (m, 4H), of 1.12 (t, 3H, J=7.2 Hz).

Example 116 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperaz-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide, HCl salt

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (192 mg, 0.70 mmol) were introduced in the reaction with 3-(2-piperaz-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (230 mg, or 0.57 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-Boc-piperaz-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide. The acrylamide was treated with 4 M HCl in dioxane, after receiving treatment using MeOH target compound (90 mg, 28%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ to 9.57 (c OSiR., 2H), the remaining 9.08 (c, 1H), up 8.75 (t, 1H, J=5.7 Hz), 7,86 (d, 1H, J=7.8 Hz), 7,49 (d, 1H, J=15,9 Hz), 7,30 (d, 1H, J=7.8 Hz), 7.23 percent (c, 1H), 7,12 (DD, 1H, J=2,1 and 10.2 Hz), 6.75 in (d, 1H, J=15,9 Hz), 4,37 (d, 2H, J=5,7 Hz), 3,68 (c, 1H), 3,51 (m, 4H), of 3.25 (m, 4H), 3,03 (c, 3H).

Example 117: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (84 mg, 0.30 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.24 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (75 mg, 63%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 9,40 (c OSiR., 1H), 8,71 (who, 1H), 7,74 (d, 1H, J=7.8 Hz), to 7.64 (d, 1H, J=15.3 Hz), 7,26 (m, 2H), 6.87 in (d, 1H, J=7.8 Hz), of 6.68 (d, 1H, J=8.1 Hz), 6,59 (d, 1H, J=15.3 Hz), 4,39 (d, 2H, J=6.0 Hz), to 4.38 (c, 1H), 4.09 to (m, 1H), 3,05 (c, 3H), of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz), 0,86 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 514.

Example 118 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methyl-butoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (17.3 mg, holding 0.062 mmol) were introduced in the reaction with 3-[2-(3-methyl-butoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (15.7 mg, 0,052 mmol)to give after purification by chromatography (Hex/EtOAc=1/2) N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (22 mg, 80%).

1H NMR (300 MHz, DMSO): δ 10,08 (c, 1H, usher.), 8,83 (t, 1H, J=5.7 Hz), to 8.12 (d, 1H, J=7.5 Hz), to 7.59 was 7.45 (m, 4H), 6,86 (d, 1H, J=16.2 Hz), 4,49-of 4.35 (m, 4H), to 3.02 (c, 3H), 1,73 is 1.60 (m, 3H), of 0.87 (d, 6H, J=6.0 Hz).

Example 119 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

Ethyl ester of 3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid was obtained according to the General procedure described in example 107 (step 1).

Ethyl ester of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0,357 mmol) was introduced in the eakly 3-thienylboronic acid (2 equiv.) getting ethyl ester 3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (80 mg, 68%).

1H NMR (300 MHz, CDCl3): δ to 7.99 (d, 1H, J=6.0 Hz), to $ 7.91 (d, 1H, J=16.5 Hz), to 7.61 (DD, 1H, J=2.7, and 1.2 Hz), EUR 7.57 (d, 1H, J=8.1 Hz), 7,49 (DD, 1H, J=4,8, 1.2 Hz), 7,39 (DD, 1H, J=5,4, 3.0 Hz), to 6.43 (d, 1H, J=15,9 Hz), 4,24 (q, 2H, J=7,2 Hz), of 1.30 (t, 3H, J=7.2 Hz).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-thiophene-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (19 mg, 0,068 mmol) were introduced in the reaction with 3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (17 mg, 0,057 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-Tien-3-yl-6-trifluoromethyl-pyridine-3-yl)-acrylamide (12 mg, 34%).

1H NMR (300 MHz, DMSO): δ 9,39 (c, 1H, usher.), 8,80 (t, 1H, J=6.0 Hz), compared to 8.26 (d, 1H, J=8.1 Hz), 7,86 (d, 1H, J=8,4 Hz), 7,76 (d, 1H, J=2.4 Hz), 7,66 (DD, 1H, J=4,8, 2.7 Hz), 7,56 (d, 1H, J=15.6 Hz), 7,35 (d, 1H, J=5.4 Hz), 7.23 percent (c, 1H), 7,22 (d, 1H, J=7.5 Hz), 6.75 in (d, 1H, J=15.6 Hz), 4,45 (c, 1H), 4,33 (d, 2H, J=5.4 Hz), 3.00 and (c, 3H).

Example 120 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: synthesis of ethyl ester of 3-[2-(3-forfinal)-6-trifluoromethyl-p is ridin-3-yl]-acrylic acid

Ethyl ester of 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid was obtained according to the General procedure described in example 107 (step 1).

Ethyl ester of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (110 mg, 0,393 mmol) were introduced in the reaction with 3-ftorhinolonovy acid (2 equiv.) getting ethyl ester of 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (70 mg, 53%).

1H NMR (300 MHz, CDCl3): δ 8,13 (d, 1H, J=8.1 Hz), 7,76 (d, 1H, J=15.6 Hz), 7,72 (d, 1H, J=8,4 Hz), 7,51-the 7.43 (m, 1H), 7,38-7,33 (m, 2H), 7,27-7,16 (m, 1H), 6,50 (d, 1H, J=15.6 Hz), 4.26 deaths (q, 2H, J=7,2 Hz), of 1.30 (t, 3H, J=7.2 Hz).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (71,45 mg, 0,255 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (53 mg, 0,170 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridine-3-yl]-acrylamide (52 mg, 57%).

1H NMR (300 MHz, DMSO): δ 9,45 (c, 1H, usher.), 8,86 (t, 1H, J=6.0 Hz), 8,40 (d, 1H, J=8.1 Hz), 8,01 (d, 1H, J=8.1 Hz), 7,63-7,56 (m, 1H), 7,45-7,35 (m, 4H), 7,27 (c, 1H), 7,26 (d, 1H, J=8.7 Hz), 6,83 (d, 1H, J=15,9 Hz), 4,51 (c, 1H), 4,36 (d, 2H, J=6,0 Hz), 3,06 (c, 3H).

p> Example 121 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (95 mg, of 0.37 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (84 mg, 0.31 mmol)to give after purification by crystallization from methylene chloride target compound (125 mg, 84%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c OSiR., 1H), 8,72 (t, 1H, J=5.7 Hz), 7,78 (d, 1H, J=7.5 Hz), 7,63 (d, 1H, J=15.6 Hz), 7,34 (t, 1H, J=8,4 Hz), 7,20 (DD, 1H, J=2,1 and 11.4 Hz), 7,13 (d, 1H, J=8,4 Hz), of 6.96 (d, 1H, J=7.5 Hz), PC 6.82 (d, 1H, J=7.5 Hz)that is 6.61 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5.7 Hz), is 4.21 (m, 1H), 3.00 and (c, 3H), of 1.18 (d, 6H, J=6.6 Hz).

Example 122 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-5-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (104 mg, and 0.37 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (84 mg, 0.31 mmol)to give after purification by crystallization from methylene chloride target compound (115 mg, 74%).

1H NMR (300 MHz, DMSO-d6): δ 10,1 (c OSiR., 1H), 8,79 (t, 1H, J=5.7 Hz), 7,80 (d, 1H, J=7.5 Hz), 7,63 (m, 2H), of 6.96 (d, 1H, J=7.5 Hz), PC 6.82 (d, 1H, J=7.5 Hz), is 6.61 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5.7 Hz), is 4.21 (m, 1H), 3,10 (c, 3H), of 1.18 (d, 6H, J=6.6 Hz).

ESI [M+H]+: 500.

Example 123: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (325 mg, of 1.27 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (306 mg, 1.06 mmol)to give after purification by crystallization from a simple ester of the target compound (490 mg, 95%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c OSiR., 1H), to 8.70 (t, 1H, J=6.0 Hz), to 7.77 (d, 1H, J=7.8 Hz), to 7.64 (d, 1H, J=15.3 Hz), 7,35 (t, 1H, J=8,4 Hz), 7,21 (DD, 1H, J=1,5 and 11.4 Hz), 7,13 (d, 1H, J=8,4 Hz)6,94 (d, 1H, J=7.5 Hz), 6,74 (d, 1H, J=7,8 Hz), 6,63 (d, 1H, J=15.3 Hz), and 4.40 (d, 2H, J=6.0 Hz), 4,07 (m, 1H), 3.00 and (c, 3H), of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz), 0,86 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 489.

Example 124: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-5-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (104 mg, and 0.37 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.34 mmol)to give after purification by crystallization from a simple ester of the target compound (130 mg, 74%).

1H NMR (300 MHz, DMSO-d6): δ 10,1 (c OSiR., 1H), 8,77 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7,2 Hz), 7,63 (m, 3H), 6,94 (d, 1H, J=7.8 Hz), 6,76 (d, 1H, J=7.8 Hz), 6,62 (d, 1H, J=15.6 Hz), 4,55 (d, 2H, J=6.0 Hz), 4,07 (m, 1H), 3,09 (c, 3H), of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz)to 0.85 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 514.

Example 125 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxyphenyl)-6-trifluoromethyl-Piri is INF-3-yl]-acrylamide

Stage 1: synthesis of ethyl ester of 3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid

Ethyl ester of 3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid was obtained according to the General procedure described in example 107 (step 1).

Ethyl ester of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (103 mg, 0,368 mmol) were introduced in the reaction with 3-methoxyphenylacetic acid (2 equiv.) getting ethyl ester of 3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (70 mg, 54%).

1H NMR (300 MHz, CDCl3): δ of 8.09 (d, 1H, J=8,4 Hz), 7,79 (d, 1H, J=15,9 Hz), to 7.68 (d, 1H, J=7.8 Hz), 7,39 (DD, 1H, J=7,2, 1.5 Hz), 7,51 for 7.12 (m, 2H),? 7.04 baby mortality-7,00 (m, 1H), 6,47 (d, 1H, J=15,9 Hz), 4,25 (q, 2H, J=7,2 Hz), 3,85 (c, 3H), is 1.31 (t, 3H, J=7.2 Hz).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (15.6 mg, 0,056 mmol) were introduced in the reaction with 3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (15 mg, 0.046 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxyphenyl)-6-trifluoromethyl-pyridine--yl]-acrylamide (15 mg, 60%).

1H NMR (300 MHz, DMSO): δ 9,44 (c, 1H, usher.), 8,84 (t, 1H, J=6.0 Hz), of 8.37 (d, 1H, J=8.1 Hz), of 7.97 (d, 1H, J=8.1 Hz), 7,47 (d, 1H, J=15,9 Hz), 7,46 (t, 1H, J=7.8 Hz), 7,27 (c, 1H), 7,25 (d, 1H, J=8.1 Hz), 7,11 (DD, 2H, J=3,0, 2.4 Hz), 7,07 (DD, 1H, J=5,1, 1.8 Hz), PC 6.82 (d, 1H, J=15,9 Hz), 4,51 (c, 1H), 4,37 (d, 2H, J=5.7 Hz), 3,79 (c, 3H), 3,06 (c, 3H).

Example 126 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

Ethyl ester of 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid was obtained according to the General procedure described in example 107 (step 1).

Ethyl ester of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (103 mg, 0,368 mmol) were introduced in the reaction with 3-pyridineboronic acid (2 equiv.) getting ethyl ester 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (60 mg, 50%).

1H NMR (300 MHz, CDCl3): δ 8,84 (d, 1H, J=1.8 Hz), a total of 8.74 (d, 1H, J=4,8 Hz)to 8.14 (d, 1H, J=8.1 Hz), 7,79 (DD, 1H, J=6,3, 1.8 Hz), of 7.75 (d, 1H, J=7.8 Hz), 7,72 (d, 1H, J=15,9 Hz), 7,46 (DD, 1H, J=4,8, 3.0 Hz), is 6.54 (d, 1H, J=15,9 Hz), 4.26 deaths (q, 2H, J=7,2 Hz), 1,32 (t, 3H, J=7.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide.

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide was obtained which according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (68 mg, 0.24 mmol) were introduced in the reaction with 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (60 mg, 0.20 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyridin-3-yl-6-trifluoromethyl-pyridine-3-yl)-acrylamide (60 mg, 58%).

1H NMR (300 MHz, CDCl3): δ 8,81 (d, 1H, J=2.4 Hz), 8,69 (DD, 1H, J=3,6, 1.5 Hz), 8,11 (d, 1H, J=8.1 Hz), of 7.97 (DD, 1H, J=4.2, and 1.2 Hz), 7,72 (d, 1H, J=8,4 Hz), 7,69 (d, 1H, J=15.6 Hz), 7,44 (DD, 1H, J=7,8, 5,1 Hz), 7,72 (DD, 1H, J=9,0, 1.8 Hz), 6,53 (d, 1H, J=15.6 Hz), 6,45 (t, 1H, J=5.7 Hz), 4,46 (d, 2H, J=6.3 Hz), 3,50 (c, 1H), 3,24 (c, 3H).

Example 127 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide, HCl salt (74 mg, 0.29 mmol) were introduced in the reaction with 3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.29 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (100 mg, 67%).

1H NMR (300 MHz, DMSO-d6): δ to 9.57 (c, 1H), 8,80 (m, 1H), 8,02 (d, 1H, J=7.8 Hz), 7,80 (d, 1H, J=15,9 Hz), 7,63 (m, 2H), 7,29 (m, 6H), 6,98 (m, 1H), 6.73 x (d, 1H, J=15.6 Hz), to 4.41 (d, 2H, J=5,1 Hz), 2,99 (c, 3H).

Example 128 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (81 mg, 0.29 to which mol) were introduced in the reaction with 3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.29 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/3) of the target compound (95 mg, 61%).

1H NMR (300 MHz, DMSO-d6): δ of 10.09 (c, 1H), 9,01 (c, 1H), 8,88 (m, 1H), 8,04 (d, 1H, J=7.5 Hz), 7,82 (m, 1H), to 7.64 (m, 4H), 7,29 (m, 3H), 6,98 (m, 1H), 6,74 (d, 1H, J=15.6 Hz), 4,48 (d, 2H, J=6.0 Hz), 3,10 (c, 3H).

Example 129: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (86 mg, 0.32 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.31 mmol)to give after purification by crystallization from a simple ester of the target compound (106 mg, 68%).

1H NMR (300 MHz, DMSO-d6): δ 8,76 (t, 1H, J=6.0 Hz), 7,79 (d, 1H, J=7.5 Hz), the 7.65 (d, 1H, J=15.3 Hz), 7,11 (d, 2H, J=8,4 Hz), to 6.95 (d, 1H, J=7.8 Hz), 6,78 (d, 1H, J=7.8 Hz), 6,62 (d, 1H, J=15.3 Hz), to 4.41 (d, 2H, J=6.0 Hz), 4,07 (m, 1H), 3,03 (c, 3H), of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz), 0,86 (t, 3H, J=7.5 Hz).

Example 130: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (99 mg, and 0.37 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.34 mmol)to give the target compound (140 mg, 82%) after purification by crystallization from a simple ether.

1H NMR (300 MHz, DMSO-d 6): δ 10,1 (c OSiR., 1H), 8,64 (t, 1H, J=5.7 Hz), of 7.75 (d, 1H, J=7.5 Hz), 7,63 (d, 1H, J=15.3 Hz), 7,16 (m, 2H), 6,94 (d, 1H, J=7,2 Hz), 6,76 (d, 1H, J=7.8 Hz), 6,62 (d, 1H, J=15.3 Hz), and 4.40 (d, 2H, J=5.7 Hz), 4,06 (m, 1H), 2,97 (c, 3H), of 2.20 (d, 3H, J=2,4 Hz)of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz)to 0.85 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 503.

Example 131 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (50 mg, 0,19 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0,19 mmol)to give after purification by recrystallization from a mixture of EtOAc/hexane N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-piperid-1-Il-6-trifluoromethyl-pyridinyl-3-yl)-acrylamide (66 mg, 69%).

1H NMR (300 MHz, DMSO-d6): δ 9,26 (c, 1H), 8,72 (t, 1H, J=5.7 Hz), of 7.97 (d, 1H, J=7.8 Hz), 7,46~7,37 (m, 2H), 7,22~7,10 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), to 4.41 (d, 2H, J=5.7 Hz), 3,20~3,17 (m, 4H), 2,98 (c, 3H), of 2.21 (d, 3H, J=and 2.1 Hz), 1,62 (user., 6H).

Example 132 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (41.7 mg, rate £ 0.162 mmol) were introduced in the reaction with NMM (0,07 ml), DMTMM (to 44.7 mg) and 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (45 mg, 0.15 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (63 mg, 85%).

1NMR (300 MHz, CDCl3): δ of 7.96 (d, 1H, J=7.8 Hz), 7,86 (d, 1H, J=15.6 Hz), 7,53 (t, 1H, J=7.8 Hz), 7,39 (m, 3H), to 7.15 (m, 4H), 6.87 in (d, 1H, J=15.6 Hz), 6,53 (c, 1H), 6,13 (t, 1H), 4,56 (d, 2H, J=6.0 Hz), 3,01 (c, 3H).

Example 133 N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt (85 mg, 0,302 mmol) were introduced in the reaction with NMM (0.1 ml), DMTMM (83,7 mg) and 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (69 mg, 0,245 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (69 mg, 53%).

1H NMR (300 MHz, CDCl3): δ of 7.96 (d, 1H, J=8.1 Hz), 7,87 (d, 1H, J=15.6 Hz), 7,40 (m, 3H), 7,17 (m, 2H), 7,10 (m, 2H), to 6.88 (d, 1H, J=15.6 Hz), of 6.20 (t, 1H), 6,09 (m, 1H), 5,80 (DD, 1H, J=3,6 and 17.4 Hz), 5,46 (d, 1H, J=11,1 Hz), of 4.57 (d, 2H, J=6.0 Hz), 3,37 (c, 1H), 3,07 (c, 3H).

Example 134 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(pyridine-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: 3-[2-(pyridine-3-yloxy)-4-trifluoromethyl-phenyl]-acrylic acid

3 Hydroxypyridine (69,1 mg) and sodium hydride (65 mg, 1.6 mmol) was added in THF. To the reaction mixture were added 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (156 mg, 0,620 mmol). The reaction mixture was purified, obtaining the target compound (15 mg) after purification by chromatography on columns (Hex/EtOAc=1/4).

1H NMR (300 MHz, CD3 OD): δ 8,48 (m, 1H), 8,32 (d, 1H, J=7.8 Hz), 8,03 (c, 1H), to 7.93 (d, 1H, J=16.2 Hz), 7,73 (m, 1H), 7,51 (m, 1H), 7,21 (m, 1H), 6,79 (d, 1H, J=16.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(pyridine-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-6-ethinyl-phenyl)-methanesulfonamide, HCl salt (50.5 mg, 0,198 mmol) were introduced in the reaction with NMM (0,08 ml), DMTMM (57,8 mg) and 3-[2-(pyridine-3-yloxy)-4-trifluoromethyl-phenyl]-acrylic acid (40.5 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/4) of the target compound (29 mg).

1H NMR (300 MHz, CD3OD): δ charged 8.52 (d, 1H, J=2.7 Hz), 8,45 (MD, 1H), 8.30 to (d, 1H, J=7,2 Hz), 7,88 (d, 1H, J=15,9 Hz), to 7.77 (m, 1H), 7,55 (m, 2H), 7,33 (c, 1H), 7,21 (DD, 1H, J=1,2 and 10.2 Hz), 7,02 (d, 1H, J=15,9 Hz), 4,49 (c, 2H), 3,31 (c, 1H), 3,11 (c, 3H).

Example 135 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: synthesis of ethyl ester of 3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid

Ethyl ester of 3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid was obtained according to the General procedure described in example 107 (step 1).

Ethyl ester of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (110 mg, 0,393 mmol) were introduced in the reaction with 2-fluoro-5-pyridine Bronevoy acid (2 equiv.) getting ethyl ester of 3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-the feast of the DIN-3-yl]-acrylic acid (40 mg, 30%).

1H NMR (300 MHz, CDCl3): δ to 8.45 (d, 1H, J=2.4 Hz), 8,16-8,08 (m, 2H), 7,76 (d, 1H, J=8,4 Hz), of 7.70 (d, 1H, J=15,9 Hz), 7,11 (DD, 1H, J=5,4, 3.0 Hz), 6,55 (d, 1H, J=15,9 Hz), 4,27 (q, 2H, J=7,2 Hz), of 1.33 (t, 3H, J=7.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(4'-fluoro-6-trifluoromethyl-[2,3']bipyridinyl-3-yl)-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (29.5 mg, 0,107 mmol) were introduced in the reaction with 3-[2-(4-fluoro-pyridin-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (22 mg, 0,070 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-fluoro-pyridine-3-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (14 mg, 39%).

1H NMR (300 MHz, DMSO): δ 9,46 (c, 1H, usher.), 8,88 (t, 1H, J=6.0 Hz), 8,43 (d, 1H, J=8.1 Hz), to 8.41 (c, 1H), 8,23-8,16 (m, 1H), 8,04 (d, 1H, J=8.1 Hz), 7,42 (d, 1H, J=15.6 Hz), 7,41 (d, 1H, J=2.7 Hz), 7,28 (c, 1H), 7,26 (d, 1H, J=4,8 Hz), 6,83 (d, 1H, J=15.6 Hz), to 4.52 (c, 1H), 4,37 (d, 2H, J=5.7 Hz), 3,06 (c, 3H).

Example 136 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (18 mg, 0,065 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (17 mg, 0,054 mmol)to give after purification PE is kristallizatsiei from a mixture of n-hexane/EtOAc N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (21 mg, 62%).

1H NMR (300 MHz, DMSO): δ of 8.90 (t, 1H, J=6.0 Hz), to 8.41 (d, 1H, J=8.1 Hz), 8,02 (d, 1H, J=8.1 Hz), a 7.62 EUR 7.57 (m, 3H), 7,45-7,35 (m, 4H), 6,83 (d, 1H, J=15.6 Hz), 4,42 (d, 2H, J=6.0 Hz), 3,06 (c, 3H).

Examples 137 and 138 are missing

Example 139 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: 3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

Methyl ester 3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (80 mg) was hydrolyzed in 1 M solution (3 mmol) LiOH at room temperature, obtaining the target compound (63 mg).

1H NMR (300 MHz, CDCl3): δ 8,13 (d, 1H, J=15.6 Hz), 7,81 (m, 1H), 7,53 (m, 2H), 7,38 (m, 3H), 6.48 in (d, 1H, J=15,9 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-ethinyl-phenyl)-methanesulfonamide, HCl salt (43 mg, 0,154 mmol) were introduced in the reaction with NMM (0.1 ml), DMTMM (46 mg) and 3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (41 mg, 0,126 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (25.6 mg, 37%).

1H NMR (300 MHz, CDCl3): δ 7,88 (d, 1H, J=15.6 Hz), 7,76 (d, 1H, J=8.1 Hz), of 7.48 (m, 2H), 7,32 (m, 4H), 7,21 (c, 1H), was 7.08 (d, 1H, J=10.5 Hz), 6,45 (d, 1H, J=15.3 Hz), to 6.43 (c, 1H), of 4.44 (d, 2H, J=6.3 Hz), 3,40 (c, 1H), 3,20 (c, 3H).

Example 140 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylthio-6-trif ormetal-pyridine-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0,082 mmol) were introduced in the reaction with NMM (0.1 ml), DMTMM (26 mg) and 3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (18 mg, 53%).

1H NMR (300 MHz, CDCl3): 7,88 (d, 1H, J=15.6 Hz), 7,76 (d, 1H, J=7.8 Hz), of 7.48 (m, 2H), 7,32 (m, 4H), 7,11 (c, 1H), 6,91 (m, 2H), to 6.43 (d, 1H, J=15.3 Hz), 6.42 per (c, 1H), to 4.52 (d, 2H, J=6.3 Hz), 3.00 and (c, 3H).

Example 141 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: methyl ether 2-phenethyl-4-trifluoromethyl-nicotinic acid

To a solution of β-keeeper (2,43 g, 17.5 mmol) in toluene (30 ml) was added 4-amino-1,1,1-triptorelin-2-he (of 3.60 g, 17.5 mmol) and triperoxonane acid (1,30 ml, 17.5 mmol)and the resulting mixture was stirred at 90°C for 60 hours. This mixture is washed with aqueous 20%solution of Na2CO3and dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on columns (Hex/EtOAc=10:1)to give methyl ester of 2-phenethyl-4-trifluoromethyl-nicotinic acid (1.84 g, 41%).

1H NMR (300 MHz, CDCl3): δ 8.30 to (d, 1H, J=8.1 Hz), to 7.59 (d, 1H, J=8.1 Hz), from 7.24 (m, 5H), 3,92 (c, 3H), 3,53 (m, 1H), of 3.07 (m, 1H).

Stage 2: 2-phenethyl-4-trifluoromethyl-pyridine-3-ymetray alcohol

To susp is nsii methyl ester 2-phenethyl-4-trifluoromethyl-nicotinic acid (1.84 g, 5,95 mmol) in THF (50 ml) was added dropwise at 0°C 1,0 M LiAlH4(6.0 ml, 6.0 mmol). After stirring at 0°C for 1 hour the reaction was stopped by adding 10%natinality (50 ml)and the resulting mixture was vigorously stirred for 1 hour. The two phases were separated, and the aqueous phase was extracted with simple ether. The combined organic layer was washed with saline, dried over Bezbog. MgSO4,was filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on columns (Hex/EtOAc=10:1)to give the alcohol product (1.55 g, 93%).

1H NMR (300 MHz, CDCl3): δ 7,87 (d, 1H, J=8.1 Hz), 7,54 (d, 1H, J=8.1 Hz), 7,20 (m, 5H), 5,59 (d, 2H, J=5.4 Hz), 3,11 (c, 4H).

Stage 3: 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester

To a solution of oxalicacid (540 ml, the 6.06 mmol) in CH2Cl2(30 ml) at -78°C was added dropwise DMSO (860 ml, 12.2 mmol)and the resulting solution was stirred for 5 minutes at -78°C. To the reaction mixture was added dropwise a solution of the alcohol obtained at the specified stage 2, (1.55 g, 5.51 mmol) in CH2Cl2(10 ml). After stirring at -78°C for 30 minutes the reaction was stopped by adding triethylamine (3,84 ml, 27.6 mmol)and the resulting mixture was heated to room temperature. To the reaction mixture were added water (40 ml), and the two phases were separated. The aqueous phase was extracted with CH2 Cl2. The combined organic layer was washed with saline, dried over Bezbog. MgSO4,was filtered and concentrated under reduced pressure to obtain the aldehyde product, which was used without further purification.

To a solution of the aldehyde product obtained above in toluene (20 ml) was added methyl(triphenylphosphonium)acetate (1.77 g, 5.51 mmol)and the resulting mixture was heated at 90°C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was purified by chromatography on columns (Hex/EtOAc=10/1)to give methyl ester 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (1,46 g, 79% stage 2).

1H NMR (300 MHz, CDCl3): δ 7,88 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=15,9 Hz), 7,54 (d, 1H, J=7.8 Hz), 7,20 (m, 5H), 6.30-in (d, 1H, J=15,9 Hz), 3,82 (c, 3H), 3,29 (m, 2H), of 3.07 (m, 2H).

Stage 4: 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a suspension of methyl ester 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (1,46 g, 4.35 mmol) in THF (3 ml) was added 1 n LiOH solution (6.0 ml)and the mixture was stirred for 3 hours at room temperature. The obtained residue was dissolved in H2O and then washed with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times methylthio the home and then dried over Bezbog. MgSO4, and concentrated in vacuum, obtaining 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (1,37 g, 98%).

1H NMR (300 MHz, CDCl3): δ to $ 7.91 (m, 2H), 7,58 (d, 1H, J=7.8 Hz), 7,20 (m, 5H), of 6.31 (d, 1H, J=15,9 Hz)and 3.31 (m, 2H), to 3.09 (m, 2H).

Stage 5: synthesis of N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (153 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (160 mg, 0.50 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (174 mg, 67%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 8,70 (c OSiR., 1H), to $ 7.91 (m, 2H), 7,82 (d, 1H, J=15.3 Hz), 7,54 (d, 1H, J=8.1 Hz), 7,46 (t, 1H, J=8.1 Hz), 7,20 (m, 7H), 6,51 (d, 1H, J=15.3 Hz), 4,50 (d, 2H, J=5.7 Hz), 3,29 (m, 2H), is 3.08 (m, 2H), 3.00 and (c, 3H).

ESI [M+H]+: 528.

Example 142 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (167 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (160 mg, 0.50 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (175 mg, 64%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 8,20 (c OSiR., 1H), 8,11 (t, 1H), 7,92 (who, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,55 (d, 1H, J=8.1 Hz), 7,33 (c, 1H), 7,20 (m, 6H), of 6.52 (d, 1H, J=15.3 Hz), 4,49 (d, 2H, J=6.0 Hz), 3,47 (c, 1H), 3,29 (m, 2H), 3,18 (c, 3H), is 3.08 (m, 2H).

ESI [M+H]+: 546.

Example 143: 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (153 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (137 mg, 0.50 mmol)obtained by the method similar to that described above, receiving after purification by crystallization from a mixture of Hex/EtOAc target compound (160 mg, 68%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c usher, 1H), 8,84 (t, 1H, J=5.7 Hz), 8,16 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,35 (t, 1H, J=8.1 Hz), 7,16 (m, 2H), 6,74 (d, 1H, J=15.3 Hz), and 4.40 (d, 2H, J=6.3 Hz), 2,99 (c, 3H), equal to 2.94 (m, 2H), 1,60 (m, 2H), 1,35 (m, 2H), of 0.90 (t, 3H, J=7.2 Hz).

Example 144: 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (167 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (137 mg, 0.50 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (158 mg, 64%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (c OSiR., 1H), 8,88 (t, 1H, J=5.7 Hz), 8,18 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=8,4 Hz), 7,71 (d, 1H, J=15.6 Hz), 7,29 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), to 4.52 (c,1H), however, 4.40 (d, 2H, J=5.7 Hz), 3,06 (c, 3H), equal to 2.94 (m, 2H), 1,60 (m, 2H), 1,35 (m, 2H), of 0.90 (t, 3H, J=6.9 Hz).

ESI [M+H]+: 498.

Example 145 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethinyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-(6-trifluoromethyl-2-trimethylsilylethynyl-pyridine-3-yl)-acrylic acid

In a microwave vial was loaded ethyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (103 mg, 0,368 mmol), Pd(PPh3)2Cl2(0.06 equiv.) CuI (0.06 equiv.) PPh3(0.2 equiv.) Et3N (15 equiv.) (trimethylsilyl)acetylene and DMF (0.25 ml). The vial was irradiated in a microwave synthesizer at 120°C for 25 minutes the Contents of the vial were filtered through a layer of celite, which is carefully washed with EtOAc. The filtrate was evaporated, and the residue was purified by chromatography on columns, obtaining the ethyl ester of 3-(6-trifluoromethyl-2-trimethylsilylethynyl-pyridine-3-yl)-acrylic acid (58 mg, 46%).

1H NMR (300 MHz, CDCl3): δ 8,08 (d, 1H, J=16.4 Hz), and 8.0 (d, 1H, J=8.1 Hz), 6,55 (d, 1H, J=8.1 Hz), is 6.54 (d, 1H, J=16.4 Hz), 4,25 (q, 2H, J=7,2 Hz), of 1.30 (t, 3H, J=7.2 Hz), 0,27 (c, 9H).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethinyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

To a suspension of ethyl ester of 3-(6-trifluoromethyl-2-trimethylsilylethynyl-pyridine-3-yl)-acrylic acid (68 mg, 0,169 mmol) in THF (1 ml) and CH 3OH (0.5 ml) was added 1 n NaOH solution (0.5 ml)and the mixture was stirred for 50 minutes at room temperature. The obtained residue was dissolved in H2O and then washed three times with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4, and concentrated in vacuum, obtaining 3-(2-ethinyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 99%).

To a suspension of N-(4-aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt, (83 mg, 0,298 mmol) in THF (3 ml) was added N-methylmorpholine (of 0.066 ml, 0,597 mmol). The mixture was stirred for 5 minutes, then was added 3-(2-ethinyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 0,065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazine-2-yl)-4-methylmorpholinium hydrate (DMTMM of 71.4 mg, 0,258 mmol). The mixture was stirred over night at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1 N. HCl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2receiving N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethinyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (30 mg, 32%).

1H NMR (300 MHz, DMSO): δ 9,46 (c, 1H, usher.), 8,94 t, 1H, J=5.4 Hz), 8,39 (d, 1H, J=8,4 Hz), 8,00 (d, 1H, J=8,4 Hz), 7,83 (d, 1H, J=15,9 Hz), 7,30 (c, 1H), 7,28 (d, 1H, J=7.8 Hz), 6,97 (d, 1H, J=15,9 Hz), 4,94 (c, 1H), 4,51 (c, 1H), to 4.41 (d, 2H, J=5.7 Hz), 3,06 (c, 3H).

Example 146: none

Example 147 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (153 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (137 mg, 0.50 mmol)obtained by the method similar to that described above, receiving after purification by crystallization from a mixture of Hex/EtOAc target compound (151 mg, 64%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c OSiR., 1H), 8,83 (t, 1H), 8,17 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=7.8 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,35 (t, 1H, J=8,4 Hz), 7,16 (m, 2H), 6,74 (d, 1H, J=15.3 Hz), and 4.40 (d, 2H, J=5.7 Hz), 3.00 and (c, 3H), and 2.83 (d, 2H, J=6.9 Hz), a 2.01 (m, 1H), 0,89 (t, 6H, J=6.6 Hz).

Example 148 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (167 mg, of 0.60 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (137 mg, 0.50 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (153 mg, 62%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (c OSiR., 1H), 8,86 (t, 1H, J=5.7 Hz), 8,19 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,29 (who, 2H), 6,74 (d, 1H, J=15.3 Hz), 4,50 (c, 1H), to 4.41 (d, 2H, J=5.7 Hz), 3,07 (c, 3H), and 2.83 (d, 2H, J=7,2 Hz), a 2.01 (m, 1H), 0,89 (t, 6H, J=6.6 Hz).

ESI [M+H]+: 498.

Example 149: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-Amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (78 mg, 0.29 mmol) were introduced in the reaction with 3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.29 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (120 mg, 80%).

1H NMR (300 MHz, DMSO-d6): δ a 8.34 (d, 1H, J=8.1 Hz), 8,12 (c, 1H), 7,72 (m, 5H), 7,40 (m, 1H), 7,29 (m, 2H), to 7.15 (m, 3H), 7,01 (m, 1H), 6,66 (d, 1H, J=15.6 Hz), 5,16 (kV, 1H, J=6.6 Hz), 2,93 (c, 3H)and 1.51 (d, 3H, J=6.9 Hz).

Example 150: 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide

N-Methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide was obtained according to the General procedure described in example 145 (stage 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1.2 g, to 4.52 mmol) were introduced in the reaction with (trimethylsilyl)acetylene (0,689 ml, equal to 4.97 mmol)to give N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide (896 mg, 60%).

1H NMR (300 MHz, CDClsub> 3): δ 7,83 (d, 1H, J=7.8 Hz), 7,66 (d, 1H, J=7.8 Hz), 3,51 (c, 3H), 3,39 (c, 3H), 0,26 (c, 9H).

Stage 2: synthesis of 2-ethinyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide (148 g, 0,449 mmol) in THF (1 ml) and CH3OH (0.5 ml) was added 1 n NaOH solution (0.5 ml)and the mixture was stirred for 50 minutes at room temperature. The obtained residue was dissolved in H2O and then washed three times with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4, and concentrated in vacuum, obtaining 2-ethinyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (116 mg, 99%).

1H NMR (300 MHz, CDCl3): δ of 7.82 (d, 1H, J=7.8 Hz), the 7.65 (d, 1H, J=7.8 Hz), 3,69 (c, 3H), 3.45 points (c, 3H).

Stage 3: synthesis of 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of 2-ethinyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (145 mg, 0,561 mmol) in 5%om Pd/C (30 mg) was added CH3OH (4 ml). The mixture was purged three times with gaseous hydrogen (50 psi) and which was for 2 hours at room temperature. The reaction mixture was filtered through a layer of celite and concentrated under reduced pressure. The crude residue was chromatographically, receiving 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (112 mg, 76%).

1H NMR (300 MHz, CDCl3): δ of 7.75 (d, 1H, J=7.8 Hz), 7,54 (d, 1H, J=7.8 Hz), 3.43 points (c, H), 3,39 (c, 3H), 2,89 (q, 2H, J=7.5 Hz), of 1.33 (t, 3H, J=7.5 Hz).

Stage 4: methyl ester 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a cooled (-78°C) solution of 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (113 mg, 0.43 mmol) in THF (4 ml) was added lithium-aluminiumhydride (1M LAH in THF and 0.22 ml). The mixture was stirred for 15 minutes and then was heated to -10°C. After additional stirring for 30 minutes, the mixture was suppressed with a saturated solution of potassium hydrosulfate (1 ml) and was extracted with simple diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 2-ethyl-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively in the form of oil. The crude product was used directly in the next reaction.

To a solution of 2-ethyl-6-trifluoromethyl-pyridine-3-carbaldehyde in toluene (10 ml) was added methyl(triphenylphosphonium)acetate (172 mg, 0,516 mmol). The mixture was heated at 110°C overnight, cooled to room temperature and was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on columns (EtOAc/hexane=1/4)to give methyl ester 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (89 mg, 80%).

1H NMR (300 MHz, CDCl3: δ of 7.95 (d, 1H, J=15,9 Hz), 7,94 (d, 1H, J=7.8 Hz), 7,54 (d, 1H, J=8.1 Hz), 6,44 (d, 1H, J=15,9 Hz), 3,85 (c, 3H), to 3.02 (q, 2H, J=7.5 Hz), is 1.31 (t, 3H, J=7.5 Hz).

Stage 5: 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

3-(2-Ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (74 mg, to 0.263 mmol) were introduced in the reaction with 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (43 mg, 0,175 mmol)to give 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (45 mg, 37%).

1H NMR (300 MHz, DMSO): δ 9,45 (c, 1H, usher.), 8,87 (t, 1H, J=6.0 Hz), 8,18 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,71 (d, 1H, J=15.6 Hz), 7,30 (c, 1H), 7,28 (d, 1H, J=8,4 Hz), 6,74 (d, 1H, J=15.6 Hz), 4,51 (c, 1H), and 4.40 (d, 2H, J=5.7 Hz), 3,00 (c, 3H), 2,96 (q, 2H, J=7.5 Hz), to 1.21 (t, 3H, J=7.5 Hz).

Example 151 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (153 mg, of 0.60 mmol) were introduced in the reaction with 3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (144 mg, 0.50 mmol)obtained by the method similar to that described above, receiving after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (176 mg, 72%).

1H NMR (300 is Hz, DMSO-d6): δ of 9.55 (c OSiR., 1H), 8,83 (t, 1H), 8,17 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=7.8 Hz), 7,72 (d, 1H, J=15.3 Hz), 7,35 (t, 1H, J=8,4 Hz), 7,16 (m, 2H), 6,74 (d, 1H, J=15.3 Hz), and 4.40 (d, 2H, J=5.7 Hz), 3.00 and (c, 3H), of 2.97 (m, 1H), 2,70 (m, 1H), 1,80 (m, 1H), 1,30 (m, 2H), of 0.87 (t, 3H, J=7.2 Hz), 0,81 (d, 3H, J=6.6 Hz).

Example 152 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (167 mg, of 0.60 mmol) were introduced in the reaction with 3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (144 mg, 0.50 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (175 mg, 68%).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c OSiR., 1H), cent to 8.85 (t, 1H, J=5.7 Hz), 8,19 (d, 1H, J=8,4 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.6 Hz), 7,28 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), to 4.52 (c, 1H), to 4.41 (d, 2H, J=6.0 Hz), 3,07 (c, 3H), of 2.97 (m, 1H), 2,70 (m, 1H), 1,80 (m, 1H), 1,30 (m, 2H), of 0.87 (t, 3H, J=7.2 Hz), 0,81 (d, 3H, J=6.6 Hz).

ESI [M+H]+: 512.

Example 153 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide

N-Methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilylethynyl-nicotinamide was obtained according to the General procedure described in example 145 (stage 1).

2-Chloro-N-methoxy-N-m is l-6-trifluoromethyl-nicotinamide (128 mg, 0,457 mmol) were introduced in the reaction with 3-methoxypropanol (0.042 mg, 0,504 mmol)to give ethyl ester of 3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (89 mg, 62%).

1H NMR (300 MHz, CDCl3): δ 8,11 (d, 1H, J=16.2 Hz), 8,08 (d, 1H, J=9.0 Hz), 7,66 (d, 1H, J=9.0 Hz), 6,60 (d, 1H, J=16.2 Hz), of 4.44 (c, 2H), 4,30 (d, 2H, J=7,2 Hz), 3,53 (c, 3H), of 1.36 (t, 3H, J=7.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (59 mg, 0.21 mmol) were introduced in the reaction with 3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (40 mg, 0.14 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (35 mg, 33%).

1H NMR (300 MHz, CDCl3): δ of 8.04 (d, 1H, J=7,2 Hz), 8,00 (d, 1H, J=16.5 Hz), a 7.62 (d, 1H, J=8.1 Hz), 7,22 (c, 1H), to 7.09 (DD, 1H, J=10,8, 1.8 Hz), 6.73 x (d, 1H, J=15,9 Hz), of 6.68 (d, 1H, J=5.7 Hz), 6,61 (c, 1H), 4,47 (d, 2H, J=5,7 Hz), 4,40 (c, 2H), 3,47 (c, 3H), 3,24 (c, 3H).

Example 154 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (19.1 mg of 0.075 mmol) were introduced in the reaction with 3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (18 mg, 0,063 mmol)to give N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-prop-1-inyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (35 mg, 33%).

1H NMR (300 MHz, CDCl3): δ of 8.04 (d, 1H, J=16.2 Hz), 8,01 (d, 1H, J=7,2 Hz), 7,63 (d, 1H, J=8.1 Hz), 7,52 (t, 1H, J=8.1 Hz), 7,17-7,11 (m, 2H), 6.73 x (d, 1H, J=15.6 Hz), 6,56 (c, 1H), from 6.22 (t, 1H, J=6.0 Hz), 4,56 (d, 2H, J=6,0 Hz), 4,42 (c, 2H), 3,48 (c, 3H), 3,03 (c, 3H).

Example 155 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

Stage 1: synthesis of N-methoxy-2-(3-methoxy-prop-1-inyl)-N-methyl-6-trifluoromethyl-nicotinamide

N-Methoxy-2-(3-methoxy-prop-1-inyl)-N-methyl-6-trifluoromethyl-nicotinamide was obtained according to the General procedure described in example 145 (stage 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1000 mg, 3.72 mmol) were introduced in the reaction with 3-methoxypropanol (0,345 ml, 4.09 to mmol)to give N-methoxy-2-(3-methoxy-prop-1-inyl)-N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 22%).

1H NMR (300 MHz, CDCl3): δ 7,87 (d, 1H, J=7.8 Hz), to 7.68 (d, 1H, J=7.8 Hz), 4,35 (c, 3H), 3,51 (c, 3H), 3,44 (c, 3H), 3,41 (c, 3H).

Stage 2: synthesis of N-methoxy-2-(3-methoxypropyl)-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of N-methoxy-2-(3-methoxy-prop-1-inyl)-N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 0,817 mmol) in 5%om Pd/C (50 mg) was added CH3OH (6 ml). The mixture was purged three times with gaseous hydrogen (50 psi) and usbutil is whether for 2 hours at room temperature. The reaction mixture was filtered through a layer of celite and concentrated under reduced pressure. The crude residue was chromatographically, receiving N-methoxy-2-(3-methoxypropyl)-N-methyl-6-trifluoromethyl-nicotinamide (160 mg, 64%).

1H NMR (300 MHz, CDCl3): δ 7,74 (d, 1H, J=7.8 Hz), to 7.68 (d, 1H, J=7.8 Hz), 3.46 in-to 3.34 (m, 8H), 3,32 (c, 3H), of 2.93 (t, 2H, J=7.8 Hz), 2,12-2,03 (m, 2H).

Stage 3: synthesis of methyl ester of 3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid

Methyl ester of 3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid was obtained according to the General procedure described in example 150 (stage 4).

N-Methoxy-2-(3-methoxypropyl)-N-methyl-6-trifluoromethyl-nicotinamide (156 mg, 0,509 mmol) were introduced in the reaction with 1M LAH in THF solution, obtaining 2-(3-methoxypropyl)-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively in the form of oil. The crude product was used directly in the next reaction. 2-(3-Methoxypropyl)-6-trifluoromethyl-pyridine-3-carbaldehyde was introduced in the reaction with methyl(triphenylphosphonium)acetate (204 mg, 0.61 mmol)to give methyl ester of 3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (124 mg, 80%).

1H NMR (300 MHz, CDCl3): δ 7,98 (d, 1H, J=15,9 Hz), to 7.93 (d, 1H, J=7.8 Hz), 7,53 (d, 1H, J=7.8 Hz), to 6.43 (d, 1H, J=15,9 Hz), 3,84 (c, 3H), 3.43 points (t, 2H, J=6.0 Hz), 3.33 and (c, 3H), 3,09 totaling 3.04 (m, 2H), 2,09 of 1.99 (m, 2H).

Stage 4: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxyp the filing)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (to 57.9 mg, 0,207 mmol) were introduced in the reaction with 3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (40 mg, was 0.138 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridine-3-yl]-acrylamide (18 mg, 17%).

1H NMR (300 MHz, CDCl3): δ a 7.92 (d, 1H, J=15,9 Hz), of 7.90 (d, 1H, J=8.1 Hz), 7,52 (d, 1H, J=8.1 Hz), 7,27 (d, 1H, J=5.4 Hz), 7,16 (DD, 1H, J=9,0, 1.8 Hz), 6.48 in (d, 1H, J=11.7 Hz), 6,41-6,36 (m, 2H), 4,51 (d, 2H, J=5.7 Hz), 3,47-of 3.42 (m, 3H), 3,31 (c, 3H), 3,26 (c, 3H), 3,09 totaling 3.04 (m, 2H), 2,07-to 1.98 (m, 2H).

Example 156 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(3-Fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide was obtained according to the General procedure described in example 107 (step 2).

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0,083 mmol) were introduced in the reaction with 3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (20 mg, 0,096 mmol)to give N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxypropyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (18 mg, 17%).

1H NMR (300 MHz, CDCl3) δ to 7.93 (d, 1H, J=15,0 Hz), 7,89 (d, 1H, J=7.4 Hz), 7,55-7,49 (m, 2H), 7,17-7,10 (m, 2H), 6,59 (c, 1H), gold 6.43 (d, 1H, J=15.6 Hz), 6,27 (t, 1H, J=6.0 Hz), 4,55 (d, 2H, J=6.0 Hz), 3,44 (t, 2H, J=2.0 Hz), 3,31 (c, 3H), 3,09 totaling 3.04 (m, 2H), 3,02 (c, 3H), 2,07-to 1.98 (m, 2H).

Example 157 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

In a microwave vial was loaded ethyl ester 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0,357 mmol), Pd(OAc)4(of 0.05 equiv.) NaHCO3(2 equiv.) PPh3(0.5 equiv.) styrene (5 EQ.) and DMF (1 ml). The vial was irradiated in a microwave synthesizer at 135°C for 3 hours. The contents of the vial were filtered through a layer of celite, which is carefully washed with EtOAc. The filtrate was evaporated, and the residue was purified by chromatography on columns, obtaining the ethyl ester of 3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (37 mg, 20%).

1H NMR (300 MHz, CDCl3): δ 8,10 (d, 1H, J=15.6 Hz), 7,95 (d, 1H, J=15.6 Hz), to 7.93 (d, 1H, J=7.8 Hz), 7,63 (d, 1H, J=7,2 Hz), 7,52 (d, 1H, J=7.8 Hz), 7,43-7,34 (m, 5H), of 6.45 (d, 1H, J=15,9 Hz), 4,32 (q, 2H, J=7,2 Hz), of 1.36 (t, 3H, J=7.2 Hz).

Stage 2: synthesis of N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (36 mg, to 0.127 mmol) were introduced in the reaction with 3-(2-what tiril-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (37 mg, 0,115 mmol)to give N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (38 mg, 55%).

1H NMR (300 MHz, DMSO): δ 9,45 (c, 1H, usher.), 8,91 (t, 1H, J=6.0 Hz), 8,23 (d, 1H, J=8.1 Hz), of 7.97 (d, 1H, J=15,9 Hz), 7,82-7,74 (m, 4H), to 7.61 (d, 1H, J=15,9 Hz), 7,46-7,29 (m, 5H), 6.75 in (d, 1H, J=15.6 Hz), 4,51 (c, 1H), 4,42 (d, 2H, J=5.7 Hz), 3,07 (c, 3H).

Example 158 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(N-methyl-N-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (53 mg, 0.21 mmol) were introduced in the reaction with 3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.18 mmol)to give the target compound (62 mg, 71%) after purification by chromatography on columns (Hex/EtOAc=2/3).

1H NMR (300 MHz, DMSO-d6): δ 9,56 (c OSiR., 1H), up 8.75 (t, 1H), 8,17 (d, 1H), 7,92 (d, 1H, J=7,2 Hz), 7,49 (d, 1H, J=15.6 Hz), 7,20 (m, 4H), 6,63 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5,1 Hz), 3,21 (m, 2H), 3.00 and (c, 3H), 2.91 in (c, 3H), and 1.63 (m, 2H), 0,81 (t, 3H, J=4,8 Hz).

Example 159 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(N-methyl-N-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (93 mg, 0.33 mmol) were introduced in the reaction with 3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (80 mg, 0.28 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (96 m is, 57%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (c OSiR., 1H), 8,78 (t, 1H, J=5.3 Hz), to 7.93 (d, 1H, J=7.5 Hz), 7,49 (d, 1H, J=15.6 Hz), 7,28 (m, 3H), 6,63 (d, 1H, J=15.6 Hz), 4,51 (c, 1H), and 4.40 (d, 2H, J=5.7 Hz), 3,21 (m, 2H), 3,07 (c, 3H), 2.91 in (c, 3H), 1,63 (m, 2H), 0,81 (t, 3H, J=7.5 Hz).

Example 160 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (53 mg, 0.21 mmol) were introduced in the reaction with 3-(2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (52 mg, 0,19 mmol)obtained by the method similar to that described above, receiving after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (53 mg, 59%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 8,03 (m, 2H), 7,86 (t, 1H), 7,65 (d, 1H, J=7.8 Hz), 7,46 (t, 1H, J=7.8 Hz), 7,13 (m, 2H), only 6.64 (d, 1H, J=15.3 Hz), 4,77 (c, 2H), to 4.52 (d, 2H, J=5.7 Hz), 3,66 (q, 2H, J=6.9 Hz), 3,01 (c, 3H), 1,25 (t, 3H, J=6.9 Hz).

Example 161 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (140 mg, 0.50 mmol) were introduced in the reaction with 3-(2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (125 mg, 0.45 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (141 mg, 63%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): to 8.41 δ (c, 1H), to 8.20 (t, 1H), 8,01 (d, 1H, J=7,8 G is), 7,94 (d, 1H, J=15.6 Hz), to 7.61 (d, 1H, J=8.1 Hz), 7,27 (c, 1H), 7,14 (d, 1H, J=10,2 Hz), 6,51 (d, 1H, J=15.6 Hz), 4,71 (c, 2H), 4,4 (d, 2H, J=5.7 Hz), of 3.60 (q, 2H, J=6.9 Hz), 3,11 (c, 3H), 1,19 (t, 3H, J=6,9 Hz).

Example 162: 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (43 mg, 0,156 mmol) were introduced in the reaction with NMM (0.1 ml), DMTMM (44 mg) and 3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (42 mg)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (52,7 mg, 75%).

1H NMR (300 MHz, CDCl3): δ 7,80 (d, 1H, J=7.8 Hz), of 7.75 (d, 1H, J=16.2 Hz), 7,41 (d, 2H, J=8.1 Hz), 7,21 (m, 3H), 6,70 (d, 2H, J=15.6 Hz), to 6.19 (c, 1H), 5,95 (t, 1H), 4.53-in (d, 2H, J=6.0 Hz), to 3.02 (c, 3H), 2,32 (c, 3H), 1,75 (m, 2H), of 1.36 (d, 3H, J=6.0 Hz), of 0.97 (t, 3H, J=7.2 Hz).

Example 163 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-cyano-2-fluoro-phenyl)-methanesulfonamide, HCl salt (101 mg, 0.36 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.30 mmol)to give after purification by crystallization from methylene chloride target compound (102 mg, 68%).

1H NMR (300 MHz, DMSO-d6): δ 8,78 (t, 1H), 8,04 (d, 1H, J=8,4 Hz), 7,81 (m, 2H), 7,60 (d, 1H, J=7.8 Hz), 7,53 (c, 1H), 7,47 (d, 1H, J=10,2 Hz), to 6.67 (d, 1H, J=15.6 Hz), 4,51 (d, 2H, J=5.4 Hz), 3,12 (c, 3H), 2,86 (d, 2H, J=7,5 Hz), of 2.15 (m, 1H), of 0.93 (d, 6H, J=6.6 Hz).

Example 164 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (89 mg, 0.33 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.30 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (116 mg, 79%).

1H NMR (300 MHz, DMSO-d6): δ of 9.30 (c OSiR., 1H), 8,78 (t, 1H), 8,15 (d, 1H, J=8,4 Hz), 7,79 (d, 1H, J=8.1 Hz), of 7.70 (d, 1H, J=15.6 Hz), 7,13 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), 4,42 (d, 2H, J=5.7 Hz), 2,97 (c, 3H), 2,82 (d, 2H, J=7,2 Hz), 2,20 (d, 3H, J=2.1 Hz), 2,10 (m, 1H), from 0.88 (d, 6H, J=6.6 Hz).

ESI [M+H]+: 488.

Example 165: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(methyl-phenylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (46 mg, 0,17 mmol) were introduced in the reaction with 2-methyl-phenylamino-6-trifluoromethyl-pyridin-3-yl-acrylic acid (55 mg, 0,17 mmol)to give after purification by chromatography on columns (Hex/EtOAc=3/2) of the target compound (45 mg, 49%).

1H NMR (300 MHz, CDCl3): δ 7,66 (m, 1H), 7,53 (m, 1H), 7.23 percent (m, 4H), 7,03 (m, 4H), 6.89 in (d, 1H, J=15,9 Hz), 6,47 (c OSiR., 1H), 6,03 (d, 1H, J=16.2 Hz), 5,16 (d, 1H, J=7.5 Hz), 5,00 (kV, 1H, J=7,2 Hz), 3,53 (c, 3H), 3.04 from (c, 3H), of 1.40 (d, 3H, J=6.9 Hz).

Example 166 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-phenylamino)-6-trifluoromethyl-PI is one-3-yl]-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (47 mg, 0,17 mmol) were introduced in the reaction with 3-(2-methyl-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0,17 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (30 mg, 32%).

1H NMR (300 MHz, CDCl3): δ the 7.65 (m, 1H), 7,20 (m, 4H), 7,00 (m, 5H), to 6.43 (c OSiR., 1H), 6,02 (d, 1H, J=16.2 Hz), 5,31 (c OSiR., 1H), 4,32 (d, 2H, J=6.0 Hz), 3,52 (c, 3H), 3,48 (c, 1H), 3,29 (c, 3H).

ESI [M+H]+: 547.

Example 167 N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-(methyl-phenylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-3-methyl-phenyl)-methanesulfonamide, HCl salt (46 mg, 0,17 mmol) were introduced in the reaction with 3-(2-methyl-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0,17 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (32 mg, 36%).

1H NMR (300 MHz, CDCl3): δ 7,66 (m, 1H), 7,42 (m, 1H), was 7.08 (m, 9H), 6,18 (c OSiR., 1H), equal to 6.05 (d, 1H, J=16.2 Hz), 5.25 in (c OSiR., 1H), or 4.31 (d, 2H, J=5.7 Hz), 3,51 (c, 3H), 3.04 from (c, 3H), 2,33 (c, 3H).

Example 168: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl)-methanesulfonamide, HCl salt (68 mg, 0.21 mmol) were introduced in the reaction with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic is islote (51 mg, 0,17 mmol)to give 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-acrylamide (80 mg, 68%).

1H NMR (300 MHz, CDCl3): δ of 7.82 (d, 1H, J=7.5 Hz), 7,76 (d, 1H, J=15,9 Hz), 7,40-of 7.23 (m, 3H), 6,76 (d, 1H, J=15.6 Hz), 6,37-6,34 (m, 2H), 4,57 (d, 2H, J=6.0 Hz), 4,48-of 4.44 (m, 2H), 3.27 to (c, 3H), 1,83 to 1.76 (m, 2H), 1,51-of 1.44 (m, 2H), of 0.97 (t, 3H, J=7.5 Hz).

Example 169: (R)-3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (57 mg, 0.21 mmol) were introduced in the reaction with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (51 mg, 0,17 mmol)to give (R)-3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide (57 mg, 54%).

1H NMR (300 MHz, CDCl3): δ 7,80 (d, 1H, J=7.5 Hz), 7,73 (d, 1H, J=15.6 Hz), 7,24 (d, 1H, J=8,4 Hz), 7,16 (d, 2H, J=9.6 Hz), 6,69 (d, 1H, J=15,9 Hz), 6,53 (c, 1H), by 5.87 (d, 1H, J=7.5 Hz), 5,24-5,19 (m, 1H), 4,46 (t, 2H, J=6,9 Hz), to 3.02 (c, 3H), 1,86 to 1.76 (m, 2H), 1.56 to a 1.45 (m, 5H), and 0.9 (t, 3H, J=7.5 Hz).

Example 170: 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (58 mg, 0.21 mmol) were introduced in the reaction with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (51 mg, 0,17 mmol)to give 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-and Grilamid (58 mg, 57%).

1H NMR (300 MHz, CDCl3): δ 7,76 (d, 1H, J=9.9 Hz), 7,71 (d, 1H, J=16.5 Hz), 7,35 (DD, 1H, J=5,7, and 2.4 Hz), 7,21-7,11 (m, 3H), of 6.68 (DD, 1H, J=13,4, 2.7 Hz), 6,28 (c, 1H), 6,00 (c, 1H), 4,49-to 4.38 (m, 4H), 2,96 (c, 3H), 2.26 and (c, 3H), 1,79-of 1.74 (m, 2H), 1,47-of 1.40 (m, 2H), to 0.92 (t, 3H, J=7.2 Hz).

Example 171: 3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: 3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (214 mg, 0,850 mmol) and sodium methoxide (95 mg, 1.13 mmol) was added to a microwave vial. The capsule was irradiated in the synthesizer Biotage at 200°C for 10 min, the Reaction mixture was purified, obtaining the target compound (15 mg) (Hex/EtOAc=5/1).

1H NMR (300 MHz, CDCl3): δ a 7.92 (d, 1H), of 7.75 (d, 1H), 7,25 (d, 1H), 6,38 (d, 1H), 3,23 (kV, 2H), of 1.37 (t, 3H).

Stage 2: 3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-ethinyl-phenyl)-methanesulfonamide, HCl salt (67 mg, 0,240 mmol) were introduced in the reaction with NMM (0.2 ml), DMTMM (65 mg) and 3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0,200 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (22 mg, 21%).

1H NMR (300 MHz, CDCl3): δ a 7.92 (d, 1H, J=7.5 Hz), of 7.75 (d, 1H, J=15.3 Hz), 7,50 (d, 1H, J=7.5 Hz), 7,28 (d, 1H, J=7.8 Hz), was 7.08 (m, 1H), 6,44 (d, 1H, J=15.6 Hz), 6,37 (t, H), of 4.44 (d, 2H, J=5.7 Hz), 3,40 (c, 1H), 3,21 (t, 2H, J=7,2 Hz), to 3.02 (c, 3H), of 1.32 (t, 3H, J=7.2 Hz).

Example 172 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (57,8 mg, 0,210 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (64,8 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (76 mg, 0,236 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (61,5 mg, 57%).

1H NMR (300 MHz, CDCl3): δ 7,83 (d, 1H, J=8.7 Hz), 7,79 (d, 1H, J=15.6 Hz), 7,51 (d, 1H, J=8,4 Hz), 7,41 (d, 1H, J=8,4 Hz), 7,20 (m, 5H), 6.30-in (c, 1H), and 6.25 (d, 1H, J=15.3 Hz), of 5.99 (t, 1H), 4,51 (d, 2H, J=6.0 Hz), or 3.28 (t, 2H, J=8,4 Hz), 3,06 (t, 2H, J=8,4 Hz), 3,01 (c, 3H).

ESI [M+H]+: 518.

Example 173 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (56 mg, 0,208 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (62,4 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (74 mg, 0,230 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (62 mg, 56%).

1H NMR (300 MHz, CDCl3): δ of 7.82 (d, 1H, J=8.1 Hz), 7,76 (d, 1H, J=15.6 Hz), 7,50 (d, 1H, J=7.8 Hz), 7,20 (m, 6H), 6,62 (c, 1H), and 6.25 (d, 1H, J=15.6 Hz), 6,18 (t, 1H), 4,55 (d, 2H, J=5.4 Hz), 3,26 (t, 2H, J=8,4 Hz), 3,05 (t, 2H, J=8,4 Hz), 3,01 (c, 3H), of 2.23 (d, 3H, J=2.1 Hz).

Example 174: 3-(2-isobut is l-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (47 mg, 0,17 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (41 mg, 0.15 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (68 mg, 96%).

1H NMR (300 MHz, DMSO-d6): δ 9,05 (c OSiR., 1H), 8,78 (t, 1H, J=6.0 Hz), 8,16 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=8.1 Hz), 7,71 (d, 1H, J=15.6 Hz), 7,17 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 4,36 (d, 2H, J=5.7 Hz), 2.95 and (c, 3H), and 2.83 (d, 2H, J=6,9 Hz), to 2.29 (c, 3H), 2,10 (m, 1H), 0,89 (d, 6H, J=6.6 Hz).

ESI [M+H]+: 470.

Example 175: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (44 mg, 0,17 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (41 mg, 0.15 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (47 mg, 64%).

1H NMR (300 MHz, DMSO-d6): δ 9,56 (c OSiR., 1H), 8,78 (d, 1H, J=8.1 Hz), 8,16 (d, 1H, J=8.1 Hz), 7,80 (d, 1H, J=8.1 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,17 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), to 5.03 (t, 1H, J=7.2 Hz), 3.00 and (c, 3H), of 2.81 (d, 2H, J=7,2 Hz), a 2.01 (m, 1H), 1,41 (d, 3H, J=7.2 Hz), to 0.88 (DD, 6H, J=2.1 and 6.6 Hz).

ESI [M+H]+: 488.

Example 176: 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-METI is-phenyl)-methanesulfonamide, the HCl salt (60 mg, 0.22 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (58 mg, 0.20 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (85 mg, 88%).

1H NMR (300 MHz, DMSO-d6): δ 9,04 (c OSiR., 1H), 8,65 (t, 1H, J=6.0 Hz), 7,76 (d, 1H, J=7.8 Hz), 7,63 (d, 1H, J=15.3 Hz), 7,17 (m, 3H), 6,94 (d, 1H, J=7.5 Hz), 6,79 (d, 1H, J=7.5 Hz), is 6.61 (d, 1H, J=15.3 Hz), 4,35 (d, 2H, J=5.7 Hz), 4,07 (m, 1H), 2,94 (c, 3H), 2,28 (c, 3H), of 1.55 (m, 2H), 1.14 in (d, 3H, J=6.6 Hz)to 0.85 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 485.

Example 177 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-ethinyl-phenyl)-methanesulfonamide, HCl salt (53 mg, 0,190 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (62 mg) and 3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (51 mg, 0,175 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (65 mg, 72%).

1H NMR (300 MHz, CDCl3): δ 7,80 (d, 1H, J=15,9 Hz), 7,74 (d, 1H, J=7.5 Hz), 7,34 (d, 1H, J=8.1 Hz), 7,29 (m, 1H), 7,15 (DD, 1H, J=2.1 and up 10.8 Hz), 6,45 (d, 1H, J=15,9 Hz), 6.42 per (c, 1H), 6,16 (t, 1H), to 4.52 (d, 2H, J=6.3 Hz), 4,14 (m, 1H), 3,48 (c, 1H), 3.27 to (c, 3H), USD 1.43 (d, 6H, J=6.6 Hz).

Example 178 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: 3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

3-(2-Chloro-trifluoromethyl-pyridin-3-yl)-acrylic acid (245 mg, 0,974 mmol) were introduced in the reaction with 2-propandiol (240 mg, 3,15 mmol) and sodium hydride (143 mg, of 3.56 mmol) to give after purification by chromatography on columns (Hex/EtOAc=2,5/1) of target compound (103 mg).

1H NMR (300 MHz, CDCl3): δ 7,98 (d, 1H, J=15,9 Hz), 7,82 (d, 1H, J=7.8 Hz), 7,37 (d, 1H, J=8.1 Hz), 6,46 (d, 1H, J=15.6 Hz), 4,13 (m, 1H), of 1.44 (d, 6H, J=6.9 Hz).

Stage 2: N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (37 mg, 0,145 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (39 mg) and 3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (31 mg, 0,106 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (49 mg, 94%).

1H NMR (300 MHz, CDCl3): δ 7,80 (d, 1H, J=15.6 Hz), 7,72 (d, 1H, J=7.5 Hz), 7,53 (t, 1H, J=8.1 Hz), 7,34 (d, 1H, J=7.5 Hz), 7,16 (d, 1H, J=10,2 Hz), 7,12 (d, 1H, J=8,4 Hz), 6,52 (c, 1H), 6,45 (d, 1H, J=15.6 Hz), 6,10 (t, 1H), 4,55 (d, 2H, J=6.0 Hz), 4,11 (m, 1H), 3,03 (c, 3H), USD 1.43 (d, 6H, J=6.9 Hz).

Example 179 N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (49 mg, 0,19 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (58 mg, 71%).

1H NMR (300 MHz, DMSO): δ to 9.57 (c, 1H, usher.), 8,84 (t, 1H, J=5.7 Hz), scored 8.38 (d, 1H, J=7.8 Hz), 8,02 (d, 1H, J=7.8 Hz), to 7.61-7,56 (m, 1H), 7,45-7,31 (m, 5H), 7,18 (d, 1H, J=11,1 Hz), 7,10 (d, 1H, J=8.1 Hz), 6,83 (d, 1H, J=15.6 Hz), 4,36 (d, 2H, J=5.7 Hz), 3,00 (c, 3H).

Example 180 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (51 mg, 0,19 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridine-3-yl]-acrylamide (47 mg, 56%).

1H NMR (300 MHz, DMSO): δ 9.28 are (c, 1H, usher.), 8,80 (t, 1H, J=6.0 Hz), at 8.36 (d, 1H, J=8,4 Hz), 8,01 (d, 1H, J=8,4 Hz), to 7.59 (DD, 1H, J=7,8, 5.7 Hz), 7,43-7,34 (m, 4H), 7,19-to 7.09 (m, 2H), 6,83 (d, 1H, J=15.6 Hz), 4,37 (d, 2H, J=5.4 Hz), 2,98 (c, 3H), 2,20 (c, 3H).

Example 181: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (51 mg, 0,19 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (54 mg, 64%).

1H NMR (300 MHz, CDCl3): δ 8,07 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.3 Hz), of 7.70 (d, 1H, J=8.1 Hz), 7,56-7,41 (m, 2H), 7,35-7,30(m, 2 H), 7,19-to 7.15 (m, 3H), 6.48 in (c, 1H), 6,45 (d, 1H, J=15.3 Hz), by 5.87 (d, 1H, J=7.5 Hz), 5,20-of 5.15 (m, 1H), 3,02 (c, 3H), and 1.54 (d, 3H, J=7.2 Hz).

Example 182: 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (53 mg, 0,19 mmol) were introduced in the reaction of 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide (48 mg, 59%).

1H NMR (300 MHz, CDCl3): δ of 8.06 (d, 1H, J=8.1 Hz), of 7.75 (d, 1H, J=15.3 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,50-7,33 (m, 3H), 7,26-7,20 (m, 3H), 6,44 (d, 1H, J=15,0 Hz), 6,15 (c, 1H), 5,93 (c, 1H), 4,51 (d, 2H, J=5.7 Hz), 3,03 (c, 3H), 2,31 (c, 3H).

Example 183: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (54 mg, 0,19 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.16 mmol)to give (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-piperid-1-Il-6-trifluoromethyl-pyridin-3-yl)-acrylamide (54 mg, 64%).

1H NMR (300 MHz, CDCl3): δ 7,71 (d, 1H, J=8.1 Hz), 7,66 (d, 1H, J=15.6 Hz), 7,52 (d, 1H, J=8.1 Hz), 7,17 for 7.12 (m, 3H), 6,56 (c, 1H), 6.42 per (d, 1H, J=15.6 Hz), of 5.92 (d, 1H, J=7.5 Hz), 5,24-5,19 (m, 1H), 3,29-3,26 (m, 4H), 3,03 (c, 3H), 1.70 to of 1.64 (m, 6H), and 1.54 (d, 3H, J=7.2 Hz).

Example 184 N-(4-metasolv is ylamino-3-methyl-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (55 mg, 0,19 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.16 mmol)to give 3-N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (33 mg, 40%).

1H NMR (300 MHz, CDCl3): δ 7,72-to 7.67 (m, 2H), 7,41 (d, 1H, J=8,4 Hz), 7,21 for 7.12 (m, 3H), to 6.43 (d, 1H, J=15.6 Hz), 6,24 (c, 1H), 5,96 (t, 1H, J=5.7 Hz), a 4.53 (d, 2H, J=5.7 Hz), 3,30-of 3.25 (m, 4H), 3,03 (c, 3H), 2,32 (c, 3H), 1,71-to 1.63 (m, 6H).

Example 185 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: 3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (243 mg, 0,966 mmol) were introduced in the reaction with propanolol (229 mg, a 3.01 mmol) and sodium hydride (145 mg, 3.62 mmol) to give after purification by chromatography on columns (Hex/EtOAc=2/3) of target compound (115 mg).

1H NMR (300 MHz, CDCl3): δ of 7.97 (d, 1H, J=15,9 Hz), to 7.77 (d, 1H, J=7.8 Hz), 7,32 (d, 1H, J=7.8 Hz), 6.42 per (d, 1H, J=15,9 Hz). is 3.21 (t, 2H, J=7,2 Hz), at 1.73 (m, 2H), and 1.00 (t, 3H, J=7.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-ethinyl-phenyl)-methanesulfonamide, HCl salt (60,2 mg, 0,215 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (70,2 mg) and 3-(2-propyl) - Rev. IO-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (58,7 mg, 0,201 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (60 mg, 58%).

1H NMR (300 MHz, CDCl3): δ a 7.85 (d, 1H, J=15.6 Hz), 7,74 (d, 1H, J=7.8 Hz), 7,34 (d, 1H, J=8.1 Hz), 7,30 (m, 1H), 7,16 (DD, 1H, J=1,8 and 10.8 Hz), 6,47 (d, 1H, J=15.3 Hz), 6.42 per (m, 1H), 6,17 (m, 1H), to 4.52 (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,26 (c, 3H), 3,23 (q, 2H, J=7.5 Hz), at 1.73 (m, 2H), of 1.03 (t, 3H, J=7.5 Hz).

Example 186 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (115,3 mg, 0,420 mmol) were introduced in the reaction with NMM (0.15 ml), DMTMM (123 mg) and 3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (to 114.4 mg, 0,393 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (57 mg, 30%).

1H NMR (300 MHz, CDCl3): δ to 7.84 (d, 1H, J=15.6 Hz), 7,72 (d, 1H, J=7.8 Hz), 7,41 (d, 1H, J=7.8 Hz), 7,320 (d, 1H, J=7.8 Hz), 7,19 (m, 2H), 6,45 (d, 1H, J=15.6 Hz), to 6.22 (m, 1H), 6,03 (m, 1H), to 4.52 (d, 2H, J=5.7 Hz), 3,23 (kV, 2H, J=6.9 Hz), to 3.02 (c, 3H), at 1.73 (m, 2H), of 1.03 (t, 3H, J=6.9 Hz).

Example 187 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (47 mg, 0,17 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0,17 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (39 m is, 47%).

1H NMR (300 MHz, CDCl3): δ to 7.61 (m, 2H), 7,42 (m, 1H), 7,20 (m, 2H), 6.89 in (d, 1H, J=7.5 Hz), 6,33 (d, 1H, J=15,0 Hz), 6,17 (c OSiR., 1H), 5,90 (c OSiR., 1H), 4,80 (c OSiR., 1H), 4.53-in (d, 2H, J=5.7 Hz), 3,50 (m, 2H), 3,03 (c, 3H), 2,32 (c, 3H), 1,49 (m, 4H), of 1.40 (m, 2H), of 0.96 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 485.

Example 188 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (56 mg, 0.21 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (60 mg, 0.21 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (60 mg, 57%).

1H NMR (300 MHz, CDCl3): δ 7,60 (m, 2H), 7.23 percent (m, 2H), 6.89 in (d, 1H, J=7.8 Hz), 6,33 (d, 1H, J=15.3 Hz), 6,30 (c OSiR., 1H), 6,01 (c OSiR., 1H), 4,84 (c OSiR., 1H), 4,59 (d, 2H, J=6.0 Hz), 3,49 (m, 2H), 3,05 (c, 3H), of 2.25 (d, 3H, J=2.1 Hz), 1,60 (m, 2H), 1.39 in (m, 2H), of 0.95 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 503.

Example 189 N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl)-methanesulfonamide, HCl salt (51,7 mg, 0,160 mmol) were introduced in the reaction with NMM (0.17 ml), DMTMM (57,2 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (49,7 mg, 0,154 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (82 mg, 90%).

1H NMR (300 MHz, CDCl 3): δ a 7.85 (d, 1H, J=8.1 Hz), to 7.77 (d, 1H, J=15.3 Hz), 7,53 (d, 1H, J=8.1 Hz), the 7.43 (m, 1H), 7,39 (d, 1H, J=9.9 Hz), 7,22 (m, 2H), 7,17 (c, 1H), 7,14 (m, 1H), and 6.25 (d, 1H, J=15.3 Hz), 6,18 (c, 1H), between 6.08 (t, 1H), 4,58 (d, 2H, J=6.0 Hz), 3,29 (t, 2H, J=8.7 Hz), 3,28 (c, 3H), is 3.08 (t, 2H, J=8.7 Hz).

Example 190: 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

Stage 1: synthesis of ethyl ester of 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-acrylic acid

Ethyl ester of 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-acrylic acid was obtained according to the General procedure described in example 145 (stage 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (50 mg, 0,178 mmol) was introduced into the reaction as described above with diethyl-prop-2-inyl-amine (2 EQ.), getting ethyl ester of 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-acrylic acid (30 mg, 47%).

1H NMR (300 MHz, CDCl3): δ to 8.14 (d, 1H, J=16.2 Hz), with 8.05 (d, 1H, J=8,4 Hz), 7,63 (d, 1H, J=8,4 Hz), to 6.57 (d, 1H, J=16.2 Hz), 4,30 (q, 2H, J=7,2 Hz), 3,81 (c, 2H), 2,69 (q, 4H, J=7,2 Hz), of 1.35 (t, 3H, J=7.2 Hz)and 1.15 (t, 6H, J=7,2 Hz).

Stage 2: synthesis of 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

3-[2-(3-Diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide was obtained according to the General procedure, the description of the Noi in example 107 (step 2).

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (31 mg, 0.11 mmol) were introduced in the reaction with 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-acrylic acid (30 mg, 0,092 mmol), as described above, receiving 3-[2-(3-diethylamino-prop-1-inyl)-4-trifluoromethyl-phenyl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide (7 mg, 12%).

1H NMR (300 MHz, CDCl3): δ with 8.05 (d, 1H, J=15,9 Hz), 8,81 (d, 1H, J=8.1 Hz), to 7.61 (d, 1H, J=8,4 Hz), 7,28-7,26 (m, 2H), 7,16 (d, 1H, J=10,2 Hz), 6,70 (d, 1H, J=15.6 Hz), 6,60 (c, 1H), to 4.52 (d, 2H, J=6.0 Hz), of 3.77 (c, 2H), 3,47 (c, 1H), 3,25 (c, 3H), 2,71 (q, 4H, J=7,2 Hz), of 1.13 (t, 6H, J=7.2 Hz).

Example 191: 3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (40 mg, 0.15 mmol) were introduced in the reaction with 3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0.12 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (32 mg, 51%).

1H NMR (300 MHz, DMSO-d6): δ 9,04 (c OSiR., 1H), 8,63 (t, 1H), 7,78 (m, 2H), 7,63 (d, 1H, J=15,9 Hz), 7,25 (m, 8H), of 6.99 (d, 1H, J=8.1 Hz), of 6.65 (d, 1H, J=15,9 Hz), a 4.53 (d, 2H, J=5,1 Hz), 4,35 (d, 2H, J=6.3 Hz), 2,99 (c, 3H), 2,28 (c, 3H).

Example 192: 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (65 mg, 0.24 mmol) was introduced by the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0.20 mmol)to give after purification by crystallization from methylene chloride target compound (43 mg, 44%).

1H NMR (300 MHz, DMSO-d6): δ 9,18 (c OSiR., 1H), 8,77 (t, 1H, J=5.7 Hz), 8,14 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=8,4 Hz), of 7.70 (d, 1H, J=15.6 Hz), 7,16 (m, 2H), 6,74 (d, 1H, J=15.6 Hz), 4,42 (d, 2H, J=5.4 Hz), 2,99 (c, 3H), equal to 2.94 (m, 2H), 2,22 (d, 3H, J=2.7 Hz), of 1.62 (m, 2H), 1,35 (m, 2H), of 0.91 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 488.

Example 193: (R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (65 mg, 0.24 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0.20 mmol)to give after purification by crystallization from methylene chloride target compound (49 mg, 50%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c OSiR., 1H), 8,76 (d, 1H, J=7.8 Hz), 8,15 (d, 1H, J=7.8 Hz), 7,80 (d, 1H, J=8.1 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,24 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 5,04 (t, 1H, J=7.5 Hz), 3,01 (c, 3H), of 2.93 (m, 2H), 1,60 (m, 2H), of 1.42 (d, 3H, J=7.5 Hz), of 1.33 (m, 2H), of 0.90 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 488.

Example 194: 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (66 mg, 0.24 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0.20 mmol)to give the target compound (69 mg, 73%) after purification chromatograph is her columns (Hex/EtOAc=1/2).

1H NMR (300 MHz, CDCl3): δ of 7.97 (d, 1H, J=15.6 Hz), 7,88 (d, 1H, J=8,4 Hz), 7,51 (d, 1H, J=8,4 Hz), 7,44 (d, 1H, J=8.1 Hz), 7,20 (m, 2H), 6,37 (d, 1H, J=15.6 Hz), 6,11 (c OSiR., 1H), of 5.92 (t, 1H), 4,55 (d, 2H, J=5.4 Hz), 3,03 (c, 3H), 2,99 (m, 2H), 2,33 (c, 3H), of 1.70 (m, 2H), 1,41 (m, 2H), of 0.95 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 470.

Example 195: (R)-3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (27 mg, 0.10 mmol) were introduced in the reaction with 3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (30 mg, 0,093 mmol)to give the target compound (39 mg, 78%) after purification by chromatography on columns (Hex/EtOAc=2/3).

1H NMR (300 MHz, DMSO-d6): δ of 9.30 (c OSiR., 1H), 8,35 (d, 1H, J=7.8 Hz), to 7.64 (m, 2H), 7,27 (m, 8H), 7,01 (t, 1H), 6.89 in (d, 1H, J=7.8 Hz), 6,59 (d, 1H, J=15.3 Hz), 5,11 (t, 1H, J=7.5 Hz), 4,63 (d, 2H, J=5.7 Hz), 2,98 (c, 3H), of 1.48 (d, 3H, J=6,9 Hz).

ESI [M+H]+: 537.

Example 196: 3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (28 mg, 0.10 mmol) were introduced in the reaction with 3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (30 mg, 0,093 mmol)to give the target compound (44 mg, 87%) after purification by chromatography on columns (Hex/EtOAc=2/3).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c OSiR., 1H), up 8.75 (t, 1H), 7,81 (m, 2H), 765 (d, 1H, J=15.3 Hz), 7,27 (m, 7H), of 6.99 (d, 1H, J=7,2 Hz), of 6.66 (d, 1H, J=15.3 Hz), a 4.53 (d, 2H, J=6.0 Hz), 4,48 (c, 1H), 4,39 (d, 2H, J=5.7 Hz), 3.04 from (c, 3H).

ESI [M+H]+: 547.

Example 197 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

Stage 1: 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid

To a suspension of methyl ester of 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (366 mg, 1,22 mmol) in THF (3 ml) was added 1 n LiOH solution (3.0 ml)and the mixture was stirred for 3 hours at room temperature. The obtained residue was dissolved in H2O and then washed with EtOAc, acidified 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. MgSO4, and concentrated in vacuum, obtaining 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (340 mg, 97%).

1H NMR (300 MHz, CDCl3): δ with 8.05 (d, 1H, J=15,9 Hz), 7,98 (d, 1H, J=8,4 Hz), 7,56 (d, 1H, J=8.1 Hz), 6,46 (d, 1H, J=15.6 Hz), of 3.00 (t, 2H, J=7.8 Hz), at 1.73 (m, 2H), 1.39 in (m, 4H), of 0.91 (t, 3H, J=7.2 Hz).

Stage 2: N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (74 mg, 0.27 mmol) were introduced in the reaction with 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (77 mg, 0.27 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) N-(3-ethinyl-5-FPO is-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide (57 mg, 42%).

1H NMR (300 MHz, CDCl3): δ to 7.93 (m, 2H), 7,52 (d, 1H, J=8.1 Hz), 7,30 (c OSiR., 1H), 7,17 (m, 1H), to 6.39 (d, 1H, J=15.3 Hz), 6.42 per (c OSiR., 1H), 6,09 (c OSiR., 1H), 4,54 (d, 2H, J=6.0 Hz), 3,49 (c, 1H), 3.27 to (c, 3H), 2,98 (m, 2H), 1,72 (m, 2H), to 1.37 (m, 4H), to 0.89 (m, 3H).

ESI [M+H]+: 512.

Example 198 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (70 mg, 0.26 mmol) were introduced in the reaction with 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (74 mg, 0.26 mmol)to give after purification by chromatography on columns (Hex/EtOAc=3/2) N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-Il-acrylamide (57 mg, 46%).

1H NMR (300 MHz, CDCl3): δ of 7.96 (d, 1H, J=15,9 Hz), 7,88 (d, 1H, J=7.8 Hz), 7,47 (m, 2H), 7,22 (m, 2H), 6,37 (d, 1H, J=15.3 Hz), 6,14 (c OSiR., 1H), 5,94 (c OSiR., 1H), 4,55 (d, 2H, J=5.7 Hz), 3,03 (c, 3H), 2,98 (c, 3H), 2,32 (c, 3H), 1,72 (m, 2H), to 1.37 (m, 4H), to 0.89 (m, 3H).

ESI [M+H]+: 484.

Example 199 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (49 mg, 0.18 mmol) were introduced in the reaction with 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (52 mg, 0.18 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (58 mg, 63%).

1H NMR (300 MHz, CDCl3): δ 7,94 (m, 2H), 7,41 (m, 1H),6,99 (m, 2H), 6,40 (d, 1H, J=15,0 Hz)6,09 (c OSiR., 1H), 6,06 (c OSiR., 1H), 4,56 (d, 2H, J=6.0 Hz), 3,22 (c, 3H), 2,96 (m, 2H), 1,72 (m, 2H), to 1.37 (m, 4H), to 0.89 (m, 3H).

ESI [M+H]+: 506.

Example 200: synthesis of N-(4-methanesulfonamido-3,5-debtor-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (55 mg, 0,19 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.16 mmol)to give 3-N-(4-methanesulfonamido-3,5-debtor-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (35 mg, 41%).

1H NMR (300 MHz, DMSO): δ 9,50 (c, 1H, usher.), 8,82 (t, 1H, J=6.0 Hz), 7,01 (d, 1H, J=7.8 Hz), was 7.45 (d, 1H, J=15,9 Hz), 7,40 (d, 1H, J=7.8 Hz), 7,13 (c, 1H), 7,12 (d, 1H, J=8.7 Hz), 6.75 in (d, 1H, J=15,9 Hz), 4,42 (d, 2H, J=6.0 Hz), 3,19 (c, 4H), 3.04 from (c, 3H), 1,63 (c, 6H).

Example 201 N-(4-methanesulfonamido-3,5-debtor-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (53 mg, 0,19 mmol) were introduced in the reaction with 3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (50 mg, 0.16 mmol)to give N-(4-methanesulfonamido-3,5-debtor-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide (31 mg, 37%).

1H NMR (300 MHz, DMSO): δ 9,50 (c, 1H, usher.), 8,87 (t, 1H, J=6.0 Hz), 8,40 (d, 1H, J=8.1 Hz), 8,02 (d, 1H, J=8,4 Hz), 7,63-7,56 (m, 2H), 7,46-7,35 (m, 3H), 7,11-to 7.09 (m, 2H), at 6.84 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5.7 Hz), 3.04 from (c, 3H).

Example 202 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-butylamino-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (47 mg, 0,17 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0,17 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (52 mg, 59%).

1H NMR (300 MHz, CDCl3): δ to 7.84 (m, 1H), 7,51 (d, 1H, J=7.8 Hz), 6,79 (m, 1H), 6,47 (c OSiR., 3H), 6,30 (d, 1H, J=15.6 Hz), of 4.05 (d, 2H, J=2.1 Hz), 3,50 (m, 2H), 3,32 (c, 3H), of 1.65 (m, 2H), 1.26 in (m, 2H), 0,95 (m, 3H).

ESI [M+H]+: 507.

Example 203 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (107,2 mg, 0,393 mmol) were introduced in the reaction with NMM (0,20 ml), DMTMM (123 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (101,3 mg, 0,315 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (99 mg, 58%).

1H NMR (300 MHz, CDCl3): δ 7,86 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=15.6 Hz), 7,52 (d, 1H, J=7.8 Hz), 7,17 (m, 4H), 6,91 (d, 2H, J=8,4 Hz), 6,40 (d, 1H, J=15.6 Hz), 6,32 (t, 1H), 6,28 (c, 1H), 4,48 (d, 2H, J=6.0 Hz), 3.27 to (t, 2H, J=7,2 Hz), 3,17 (c, 3H), 3,06 (t, 2H, J=7,2 Hz).

ESI [M+H]+: 540.

Example 204 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (100 mg, of 0.37 mmol) were introduced in the reaction with 3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (102 mg, 0.35 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (107 mg, 60%).

1H NMR (300 MHz, DMSO-d6): 9,52 (c OSiR., 1H), δ 8,76 (t, 1H), 7,81 (d, 1H, J=7.8 Hz), to 7.59 (d, 1H, J=15.3 Hz), 7,11 (m, 3H), of 6.99 (d, 1H, J=7.8 Hz), only 6.64 (d, 1H, J=15.3 Hz), to 4.41 (d, 2H, J=6.0 Hz), 3,50 (m, 4H), 3,25 (c, 3H), 3,03 (c, 3H).

ESI [M+H]+: 509.

Example 205: 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (100 mg, of 0.37 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (96 mg, 0.35 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (125 mg, 73%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,88 (t, 1H), 8,18 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=7.8 Hz), 7,72 (d, 1H, J=15.6 Hz), 7,13 (d, 2H, J=8.7 Hz), 6.75 in (d, 1H, J=15.6 Hz), 4,43 (d, 2H, J=5.7 Hz), 3,05 (c, 3H), equal to 2.94 (m, 2H), 1,62 (m, 2H), 1,35 (m, 2H), of 0.90 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 492.

Example 206 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (167 mg, 0,60 IMO is b) was introduced into the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (30 mg, 0.50 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (211 mg, 87%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (c OSiR., 1H), 8,87 (t, 1H), 8,18 (d, 1H, J=8,4 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.6 Hz), 7,13 (m, 2H), 6.75 in (d, 1H, J=15.6 Hz), 4.53-in (c, 1H), to 4.41 (d, 2H, J=6.0 Hz), 3,07 (c, 3H), of 2.93 (m, 2H), 1,66 (m, 2H), were 0.94 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 484.

Example 207 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (100 mg, of 0.37 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.35 mmol)to give the target compound (134 mg, 80%) after purification by chromatography on columns (Hex/EtOAc=1/2).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,88 (t, 1H), 8,18 (d, 1H, J=8.1 Hz), 7,79 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=15.6 Hz), 7,13 (d, 2H, J=8,4 Hz), 6.75 in (d, 1H, J=15.6 Hz), 4,43 (d, 2H, J=5.7 Hz), 3,05 (c, 3H), of 2.92 (m, 2H), 1,67 (m, 2H), with 0.93 (t, 3H, J=6.9 Hz).

ESI [M+H]+: 478.

Example 208 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (102 mg, and 0.37 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.35 mmol)to give the target compound (120 mg, 75%) after purification by chromatography on columns (Hex/EtOAc=1/2).

1H I Is R (300 MHz, DMSO-d6): δ 9,03 (c OSiR., 1H), 8,77 (t, 1H), 8,15 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=8,4 Hz), of 7.70 (d, 1H, J=15.6 Hz), 7,18 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 4,37 (d, 2H, J=6.0 Hz), 2,96 (c, 3H), of 2.92 (m, 2H), 2,30 (c, 3H), 1,67 (m, 2H), were 0.94 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 456.

Example 209: (R)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (105 mg, 0,39 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (90 mg, 0.35 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (151 mg, 91%).

1H NMR (300 MHz, DMSO-d6): δ 9,56 (c OSiR., 1H), 8,77 (d, 1H, J=7.8 Hz), 8,14 (d, 1H, J=8.1 Hz), 7,80 (d, 1H, J=8,4 Hz), 7,66 (d, 1H, J=15.6 Hz), 7,27 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 5,04 (t, 1H, J=7.5 Hz), 3.00 and (c, 3H), 2.91 in (m, 2H), 1,67 (m, 2H), 1,41 (d, 3H, J=6.9 Hz), to 0.92 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 474.

Example 210: (R)-3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (92 mg, 0.34 mmol) were introduced in the reaction with 3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.28 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (133 mg, 95%).

1H NMR (300 MHz, DMSO-d6): δ 9,56 (c OSiR., 1H), 8,64 (d, 1H, J=8,4 Hz), 7,76 (d, 1H, J=7.8 Hz), 7,58 (d, 1H, J=15.6 G is), 7,25 (m, 3H), 6,94 (d, 1H, J=7.8 Hz), 6,77 (d, 1H, J=7.8 Hz), 6,53 (d, 1H, J=15.6 Hz), to 5.03 (t, 1H), 4,06 (m, 1H), 3.00 and (c, 3H), of 1.55 (m, 2H), 1,40 (d, 3H, J=7.2 Hz), 1,12 (m, 3H), 0,84 (m, 3H).

ESI [M+H]+: 503.

Example 211: (R)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (105 mg, 0,39 mmol) were introduced in the reaction with 3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (101 mg, 0.35 mmol)to give after purification by crystallization from a simple ester of the target compound (73 mg, 42%).

1H NMR (300 MHz, DMSO-d6): δ 8,76 (d, 1H, J=8.1 Hz), 8,16 (d, 1H, J=8,4 Hz), 7,78 (d, 1H, J=15.6 Hz), 7,25 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 5,04 (t, 1H, J=7.5 Hz), 3,01 (c, 3H), of 3.00 (m, 1H), 2,70 (m, 1H), 1,92 (m, 1H), 1,41 (d, 3H, J=6.9 Hz), of 1.30 (m, 2H), from 0.84 (m, 6H).

ESI [M+H]+: 502.

Example 212: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (105 mg, 0,39 mmol) were introduced in the reaction with 3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (102 mg, 0.35 mmol)to give after purification by crystallization from a simple ester of the target compound (114 mg, 65%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c OSiR., 1H), 8,65 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=7.8 Hz), 7,54 (d, 1H, J=15.3 Hz), 7,25 (m, 4H), of 6.99 (d, 1H, J=7.8 Hz), only 6.64 (d, 1H, J=15.3 Hz), 5,04(t, 1H, J=6.9 Hz), 3048 (c, 4H), 3,25 (c, 3H), 3,01 (c, 3H), of 1.41 (d, 3H, J=6.9 Hz).

Example 213: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-butylamino)-6-trifluoromethyl-pyridin-3-yl-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (103 mg, 0.38 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (110 mg, 0.38 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (120 mg, 63%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 9,23 (c OSiR., 1H), 8,24 (c OSiR., 1H), 7,56 (m, 3H), 7,41 (m, 1H), 7,17 (m, 2H), 6,86 (d, 1H, J=7.5 Hz), 6,56 (d, 1H, J=15.6 Hz), 5,15 (m, 1H), 3.46 in (m, 2H), 2,99 (c, 3H), 1,60 (m, 2H), 1,50 (d, 3H, J=7.2 Hz), were 0.94 (m, 3H).

ESI [M+H]+: 503.

Example 214 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (52 mg, 0,19 mmol) were introduced in the reaction with 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0,19 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (65 mg, 68%).

1H NMR (300 MHz, CDCl3): δ to $ 7.91 (m, 2H), 7,50 (d, 1H, J=5.8 Hz), 7,25 (m, 2H), 6,36 (d, 1H, J=15.3 Hz), 6,15 (c, user., 1H), 6,01 (c, user., 1H), br4.61 (d, 2H, J=6.0 Hz), 3,05 (c, 3H), of 2.97 (m, 2H), 2,25 (c, 3H), 1,71 (m, 2H), of 1.34 (m, 2H), 0,89 (m, 3H).

ESI [M+H]+: 502.

Example 215: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3(2-pentyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (54 mg, 0.20 mmol) were introduced in the reaction with 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (57 mg, 0.20 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (35 mg, 35%).

1H NMR (300 MHz, CDCl3): δ of 7.90 (m, 2H), 7,53 (m, 2H), 6,45 (c OSiR., 1H), 6,37 (d, 1H, J=15.6 Hz), to 5.85 (d, 1H, J=7.8 Hz), with 5.22 (m, 1H), 3.04 from (c, 3H), 2,96 (m, 2H), 1.70 to (m, 2H), 1,58 (c, 3H), of 1.36 (m, 4H), to 0.88 (m, 3H).

ESI [M+H]+: 502.

Example 216 N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-(propane-1-sulfonyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide

N-(4-Methanesulfonamido-3-methyl-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide (34,9 mg, 0,0715 mmol) for 3 hours at ambient temperature was introduced into the reaction with m-CPBA (60%, 43,7 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/4) of the target compound (31 mg, 83%).

1H NMR (300 MHz, CDCl3): δ 8,24 (d, 1H, J=14.1 Hz), to 8.20 (d, 1H, J=8.1 Hz), 7,86 (d, 1H, J=8.1 Hz), 7,33 (d, 1H, J=8,4 Hz), to 7.15 (m, 2H), 6,55 (d, 1H, J=15,9 Hz), 6,50 (t, 1H), 6,38 (c, 1H), 4,45 (d, 2H, J=6.0 Hz), 3,62 (m, 2H), 3.00 and (c, 3H), 2,68 (c, 3H), of 1.94 (m, 2H), 1,11 (t, 3H, J=7.5 Hz).

Example 217 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, salt Hl (109 mg, 0.40 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.30 mmol)to give after purification by crystallization from a simple ester of the target compound (109 mg, 74%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,76 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7.5 Hz), to 7.64 (d, 1H, J=15.6 Hz), 7,13 (d, 2H, J=8.7 Hz), of 6.96 (d, 1H, J=7.8 Hz), PC 6.82 (d, 1H, J=7.5 Hz), 6,62 (d, 1H, J=15.6 Hz), to 4.41 (d, 2H, J=6.0 Hz), 4,22 (m, 1H), 3,05 (c, 3H), of 1.18 (d, 6H, J=6.3 Hz).

ESI [M+H]+: 493.

Example 218: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (107 mg, 0.40 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.30 mmol)to give after purification by crystallization from a simple ester of the target compound (137 mg, 93%).

1H NMR (300 MHz, DMSO-d6): δ 9,54 (c OSiR., 1H), 8,65 (d, 1H, J=7.8 Hz), 7,76 (d, 1H, J=7.8 Hz), EUR 7.57 (d, 1H, J=15.3 Hz), 7,25 (m, 3H), of 6.96 (d, 1H, J=7.5 Hz), to 6.80 (d, 1H, J=7.5 Hz), 6,60 (d, 1H, J=15.3 Hz), to 5.03 (t, 1H, J=7.5 Hz), 4,20 (m, 1H), 3,01 (c, 3H), of 1.40 (d, 3H, J=6.9 Hz), 1,16 (DD, 6H, J=2.1 and 6.3 Hz).

ESI [M+H]+: 489.

Example 219: 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (110 mg, 0.40 mmol) were introduced in the reaction with 3-(2-isopro is ylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (82 mg, 0.30 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (92 mg, 65%).

1H NMR (300 MHz, DMSO-d6): δ 9,00 (c OSiR., 1H), 8,64 (t, 1H), 7,76 (d, 1H, J=7,2 Hz), a 7.62 (d, 1H, J=15.3 Hz), 7,18 (m, 3H), 6,95 (d, 1H, J=7.5 Hz), to 6.80 (d, 1H, J=7,2 Hz), is 6.61 (d, 1H, J=15.3 Hz), of 4.45 (d, 2H, J=5.4 Hz), 4,20 (m, 1H), 2.95 and (c, 3H), 2,29 (c, 3H), of 1.18 (d, 6H, J=5.7 Hz).

ESI [M+H]+: 471.

Example 220 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (71 mg, 0.26 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (55 mg, 0.20 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (88 mg, 90%).

1H NMR (300 MHz, DMSO-d6): δ 9,25 (c OSiR., 1H), 8,64 (t, 1H), of 7.75 (d, 1H, J=7.5 Hz), a 7.62 (d, 1H, J=15.3 Hz), 7,14 (m, 2H), 6,95 (d, 1H, J=6.6 Hz), to 6.80 (d, 1H, J=7.5 Hz), 6,62 (d, 1H, J=15.3 Hz), to 4.41 (d, 2H, J=5.4 Hz), is 4.21 (m, 1H), 2,99 (c, 3H), 2,21 (c, 3H), of 1.18 (d, 6H, J=6.3 Hz).

ESI [M+H]+: 489.

Example 221 N-(3-Ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (106 mg, 0,39 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.26 mmol)to give after purification by chromatography on columns (ex/EtOAc=1/2) of the target compound (86 mg, 66%).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c OSiR., 1H), a total of 8.74 (t, 1H, J=5.7 Hz), 7,79 (d, 1H, J=7.5 Hz), 7,60 (d, 1H, J=15.3 Hz), 7,29 (m, 2H), 7,15 (m, 1H), 6,95 (d, 1H, J=7.5 Hz), 6,63 (d, 1H, J=15.3 Hz), to 4.52 (c, 1H), 4,39 (d, 2H, J=5.7 Hz), 3,30 (m, 2H), 3,07 (c, 3H), 1,58 (m, 2H), of 0.87 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 499.

Example 222 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (92 mg, 0.34 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.26 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (74 mg, 58%).

1H NMR (300 MHz, DMSO-d6): δ 9,49 (c OSiR., 1H), up 8.75 (t, 1H, J=6.0 Hz), 7,79 (d, 1H, J=7.5 Hz), 7,60 (d, 1H, J=15.3 Hz), 7,13 (m, 3H), 6,95 (d, 1H, J=7.5 Hz), only 6.64 (d, 1H, J=15.3 Hz), to 4.41 (d, 2H, J=6.0 Hz), 3,30 (m, 2H), 3.04 from (c, 3H), 1,58 (m, 2H), from 0.88 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 493.

Example 223 N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (91 mg, 0.34 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.26 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (98 mg, 77%).

1H NMR (300 MHz, DMSO-d6): δ 9,27 (c OSiR., 1H), 8,64 (t, 1H), of 7.75 (d, 1H, J=7,2 Hz), 7,58 (d, 1H, J=15.6 Hz), to 7.15 (m, 3H), 6,95 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.6 Hz), and 4.40 (d, 2H, J=5.4 Hz), with 3.27 (m, 2H), 2,97 (c, 3H), 2,21 (c, 3H), of 1.57 (m, 2H), of 0.87 (t, 3H, J=7.2 Hz).

Example 224: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (91 mg, 0.34 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.26 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (106 mg, 83%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,64 (d, 1H, J=7.5 Hz), 7,76 (d, 1H, J=7.5 Hz), 7,55 (d, 1H, J=15.6 Hz), 7,25 (m, 4H), to 6.95 (d, 1H, J=8.1 Hz), 6,63 (d, 1H, J=15.6 Hz), to 5.03 (t, 1H, J=7,2 Hz), with 3.27 (m, 2H), 3.00 and (c, 3H), and 1.56 (m, 2H), 1,40 (d, 3H, J=6.6 Hz), 0,86 (t, 3H, J=7.5 Hz).

Example 225 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (93 mg, 0.34 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.26 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (85 mg, 69%).

1H NMR (300 MHz, DMSO-d6): δ 9,12 (c OSiR., 1H), 8,64 (t, 1H), 7,76 (d, 1H, J=7.8 Hz), 7,58 (d, 1H, J=15.6 Hz), 7,25 (m, 4H), to 6.95 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.6 Hz), 4,36 (d, 2H, J=4, 2 Hz), 3,30 (m, 2H), 2,92 (c, 3H), 2,29 (c, 3H), 1.57 in (m, 2H), of 0.87 (t, 3H, J=7.2 Hz).

Primer: N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (30 mg, 0.11 mmol) were introduced in the reaction with 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (20 mg, 0.73 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (30 mg, 84%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,88 (t, 1H), 8,19 (d, 1H, J=8.1 Hz), 7,80 (d, 1H, J=7.8 Hz), 7,73 (d, 1H, J=15.6 Hz), 7,13 (d, 2H, J=8.7 Hz), 6.75 in (d, 1H, J=15.6 Hz), 4,43 (d, 2H, J=5.4 Hz), 3,05 (c, 3H), and 2.83 (d, 2H, J=6,9 Hz), a 2.01 (m, 1H), from 0.88 (t, 3H, J=6.6 Hz).

Example 227: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

Stage 1: synthesis of 2,6-debtor-4-iodoaniline

To a solution of 2,6-diferencia (5.0 g, of 38.7 mmol) and p-toluensulfonate acid (1.45 g, 7.62 mmol) in DMF (70 ml) at 5°C was added dropwise N-jodatime (9.6 g, and 42.7 mmol)dissolved in DMF (50 ml). The mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated under reduced pressure and then diluted with EtOAc and water. The organic layer was washed saturated aqueous sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by crystallization from EtOAc and hexane, obtaining 2,6-debtor-4-yo is vanillin (9,12 g, 92.4 per cent).

1H NMR (300 MHz, CDCl3): δ 7,16 (d, 1H, J=1.8 Hz), 7,14 (d, 1H, J=1.8 Hz), 3,76 (c OSiR., 2H).

Stage 2: synthesis of 1-(4-amino-3,5-debtor-phenyl)-ethanone

A suspension of 2,6-debtor-4-iodoaniline (1 g, to 3.92 mmol) and Pd(OAc)2(of 0.025 equiv.) DPPP (of 0.05 EQ.) in [bmim][BF3] (6 ml) was stirred for 10 min. After three degassing the mixture successively introduced a simple butylaniline ester (5 EQ.) and Et3N (1.2 EQ.). The mixture was stirred for 15 hours at 115°C. the Mixture was cooled to room temperature and then added 1 N. HCl. After stirring the mixture for 0.5 hours was added CH2Cl2. The organic layer was washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography, obtaining 1-(4-amino-3,5-debtor-phenyl)-Etalon (300 mg, 45%).

1H NMR (300 MHz, CDCl3): δ to 7.15 (d, 1H, J=1.2 Hz), 7,13 (d, 1H, J=1.2 Hz), 3,76 (c, 2H, usher.).

Stage 3: synthesis of N-(4-acetyl-2,6-debtor-phenyl)-methanesulfonamide

To a solution of 1-(4-amino-3,5-debtor-phenyl)-ethanone (2.35 g, 13,73 mmol) and Et3N (2 ml) in CH2Cl2(10 ml) at 0°C was added dropwise MsCl (of 2.34 ml, 2.34 mmol). The mixture was stirred for 3 hours at room temperature. The mixture was then diluted with EtOAc and 1 N. HCl. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered has concentrically under reduced pressure. The crude product was used directly in the next reaction. The crude residue was dissolved in THF (8 ml), and then to the solution was added 1 N. NaOH (4 ml) and CH3OH (4 ml). After stirring for 5 hours at room temperature the mixture was diluted with EtOAc and 1 N. HCl. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography to obtain N-(4-acetyl-2,6-debtor-phenyl)-methanesulfonamide (1.85 g, 54%).

1H NMR (300 MHz, CDCl3): δ of 7.60 (d, 1H, J=3.3 Hz), 7,56 (d, 1H, J=3.3 Hz), to 6.43 (c, 1H), 3,89 (c, 3H), to 3.58 (c, 3H).

Stage 4: synthesis of N-{2,6-debtor-4-[1-(2-methyl-propane-2-sulfonylamino)-ethyl]-phenyl}-methanesulfonamide

To a solution of N-(4-acetyl-2,6-debtor-phenyl)-methanesulfonamide (1.84 g, 7,38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8,86 ml) in THF (15 ml) was added dropwise at room temperature Ti(OEt)4(2,61 ml, 12.6 mmol). The mixture was stirred overnight at 90°C. the Mixture was cooled to room temperature and then added to the salt solution. After extraction of the mixture three times using EtOAc and the mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography, obtaining N-{2,6-debtor-4-[1-(2-methyl-propane-2-sulfonylamino)-ethyl]-phenyl}-methanesulfonamide (2.2 g 85%). To a solution of N-{2,6-debtor-4-[1-(2-methyl-propane-2-sulfonylamino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6,24 mmol) in THF (20 ml) at -48°C) was added by portions NaBH4(944 mg, 24,9 mmol)dissolved in THF (2 ml). The mixture was stirred for 10 hours at a temperature of -48°C to about room temperature, and then was added dropwise CH3OH to stop gassing. The mixture was concentrated under reduced pressure and then purified by chromatography to obtain N-{2,6-debtor-4-[1-(2-methyl-propane-2-sulfonylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).

1H NMR (300 MHz, CDCl3): δ? 7.04 baby mortality (d, 1H, J=2.4 Hz), of 6.99 (d, 1H, J=2.4 Hz), 6,59 (c, 1H), 4,54 figure-4.49 (m, 1H), 3,53 (d, 1H, J=3.6 Hz), 3,20 (c, 3H), of 1.50 (d, 3H, and 6.6 Hz), 1,23 (c, 9H).

Stage 5: synthesis of (R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt

To a solution of N-{2,6-debtor-4-[1-(2-methyl-propane-2-sulfonylamino)-ethyl]-phenyl}-methanesulfonamide (789 mg, 2.22 mmol) in CH3OH (8 ml) at room temperature was added dropwise 4 M HCl in dioxane (2 ml). The mixture was stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The crude residue was purified by crystallization from CH2Cl2and Et2O, obtaining (R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (611 g, 96%).

1H NMR (300 MHz, DMSO): δ 8,73 (c, 3H, usher.), of 7.48 (d, 1H, J=2.7 Hz), the 7.43 (d, 1H, J=2.7 Hz), 4,43 (kV, 1H, J=3.6 Hz), 3,53 (d, 1H, J=3.6 G is), of 3.07 (c, 3H)and 1.51 (d, 3H, 6.9 Hz).

Step 6: synthesis of (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (70 mg, 0.24 mmol) were introduced in the reaction with 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0.24 mmol)to give after purification by crystallization from a simple ester of the target compound (108 mg, 89%).

1H NMR (300 MHz, DMSO-d6): δ 9,49 (c OSiR., 1H), 8,68 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=7.5 Hz), EUR 7.57 (d, 1H, J=15.3 Hz), 7,17 (d, 2H, J=9.0 Hz), of 6.96 (d, 1H, J=7.8 Hz), PC 6.82 (d, 1H, J=7.5 Hz), 6,62 (d, 1H, J=15.3 Hz), to 5.03 (m, 1H), 4,22 (m, 1H), 3.04 from (c, 3H), of 1.40 (d, 3H, J=6.9 Hz), 1,17 (DD, 6H, J=2.4 and 6.3 Hz).

ESI [M+H]+: 507.

Example 228: (R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (70 mg, 0.24 mmol) were introduced in the reaction with 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0.24 mmol)to give after purification by crystallization from a simple ester of the target compound (115 mg, 95%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,80 (d, 1H, J=7.5 Hz), 8,16 (d, 1H, J=8.1 Hz), 7,80 (d, 1H, J=8,4 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,17 (d, 2H, J=8,4 Hz), 6.75 in (d, 1H, J=15.6 Hz), 5,04 (m, 1H), 3,03 (c, 3H), of 2.93 (m, 2H), 1,61 (m, 2H), 1,41 (d, 3H, J=6.9 Hz), of 1.36 (m, 2H), of 0.90 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 506.

Example 229: (R)-N-[1-(3,5-debtor-4-is ethanolgasoline-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (60 mg, 0.21 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0.20 mmol)to give after purification by crystallization from a simple ester of the target compound (95 mg, 95%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,68 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=7.8 Hz), 7,55 (d, 1H, J=15.3 Hz), 7,16 (m, 3H), of 6.96 (d, 1H, J=7.5 Hz), 6,63 (d, 1H, J=15.3 Hz), to 5.03 (m, 1H), or 3.28 (m, 2H), 3.04 from (c, 3H), and 1.56 (m, 2H), 1,40 (d, 3H, J=6.5 Hz), of 0.87 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 507.

Example 230: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (62 mg, 0.22 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0.22 mmol)to give after purification by crystallization from a simple ester of the target compound (81 mg, 73%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c OSiR., 1H), 8,81 (d, 1H, J=7.8 Hz), 8,16 (d, 1H, J=8,4 Hz), 7,80 (d, 1H, J=7.8 Hz), to 7.67 (d, 1H, J=15.6 Hz), 7,18 (d, 2H, J=7,2 Hz), 6,76 (d, 1H, J=15.6 Hz), 5,04 (m, 1H), 3,05 (c, 3H), 2.91 in (m, 2H), 1,65 (m, 2H), 1,41 (d, 3H, J=6.9 Hz), to 0.92 (t, 3H, J=7.2 Hz).

ESI [M+H]+: 492.

Example 231 N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-6-ethinyl-2-fluoro-what enyl)-methanesulfonamide, the HCl salt (75 mg, 0.27 mmol) were introduced in the reaction with 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol)to give after purification by recrystallization (Hex/EtOAc) N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (54 mg, 42%).

1H NMR (300 MHz, CDCl3): δ of 8.04 (d, 1H, J=15.6 Hz), the 7.85 (d, 1H, J=7.8 Hz), 7,49 (d, 1H, J=8,4 Hz), 7,31 (c, 1H), 7,19 (m, 1H), 6,41 (c, 1H), 6.35mm (d, 1H, J=15.6 Hz), 6,02 (c OSiR., 1H), 4,55 (d, 2H, J=5.7 Hz), 3,49 (c, 1H), 3,48 (m, 1H), 3.27 to (c, 3H), 1.32 to (c, 3H), 1,29 (c, 3H).

ESI [M+H]+: 484.

Example 232 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (74 mg, 0.27 mmol) were introduced in the reaction with 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol)to give after purification by recrystallization (Hex/EtOAc) of the target compound (46 mg, 36%).

1H NMR (300 MHz, DMSO-d6): δ 9,60 (c, 1H), 8,89 (t, 1H, J=6.0 Hz), 8,15 (d, 1H, J=8,4 Hz), 7,78 (m, 2H), 7,13 (d, 1H, J=8,4 Hz), 6,72 (d, 1H, J=15,9 Hz), 4,43 (d, 2H, J=5.7 Hz), 3,47 (m, 1H), 3.04 from (c, 3H), 1,24 (c, 3H), 1,21 (c, 3H).

Example 233 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (74 mg, 0.27 mmol) were introduced in the reaction with 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic Ki is lotay (74 mg, 0.27 mmol)to give after purification by recrystallization (Hex/EtOAc) of the target compound (61 mg, 50%).

1H NMR (300 MHz, CDCl3): δ 8,03 (d, 1H, J=15.6 Hz), 7,83 (d, 1H, J=8.1 Hz), was 7.45 (m, 2H), 7,22 (c, 1H), 7,19 (c, 1H), 6,34 (d, 1H, J=15.3 Hz), to 6.19 (c, 1H), 5,98 (c, 1H), 4,54 (d, 2H, J=6.0 Hz), 3,47 (m, 1H), 3,03 (c, 3H), 2,32 (c, 3H), 1,31 (c, 3H), 1,29 (c, 3H).

Example 234: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (73 mg, 0.27 mmol) were introduced in the reaction with 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol)to give after purification by recrystallization (Hex/EtOAc) of the target compound (69 mg, 54%).

1H NMR (300 MHz, CDCl3): δ 8,49 (d, 1H, J=15.6 Hz), 7,83 (d, 1H, J=8.1 Hz), 7,51 (m, 2H), 7,17 (m, 2H), 6,50 (c, 1H), 6,34 (d, 1H, J=15,9 Hz), by 5.87 (c OSiR., 1H), a total of 5.21 (c OSiR., 1H), 3,90 (d, 1H, J=5,1 Hz), 3,44 (m, 1H), 3.04 from (c, 3H), and 1.54 (c, 3H), 1,29 (c, 3H), 1.27mm (c, 3H).

ESI [M+H]+: 474.

Example 235 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (89 mg, 0.33 mmol) were introduced in the reaction with 3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (89 mg, 0.33 mmol)to give after purification by recrystallization (Hex/EtOAc=2:3) the target compound (33 mg, 20%).

1H NMR (300 MHz, CDCl3): δ with 8.05 (d, 1H, J=15.6 Hz), 7,86 (d, 1H,J=7.8 Hz), 7,49 (d, 1H, J=7.8 Hz), 7,00 (d, 2H, J=7.8 Hz), 6.35mm (d, 1H, J=15.3 Hz), 6,03 (c OSiR., 2H), 4,57 (d, 2H, J=6.0 Hz), 3,22 (c, 3H), of 1.88 (m, 2H), of 1.66 (m, 1H), 1.27mm (d, 2H, J=6.6 Hz), of 0.82 (t, 3H, J=7.5 Hz).

Example 236: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (to 61.8 mg, 0,215 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (93 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0,208 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (98.3 mg, 85%).

1H NMR (300 MHz, CDCl3): δ to 7.84 (d, 1H, J=7.8 Hz), 7,76 (d, 1H, J=15.6 Hz), 7,51 (d, 1H, J=7.8 Hz), 7,19 (m, 4H), to 6.95 (d, 1H, J=8.1 Hz), 6.48 in (c, 1H), 6,27 (d, 1H, J=15.6 Hz), 6,12 (d, 1H), 5,14 (m, 1H), 3,24 (t, 2H, J=6,3 Hz), 3,18 (c, 3H), of 3.07 (t, 2H, J=8,4 Hz).

Example 237: (R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (to 61.4 mg, 0,228 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (97 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (72 mg, 0,224 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (80,8 mg, 67%).

1H NMR (300 MHz, CDCl3): δ 7,83 (d, 1H, J=8.1 Hz), 7,76 (d, 1H, J=15.3 Hz), 7,55 (m, 2H), 7,19 (m, 5H), 6,528 (c, 1H), from 6.22 (d, 1H, J=15.3 Hz), of 5.83 (d, 1H, J=7.5 Hz), 5,20 (m, 1H J=6,9 Hz)at 3.25 (t, 2H, J=7.8 Hz), of 3.07 (t, 2H,, J=8 Hz), to 3.02 (c, 3H).

ESI [M+H]+: 554.

Example 238: (R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[(1R)-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (80 mg, 0.28 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (96 mg, 0.33 mmol)to give after purification by crystallization from a simple ester of the target compound (140 mg, 96%).

1H NMR (300 MHz, DMSO): δ 9,49 (c, 1H), 8,68 (d, 1H, J=7,2 Hz), to 7.77 (d, 1H, J=7,2 Hz), 7,54 (d, 1H, J=15.3 Hz), 7,19 for 7.12 (m, 3H), 6,95 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.6 Hz), of 5.05-free 5.01 (m, 1H), 3,34-3,26 (m, 2H), 3,05 (c, 3H), 1,55-of 1.45 (m, 2H), 1,40 (d, 3H, J=5.7 Hz), to 0.88 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 521.

Example 239: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (80 mg, 0.28 mmol) were introduced in the reaction with 3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.33 mmol)to give after purification by crystallization from a simple ester of the target compound (140 mg, 95%).

1H NMR (300 MHz, DMSO): δ 9,95 (c, 1H), 8,68 (d, 1H, J=7.5 Hz), to 7.99 (d, 1H, J=7.5 Hz), 7,42 (d, 1H, J=7,2 Hz), 7,41 (d, 1H, J=15,0 Hz), 7,25-to 7.15 (m, 3H), 6,74 (d, 1H, J=15.6 Hz), 5,06-5,02 (m, 1H), 3,32 (c, 4H user.), 3,05 (c, 3H), 1.61 of (c, 5H, usher.), of 1.40 (t, 3H, J=5,1 Hz).

ESI [M+H]+: 533.

Example 240: (S)-3-(2-butylamino-6-triform the Teal-pyridine-3-yl)-N-[(1S)-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(S)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (40 mg, 0.14 mmol) were introduced in the reaction with 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 0.16 mmol)to give after purification by crystallization from a simple ester of the target compound (57 mg, 80%).

1H NMR (300 MHz, DMSO): δ 9,49 (c, 1H), 8,68 (d, 1H, J=7.5 Hz), to 7.77 (d, 1H, J=7.5 Hz), 7,54 (d, 1H, J=15.3 Hz), 7,19-7,14 (m, 3H), 6,95 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.3 Hz), of 5.05-5,00 (m, 1H), 3,34-3,29 (m, 2H), 3,05 (c, 3H), 1,58 is 1.48 (m, 2H), 1,40 (d, 3H, J=6.9 Hz), to 0.88 (t, 3H, J=7.5 Hz).

ESI [M+H]+: 521.

Example 241: (R)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-methyl-phenyl)-methanesulfonamide, HCl salt (98 mg, 0,359 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (99 mg) and 3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (98 mg, 0,359 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (25 mg, 15%).

1H NMR (300 MHz, CDCl3): δ 8,03 (d, 1H, J=15 Hz), to 7.84 (d, 1H, J=7.8 Hz), was 7.45 (m, 2H), 7,22 (c, 1H), 6,99 (c OSiR., 1H), 6,33 (d, 1H, J=15.3 Hz), 6,20 (c, 1H), 4,54 (d, 2H, J=5.7 Hz), 3,21 (m, 1H), 3,03 (c, 3H), 2,32 (c, 3H), of 1.85 (m, 1H), of 1.66 (m, 1H), 1.26 in (d, 3H, J=6.6 Hz), 0,81 (t, 3H, J=7.2 Hz).

Example 242: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-IU is unsulfonated, the HCl salt (77 mg, 0.27 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (90 mg) and 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (75 mg, 57%).

1H NMR (300 MHz, CDCl3): δ to 7.99 (d, 1H, J=15.6 Hz), the 7.85 (d, 1H, J=7.8 Hz), 7,49 (d, 1H, J=8.1 Hz), 7,02 (c, 1H), 6,99 (c, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6,12 (c, 1H), 5,95 (d, 1H, J=7,2 Hz), 5,19 (m, 1H), 3,44 (m, 1H), 3,22 (c, 3H), of 1.53 (d, 3H, J=6.6 Hz), 1,30 (c, 3H), 1.28 (in c, 3H).

Example 243: (R)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (69 mg, 0,256 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (85 mg) and 3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0,256 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (40 mg, 32%).

1H NMR (300 MHz, CDCl3): δ of 8.00 (d, 1H, J=15.3 Hz), to 7.84 (d, 1H, J=8.1 Hz), 7,56 (t, 1H, J=7.8 Hz), of 7.48 (d, 1H, J=8.1 Hz), 7,19 (c, 1H), 7,16 (c, 1H), 6,46 (c, 1H), 6,32 (d, 1H, J=15.3 Hz), to 5.85 (d, 1H, NH), with 5.22 (m, 1H), 3,19 (m, 1H), 3,03 (c, 3H), of 1.84 (m, 1H), 1,64 (m, 1H), 1,25 (DD, 3H, J=6,6Hz, 1.2 Hz), 0,80 (m, 3H).

Example 244: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (22 mg, 0,215 mmol) were introduced in the reaction with NMM (0.10 ml), DMTMM (43 mg) is 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, of 0.081 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (22 mg, 55%).

1H NMR (300 MHz, CDCl3): δ 8,02 (d, 1H), 7,92 (d, 1H, J=15.3 Hz), a 7.62 (m, 3H), was 7.08 (d, 1H, J=7.8 Hz), 6,53 (d, 1H, J=15.3 Hz), 5,20 (m, 1H), 3,20 (m, 2H), 2,99 (c, 3H), and 1.56 (m, 2H), 1,49 (d, 3H, J=6.5 Hz), of 0.87 (t, 3H, J=7,2 Hz).

Example 245: (R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (138 mg, 0.48 mmol) were introduced in the reaction with NMM (0,11 ml), DMTMM (138 mg, 0,499 mmol) and 3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (127 mg, 0,467 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (178 mg, 74%).

1H NMR (300 MHz, CDCl3): δ 7,94 (d, 1H, J=4, 2 Hz), of 7.90 (d, 1H, J=2.7 Hz), 7,49 (d, 1H, J=8.1 Hz), 6,93 (d, 1H, J=8,4 Hz), 6,64 (c, 1H), 6,45 (d, 1H, J=15.3 Hz), 6.35mm (d, 1H, J=7.5 Hz), 5,13 (m, 1H), 3,19 (c, 3H), and 2.83 (d, 2H, J=7,2 Hz), 2,12 (m, 1H), 1,46 (d, 3H, J=6.9 Hz), of 0.90 (d, 6H).

ESI [M-H]-: 504.

Example 246 N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-ethylamino)-6-trifluoromethyl-pyridin-3-yl-acrylamide

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (145 mg, 0.54 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (140 mg, 0.54 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (113 mg, 41%).

1H NMR (300 MHz, CDCl3): δ 7,58 (m, 3H), 7,18 (c, 1H), 7,14 (m, 1H), 6.90 to (d, 1H, J=7,2 Hz), 6.48 in (c, 1H), 6,33 (d, 1H, J=15,0 Hz), of 5.82 (c OSiR., 1H), a total of 5.21 (m, 1H), 4,78 (c OSiR., 1H), 3,53 (m, 2H), 3,03 (c, 3H), and 1.56 (d, 3H, J=5.5 Hz), 1,25 (t, 3H, J=7.5 Hz).

ESI [M-H]-: 473.

Example 247 N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-ethylamino-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-3-methyl-phenyl)-methanesulfonamide, HCl salt (78 mg, 0,284 mmol) were introduced in the reaction with 2-ethylamino-6-trifluoromethyl-pyridin-3-yl-acrylic acid (74 mg, 0,284 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2:3) the target compound (83 mg, 64%).

1H NMR (300 MHz, CDCl3): δ 7,66 (d, 1H, J=14,7 Hz), EUR 7.57 (m, 1H), 7,19 (m, 2H), 6.90 to (m, 1H), 6.35mm (d, 1H, J=15.3 Hz), 6.30-in (c, 1H), 5,96 (c, 1H), 4,86 (c, 1H), 4.53-in (d, 2H, J=5.4 Hz), of 3.54 (m, 2H), 3,02 (c, 3H), 2,31 (c, 3H), of 1.26 (t, 3H, J=6.6 Hz).

ESI [M-H]-: 455.

Example 248 N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,5-debtor-phenyl)-methanesulfonamide, HCl salt (33 mg, 0.12 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (38 mg, 0.14 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (35 mg, 59%).

1H NMR (300 MHz, DMSO-d6): δ 9,84 (c OSiR., 1H), 8,69 (t, 1H, J=5.7 Hz), to 7.77 (d, 1H, J=7.5 Hz), to 7.59 (d, 1H, J=15.6 Hz), 7,25 (m, 2H), 7,14 (m, 1H), of 6.96 (d, 1H, J=7.5 Hz), 6,62 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5.4 Hz, of 3.28 (m, 2H), 3,07 (c, 3H), of 1.57 (m, 2H), of 0.87 (t, 3H, J=7.2 Hz).

ESI [M-H]-: 491.

Example 249: 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (301 mg, 1.07 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, from 0.76 mmol)to give after purification by recrystallization from simple diethyl ether target compound (110 mg, 74%).

1H NMR (300 MHz, DMSO-d6): δ 9,45 (c, 1H), up 8.75 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7.5 Hz), to 7.59 (d, 1H, J=15.6 Hz), 7,30 (c, 1H), 7,29 (d, 1H, J=9.0 Hz), 7,13 (t, 1H, J=5,1 Hz), of 6.96 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.3 Hz), 4,51 (c, 1H), 4,39 (d, 2H, J=6.0 Hz), 3,41-3,37 (m, 2H), 3,06 (c, 3H), 1.14 in (t, 3H, J=6.9 Hz).

ESI [M-H]-: 483.

Example 250: 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt (258 mg, of 0.92 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, from 0.76 mmol)to give after purification by recrystallization from simple diethyl ether target compound (270 mg, 60%).

1H NMR (300 MHz, DMSO-d6): δ to 9.32 (c, 1H), total of 8.74 (t, 1H, J=6.0 Hz), 7,79 (d, 1H, J=7.5 Hz), 7,58 (d, 1H, J=15.3 Hz), 7,50 (c, 1H), 7.18 in? 7.04 baby mortality (m, 2H), of 6.96 (d, 1H, J=7.8 Hz), only 6.64 (d, 1H, J=15.6 Hz), 5,86 (d, 1H, J=18,0 Hz), 5,42 (d, 1H, J=11,4 Hz), 4,42 (d, 2H, J=5.7 G is), 3,50 is 3.40 (m, 2H), 3.00 and (c, 3H), of 1.13 (t, 3H, J=6.9 Hz).

ESI [M-H]-: 485.

Example 251 N-(2-chloro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

A mixture of N-(4-aminomethyl-3-chloro-phenyl)-methanesulfonamide, HCl salt and N-(4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (80 mg) was injected in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (76 mg, 0.28 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (77 mg, 57%).

1H NMR (300 MHz, DMSO-d6): δ 9,98 (c OSiR., 1H), 8,76 (t, 1H, J=5.7 Hz), 8,15 (d, 1H, J=7.8 Hz), 7,79 (d, 1H, J=7.8 Hz), of 7.70 (d, 1H, J=15,9 Hz), was 7.36 (d, 1H, J=8,4 Hz), 7,27 (d, 1H, J=2.4 Hz), 7,17 (DD, 1H, J=8.4 and 2.4 Hz), 6,78 (d, 1H, J=15,9 Hz), 4,43 (d, 2H, J=5.4 Hz), to 3.02 (c, 3H), 2.91 in (m, 2H), of 1.66 (m, 2H), of 0.93 (t, 3H, J=7.5 Hz).

ESI [M-H]-: 474.

Example 252 N-(4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

A mixture of N-(4-aminomethyl-3-chloro-phenyl)-methanesulfonamide, HCl salt and N-(4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (80 mg) was injected in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (76 mg, 0.28 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (50 mg, 39%).

1H NMR (300 MHz, DMSO-d6): δ RS 9.69 (c OSiR., 1H), 8,77 (t, 1H, J=5.7 Hz), 8,14 (d, 1H, J=7.8 Hz), 7,78 (d, 1H, J=7.8 Hz), 7,71 (d, 1H, J=15,9 Hz), 7,28 (d, 2H, J=8,4 Hz), 7,18 (d, 2H, J=8,4 Hz), 6.73 x (d, 1H, J=15,9 Hz), 4,37 (d, 2H, J=5,7 is C), 3,00 (m, 5H), of 1.66 (m, 2H), of 0.93 (t, 3H, J=7.5 Hz).

ESI [M-H]-: 440.

Example 253 N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2-chloro-phenyl)-methanesulfonamide, HCl salt (58 mg, 0.22 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (60 mg, 0.22 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (65 mg, 62%).

1H NMR (300 MHz, CDCl3): δ 7,98 (m, 1H), 7,89 (m, 1H), 7,46 (m, 4H), 6,38 (d, 1H, J=15.3 Hz), 6,02 (c OSiR., 1H), 4,59 (DD, 2H, J=7,8 Hz, 6.0 Hz), 3,49 (c, 3H), of 1.76 (m, 2H), 1.26 in (m, 2H), 1,01 (m, 3H).

Example 254 N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(3-Chloro-4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (61 mg, 0.22 mmol) were introduced in the reaction with 3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (60 mg, 0.22 mmol)to give the target compound (73 mg, 68%) after purification by chromatography on columns (Hex/EtOAc=1:1).

1H NMR (300 MHz, CDCl3): δ to 7.59 (m, 3H), 7,31 (m, 2H), 6.90 to (m, 1H), 6,84 (c OSiR., 1H), 6,36 (d, 1H, J=15,0 Hz), 6,13 (c OSiR., 1H), 4,55 (DD, 2H, J=14,1Hz, 6.3 Hz), 3,48 (c, 3H), of 1.65 (m, 4H), of 0.97 (t, 3H, J=7.2 Hz).

Example 255 N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl)-pyridine-3-yl-acrylamide

N-(4-Aminomethyl-2,5-debtor-phenyl)-methanesulfonamide, with the l HCl (61 mg, 0.22 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (58 mg, 0.22 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (20 mg, 18%).

1H NMR (300 MHz, CDCl3): δ 8,91 (m, 1H), they were 8.22 (m, 1H), to 7.67 (d, 1H, J=15.3 Hz), EUR 7.57 (d, 1H, J=7.5 Hz), 6.87 in (m, 2H), 6,36 (d, 1H, J=15,0 Hz), and 6.25 (c OSiR., 1H), 5,01 (c OSiR., 1H), 4.53-in (d, 2H, J=6.0 Hz), 3,06 (c, 3H), 3.04 from (m, 2H), 1,25 (m, 3H).

ESI [M-H]-: 477.

Example 256: 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (117 mg, 0.46 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.38 mmol)to give after purification by recrystallization from simple diethyl ether target compound (118 mg, 56%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (c, 1H), 8,71 (t, 1H, J=6.0 Hz), 7,78 (d, 1H, J=7,2 Hz), 7,58 (d, 1H, J=15.3 Hz), 7,34 (t, 1H, J=8.1 Hz), 7,21 (DD, 1H, J=11,4, 1.8 Hz), 7,14-7,11 (m, 2H), of 6.96 (d, 1H, J=7.5 Hz), 6,63 (d, 1H, J=15.6 Hz), 4,39 (d, 2H, J=5.7 Hz), 3,42-3,37 (m, 2H), 3.00 and (c, 3H), 1.14 in (t, 3H, J=6.9 Hz).

ESI [M-H]-: 459.

Example 257 N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (125 mg, 0.46 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 is g, 0.38 mmol)to give after purification by recrystallization from simple diethyl ether target compound (110 mg, 60%).

1H NMR (300 MHz, DMSO-d6): δ 9,50 (c, 1H), 8,76 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7.8 Hz), to 7.59 (d, 1H, J=15.3 Hz), 7,13 (c, 1H), 7,13 (d, 1H, J=8,4 Hz), of 6.96 (d, 1H, J=7.5 Hz), only 6.64 (d, 1H, J=15.6 Hz), to 4.41 (d, 2H, J=6.0 Hz), 3,42-to 3.35 (m, 2H), 3.04 from (c, 3H), 1.14 in (t, 3H, J=6.9 Hz).

ESI [M-H]-: 477.

Example 258: 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (124 mg, 0.46 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.38 mmol)to give after purification by recrystallization from simple diethyl ether target compound (230 mg, 62%).

1H NMR (300 MHz, DMSO-d6): δ 9,26 (c, 1H), 8,64 (t, 1H, J=6.0 Hz), of 7.75 (d, 1H, J=7.5 Hz), EUR 7.57 (d, 1H, J=15.6 Hz), 7,22-7,17 (m, 1H), of 6.96 (d, 1H, J=7.8 Hz), 6,63 (d, 1H, J=15.6 Hz), to 4.41 (d, 2H, J=5.4 Hz), 3,42-3,37 (m, 2H), 2,98 (c, 3H), 2,21 (c, 3H), 1.14 in (t, 3H, J=6.9 Hz).

ESI [M-H]-: 473.

Example 259 N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-(4-Aminomethyl-2-cyano-6-fluoro-phenyl)-methanesulfonamide, HCl salt (129 mg, 0.46 mmol) were introduced in the reaction with 3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.38 mmol)to give after purification by recrystallization from PR is stage diethyl ether target compound (113 mg, 54%).

1H NMR (300 MHz, DMSO-d6): δ 10,07 (c, 1H), 8,79 (t, 1H, J=6.0 Hz), 7,80 (d, 1H, J=7,2 Hz), 7,66-7,56 (m, 3H), 7,13 (t, 1H, J=8.1 Hz), 6,97 (d, 1H, J=7.5 Hz), only 6.64 (d, 1H, J=15.6 Hz), of 4.45 (d, 2H, J=5.7 Hz), 3,42-to 3.38 (m, 2H), 3,11 (c, 3H), 1.14 in (t, 3H, J=6.9 Hz).

Example 260: 3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

Stage 1: butyl[3-(2,2-dibromovinyl)-6-trifluoromethyl-pyridin-2-yl]-amine

A solution of 2-butylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (2.00 g, 6,55 mmol) in THF (50 ml) was cooled to -78°C was added dropwise 1 M LiAlH4in THF (3.3 ml, 3.3 mmol). The resulting mixture was stirred for 1 hour at -78°C and then slowly warmed up to -20°C within 2 hours, and then extinguished by adding 10%sodium caliterra, then EtOAc. After vigorous stirring for 30 minutes at room temperature, divided in two phases, and the aqueous phase was extracted with EtOAc twice. The combined organic layer was washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining the aldehyde.

The solution tetrabromide carbon (4.35 g, 13,1 mmol) in methylene chloride under nitrogen atmosphere at 0°C was treated with triphenylphosphine (6,87 g, 26,2 mmol) and was stirred for 1 h at 0°C. the Mixture was treated with aldehyde obtained above were mixed during the 1 h at 0°C and then extinguished with water. The separated organic phase is washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was treated with hexane and collected the supernatant. The residue was dissolved in methylene chloride and poured into hexane. The supernatant was collected. The procedure was repeated two more times. The combined supernatant was passed through silica gel and then concentrated, obtaining the target compound (1.60 g, 61%).

1H NMR (300 MHz, CDCl3): δ 7,51 (d, 1H, J=7.8 Hz), 7,09 (c. 1H), 6.89 in (d, 1H, J=7.8 Hz), 4,40 (c. user., 1H), of 3.45 (m, 2H), 1,58 (m, 2H), 1,36 (m, 2H), to 0.92 (t, 3H, J=7.2 Hz).

Stage 2: methyl ether (2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

A solution of butyl-[3-(2,2-dibromovinyl)-6-trifluoromethyl-pyridin-2-yl]-amine (1,02 g, 2.54 mmol) in THF under nitrogen atmosphere at -78°C was slowly treated with 2.5 M BuLi in hexane (2.0 ml, 5.00 mmol) and then stirred for 30 min at -78°C and 30 min at -0°C. the Mixture was treated with methylchloroform (0,235 ml of 3.05 mmol) at -78°C and warmed up to 0°C for 1 h the Mixture was diluted 1:1 mixture of saturated NaHCO3and solution of NH4Cl, and the aqueous layer was extracted with simple ether (×3). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=10/1)to give the target issue for lighting the e compound (78 mg, 10%).

1H NMR (300 MHz, CDCl3): δ a 7.85 (d, 1H, J=7.8 Hz), 7,52 (d, 1H, J=7.8 Hz), of 3.78 (m, 2H), 3,64 (c, 3H), of 1.48 (m, 2H), 1.26 in (m, 2H), of 0.82 (t, 3H, J=7.5 Hz).

Stage 3: (2-butylamino-6-trifluoromethyl-pyridin-3-yl)-popinova acid

To a suspension of methyl ether (2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (78 mg, 0.26 mmol) in THF (0,50 ml) was added 1 n LiOH solution (1.0 ml)and the mixture was stirred for 3 hours at room temperature. The reaction mixture was acidified using 1 N. HCl to pH 1~2. The solution was extracted three times with methylene chloride and then dried over Bezbog. Na2SO4, and concentrated in vacuum, obtaining the target compound (50 mg, 65%).

1H NMR (300 MHz, DMSO-d6): δ 8.17 and (d, 1H, J=7.8 Hz), 7,80 (d, 1H, J=7.8 Hz), 3,71 (m, 5H), of 1.47 (m, 2H), 1.26 in (m, 2H), 0,81 (t, 3H, J=7.2 Hz).

Stage 4: 3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated 3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

N-(4-Aminomethyl-2-ethinyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (80 mg, 0.29 mmol) were introduced in the reaction with (2-butylamino-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (70 mg, 0.24 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (84 mg, 57%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (m, 2H), scored 8.38 (d, 1H, J=7.8 Hz), 7,92 (d, 1H, J=7.8 Hz), 7,27 (m, 2H), 4.53-in (c, 1H), 4,36 (d, 2H, J=5.7 Hz), of 3.77 (m, 2H), 3,07 (c, 3H)and 1.51 (m, 2H), 1.28 (in m, 2H), of 0.82 (t, 3H, J=7.2 Hz).

Example 261: 3,5-debtor-4-methanesulfonyl the no-benzylated 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

N-(4-Aminomethyl-2,6-debtor-phenyl)-methanesulfonamide, HCl salt (82 mg, 0.30 mol) were introduced in the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (68 mg, 0.25 mmol), obtained as described in stages 1-3 of example 260, getting after purification by crystallization from a mixture of Hex/EtOAc target compound (74 mg, 50%).

1H NMR (300 MHz, DMSO-d6): δ of 9.55 (t, 1H, J=5.7 Hz), 9,50 (c OSiR., 1H), of 8.25 (d, 1H, J=8.1 Hz), 7,83 (d, 1H, J=8.1 Hz), 7,13 (d, 2H, J=8,4 Hz), and 4.40 (d, 2H, J=6.0 Hz), 3,03 (m, 5H), to 1.70 (m, 2H), 1,36 (m, 2H), of 0.91 (t, 3H, J=7.2 Hz).

Example 262: [1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (86 mg, 0.30 mol) were introduced in the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (68 mg, 0.25 mmol)to give after purification by crystallization from a mixture of Hex/EtOAc target compound (76 mg, 50%).

1H NMR (300 MHz, DMSO-d6): δ 9,24 (d, 1H), of 8.25 (d, 1H, J=8.1 Hz), 7,83 (d, 1H, J=8.1 Hz), 7,19 (d, 2H, J=8.7 Hz), 5,02 (t, 1H), 3,06 (m, 5H), to 1.70 (m, 2H), 1,38 (m, 5H), to 0.92 (t, 3H, J=7.2 Hz).

ESI [M-H]-: 502.

Example 263: 2-chloro-4-methanesulfonamido-benzylated 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

A mixture of N-(4-aminomethyl-3-chloro-phenyl)-methanesulfonamide, HCl salt and N-(4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (80 mg) which was taken in the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (76 mg, 0.28 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (80 mg, 55%).

1H NMR (300 MHz, DMSO-d6): δ 9,99 (c. user., 1H), 9,44 (c. user., 1H), 8,23 (d, 1H, J=7.8 Hz), 7,82 (d, 1H, J=8.1 Hz), 7,27 (m, 3H), to 4.41 (d, 2H, J=6.0 Hz), 3,03 (m, 5H), 1.69 in (m, 2H), 1,36 (m, 2H), of 0.91 (t, 3H, J=7.2 Hz).

Example 264 N-(4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-[4-(1-Aminomethyl)-phenyl]-methanesulfonamide, HCl salt (111 mg, 0.47 mmol) were introduced in the reaction with NMM (0,11 ml), DMTMM (138 mg, 0,499 mmol) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (132 mg, 0,472 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (144 mg).

1H NMR (300 MHz, CDCl3): δ 7,83 (d, 1H, J=8.7 Hz), 7,80 (d, 1H, J=15.6 Hz), 7,49 (d, 1H, J=8.1 Hz), 7,53 (d, 1H, J=7.8 Hz), 7,33 (m, 2H), 7,18 (m, 6H), of 6.71 (c, 1H), from 6.22 (d, 1H, J=15.3 Hz), of 5.99 (m, 1H), 4,54 (d, 2H, J=5,7 Hz), or 3.28 (m, 2H), 3,10 (m, 2H), is 3.08 (m, 3H).

Example 265: 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-benzyl)-acrylamide

N-[4-(1-Aminomethyl)-phenyl]-methanesulfonamide, HCl salt (117 mg, 0,496 mmol) were introduced in the reaction with NMM (350 μl), and DMTMM (165 mg) and 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (116 mg, 0,498 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/2) of the target compound (92 mg).

1H NMR (300 MHz, CDCl3): δ to 7.93 (d, 1H, J=15.6 Hz), of 7.90 (d, 1H, J=9.3 Hz), 7,46(d, 1H, J=8.1 Hz), 7,31 (c, 1H), 7.23 percent (m, 4H), 6.48 in (m, 1H), 6,44 (d, 1H, J=15.3 Hz), 4,51 (d, 2H, J=6.0 Hz), 2,97 (c, 3H), and 2.83 (d, J=6.9 Hz), of 2.15 (m, 1H), from 0.90 (d, 6H).

Example 266: 4 methanesulfonamido-benzylated 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

A mixture of N-(4-aminomethyl-3-chloro-phenyl)-methanesulfonamide, HCl salt and N-(4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (80 mg) was injected in the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (76 mg, 0.28 mmol)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (45 mg, 33%).

1H NMR (300 MHz, DMSO-d6): δ 9,72 (c. user., 1H), 9,45 (c. user., 1H), 8,24 (d, 1H, J=7.8 Hz), 7,83 (d, 1H, J=8.1 Hz), 7,27 (d, 2H, J=8,4 Hz), 7,18 (d, 2H, J=8,4 Hz), 4,34 (d, 2H, J=6.0 Hz), 2,97 (m, 5H), to 1.70 (m, 2H), 1,36 (m, 2H), of 0.91 (t, 3H, J=7.2 Hz).

ESI [M-H]-: 452.

Example 267 N-(4-atenololonline-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-[4-(1-Aminomethyl)-phenyl]-tinsulanond, HCl salt (and 97.8 mg, 0,392 mmol) were introduced in the reaction with NMM (0.2 ml), DMTMM (121 mg) and 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (97.9 mg)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (62 mg).

1H NMR (300 MHz, CDCl3): δ 7,86 (c, 1H), 7,65 (d, 1H, J=15.3 Hz), 7,51 (d, 1H, J=7.8 Hz), 7,11 (d, 2H, J=8,4 Hz), 7,01 (d, 2H, J=6.6 Hz), 6,77 (d, 1H, J=7.8 Hz), 6,46 (m, 1H), 6,40 (d, 1H, J=19.2 Hz), x 6.15 (d, 1H, J=16.5 Hz), to 5.85 (d, 1H, J=9.6 Hz), 5,00 (d, 1H), 4,43 (d, 2H,J=6.0 Hz), 4,30 (m, 1H), 1,20 (d, 6H).

ESI [M-H]-: 467.

Example 268 N-(4-atenololonline-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-[4-(1-Aminomethyl)-phenyl]-tinsulanond, HCl salt (or 95.5 mg, 0.384 mmol) were introduced in the reaction with NMM (0.2 ml), DMTMM (116 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (99,9 mg)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (17 mg).

1H NMR (300 MHz, CDCl3): δ 7,83 (c, 1H), 7,80 (d, 1H, J=15.3 Hz), of 7.48 (d, 1H, J=8.1 Hz), 7,22 (m, 6H), 6,47 (d, 1H, J=9.9 Hz), 6.30-in (d, 1H, J=15.3 Hz), of 6.20 (d, 1H, J=16.5 Hz), of 5.89 (d, 1H, J=9.6 Hz), 4,47 (d, 2H, J=5.7 Hz), of 3.32 (m, 2H), 3.04 from (m, 2H).

Example 269 N-(4-atenololonline-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-[4-(1-aminomethyl)-phenyl]-tinsulanond, HCl salt (to 96.6 mg, 0,388 mmol) were introduced in the reaction with NMM (0.2 ml), DMTMM (124.8 mg) and 3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (107,2 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (19 mg).

1H NMR (300 MHz, CDCl3): δ of 7.95 (d, 1H, J=15.6 Hz), 7,88 (d, 1H, J=7.5 Hz), 7,50 (d, 1H, J=8.1 Hz), 7,26 (m, 2H), 7,12 (m, 2H), of 6.96 (c, 1H), 6,40 (d, 1H, J=15.6 Hz), 6,27 (d, 1H, J=16.5 Hz), of 6.20 (m, 1H), 5,96 (d, 1H, J=9,6 Hz), a 4.53 (d, 2H, J=5.7 Hz), 2,86 (d, 1H, J=7,2 Hz), of 2.15 (m, 1H), to 0.92 (d, 6H, J=6.6 Hz).

Example 270: 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-triftormetilfullerenov-benzyl)-acrylamide

N-[4-(1-Aminomethyl)-phenyl]-triftormetilfullerenov, HCl salt (78,4 mg) was injected into the reaction with NMM (0.2 ml), DMTMM (119,8 mg) and 3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70,8 mg)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (20 mg).

1H NMR (300 MHz, CDCl3): δ 8,08 (c, 1H), to 7.61 (m, 3H), 7,28 (m, 1H), 7,10 (d, 1H, J=8.1 Hz), 6.87 in (m, 1H), 6,65 (d, 1H, J=8,4 Hz), 6,32 (d, 1H, J=16.5 Hz), 4.72 in (m, 1H), of 4.44 (d, 2H, J=8,4 Hz), 4,35 (m, 1H), 1,25 (d, 6H).

ESI [M-H]-: 509.

Example 271: 1-(3-chloro-4-methanesulfonamido-benzylated (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

1H NMR (300 MHz, CDCl3): δ 7,58 (d, 1H, J=8.1 Hz), 7,52 (d, 1H, J=8.1 Hz), 7,41 (d, 1H, J=8.1 Hz), 7,25 (m, 1H), 7,10 (m, 1H), 6.73 x (c, 1H), 5,76 (c, 1H), 5,63 (t, 1H, J=7.5 Hz), 4,34 (d, 2H, J=6.0 Hz), 3.33 and (c, 2H), 3,01 (c, 3H), 2,74 (m, 2H), to 2.29 (m, H), of 1.74 (m, 2H), 1,10 (t, 1H, J=7.5 Hz), were 0.94 (t, 3H, J=7.5 Hz).

Example 272: 1-(3-chloro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

Stage 1: 3-propionyl 2-propyl-6-trifluoromethyl-pyridin

2-Pentanon (1 ml, 9.4 mmol) was dissolved in 15 ml dry toluene in a two-neck flask, and the solution was cooled to 0°C in a stream of argon. LiHMDS (9.4 ml, 1.0 M in THF, 2.1 mmol) was added via syringe with stirring, and the resulting anion was kept for 1 minute, then added butyrylcholine (0,49 ml, 4.7 mmol) in one portion PR is stirring. The flask was then removed from the bath with ice and left for 1 minute, and was added with stirring 1 M HCl solution. The mixture solution was extracted with EtOAc. The organic mixture was then washed with saline, dried over Na2SO4and evaporated under reduced pressure. To a solution of the resulting crude residue in toluene (20 ml) was added 4-amino-1,1,1-Cryptor-3-butene-2-he (0,72 g, 4.7 mmol) and triperoxonane acid (0,42 ml, 5,64 mmol) and the mixture was stirred under reflux for 24 hours. The reaction mixture was washed with 20% aqueous solution of Na2CO3and dried using Na2SO4. After removal of solvent the residue was subjected to chromatography on a column of silica gel, obtaining the target compound (0,62 g, 51%).

1H NMR (300 MHz, CDCl3): δ to $ 7.91 (d, 1H, J=8.1 Hz), EUR 7.57 (d, 1H, J=7.8 Hz), 2,90 (m, 4H), to 1.76 (m, 4H), and 1.00 (m, 4H).

Stage 2: 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ANOVA acid

A solution of 3-propionyl 2-propyl-6-trifluoromethyl-pyridine (0,62 g, 2,39 mmol) and diethyl ether cyanomethylphosphonate acid (1.1 EQ., 2.7 g) in DMF was placed in odnogolosy a round bottom flask of 50 ml, then portions was added NaH (144 mg and 3.59 mmol) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was extinguished 10 ml of water with ice. The reaction mixture was extracted with ethyl acetate and then washed with 1 N. HCl solution, obyedinenny the organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure. The resulting liquid hydrolyzed in 20%KOH solution when heated with reverse holodilnikomami during the night. After that, the mixture washed with EtOAc, the aqueous phase was acidified with HCl and was extracted with 50 ml EtOAc three times. The combined organic layer was concentrated under reduced pressure to give crude residue (0,349 g, 49%). The crude residue was used in the next stage without further purification.

Stage 3: 1-(3-chloro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

N-(3-Chloro-4-aminomethyl-phenyl)-methanesulfonamide, HCl salt (69 mg, 0.23 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid (59 mg, 0.23 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) the target compound (69 mg, 58%).

1H NMR (300 MHz, CDCl3): δ 7,58 (d, 1H, J=8,4 Hz), was 7.45 (m, 2H), 7,10 (m, 1H), 6.73 x (c. user., 1H), of 5.82 (TC, 1H), 5,75 (c. user., 1H), 4,33 (d, 2H, J=6.3 Hz), 3,20 (m, 2H), 3,01 (c, 3H), 2,71 (m, 2H), 1,74 (m, 4H), were 0.94 (m, 3H).

ESI [M-H]-: 516.

Example 273: 3-fluoro-4-methanesulfonamido-5-methyl-benzylamine 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

N-(4-Aminomethyl-2-chloro-6-methyl-phenyl)-methanesulfonamide, HCl salt (60 mg, 0.30 mol) were introduced in the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (50 mg, 0.18 mmol), recip what I'm after purification by crystallization from a mixture of Hex/EtOAc target compound (48 mg, 55%).

1H NMR (300 MHz, DMSO-d6): δ 9,46 (t, 1H), 9,18 (c. user., 1H), 8,23 (d, 1H, J=7.8 Hz), 7,82 (d, 1H, J=7.8 Hz), 7,17 (m, 2H), 4,39 (d, 2H, J=5.4 Hz), 3,00 (m, 5H), 2,22 (d, 3H), 1.69 in (m, 2H), 1,35 (m, 2H), of 0.90 (t, 3H, J=7.5 Hz).

Example 274: [1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-amide 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid

(R)-N-[4-(1-amino-ethyl)-2-forfinal]-methanesulfonamide, HCl salt (91 mg, 0.34 mol) was introduced into the reaction with (2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid (92 mg, 0.34 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (68 mg, 43%).

1H NMR (300 MHz, CDCl3): δ of 7.90 (d, 1H, J=7.8 Hz), 7,50 (d, 1H, J=7.8 Hz), 6,97 (m, 2H), 6,77 (t, 3H, J=8,4 Hz), 6,04 (d, 1H, J=7.5 Hz), 5,12 (m, 1H), 3,03 (m, 5H), 1.77 in (m, 2H), 1.55V (m, 3H), of 1.40 (m, 2H), of 0.95 (t, 3H, J=7,2 Hz).

Example 275: 1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

1H NMR (300 MHz, CDCl3): δ 7,46 (m, 3H), 7,14 (c, 1H), 6,97 (m, 1H), 6.42 per (c, 1H), of 5.83 (c, 1H), 5,62 (t, 1H, J=7.5 Hz), 4,32 (d, 2H, J=6.0 Hz), 3,48 (c, 1H), 3,26 (c, 3H), of 2.75 (m, 2H), to 2.29 (m, 2H), of 1.75 (m, 4H), 1,10 (m, 3H), were 0.94 (m, 3H).

Example 276: 1-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

N-(4-Aminomethyl-5-ethinyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (113 mg, 0.41 mmol) were introduced in the reaction with 3-(2-impregnated the-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid (122 mg, 0.41 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) 1-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid (139 mg, 65,3%).

1H NMR (300 MHz, CDCl3): δ 7,44 (c, 2H), 7,15 (c, 1H), 6,98 (m, 1H), 6,41 (c, 1H), of 5.83 (m, 2H), 4,32 (d, 2H, J=6.0 Hz), 3,49 (c, 1H), 3.27 to (c, 3H), 2,71 (m, 2H), 1,74 (m, 4H), 1.26 in (m, 2H), of 0.95 (m, 6H).

ESI [M-H]-: 524.

Example 277: [1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

1H NMR (300 MHz, CDCl3): δ 7,44 (m, 2H), 6,82 (c, 1H), 6,79 (c, 1H), 6,14 (c, 1H), 5,62 (t, 1H, J=7,2 Hz), equal to 4.97 (m, 1H), 4,12 (m, 1H), 3,25 (m, 2H), 3,21 (c, 3H), 2,74 (m, 2H), and 2.27 (m, 2H), 1,74 (m, 2H), of 1.37 (d, 3H, J=7,2 Hz), 1,10 (t, 3H, J=7,8 Hz)of 0.95 (t, 3H, J=7.5 Hz).

ESI [M-H]-: 532.

Example 278: [1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (150 mg, 0.52 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid (158 mg, 0.52 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1:1) 1-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated ((E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid (162 mg, 58%).

1H NMR (300 MHz, CDCl3): δ 7,44 (c, 1H), 7,40 (c, 1H), 6.87 in (d, 2H, J=8,4 Hz), 6,76 (d, 1H, J=8,4 Hz), the 6.06 (c, 1H), 5,80 (t, 1H, J=7.2 for the TS) 5,59 (c, 1H), equal to 4.97 (m, 1H), 3,21 (c, 3H), 3.15 in (m, 2H), 2,71 (m, 2H), of 1.75 (m, 4H), to 1.37 (m, 3H), were 0.94 (m, 6H).

ESI [M-H]-: 532.

Example 279: 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-triftormetilfullerenov-benzyl)-acrylamide

N-[4-(1-aminomethyl)-phenyl]-triftormetilfullerenov, HCl salt (75 mg) was injected into the reaction with NMM (0.2 ml), DMTMM (119 mg) and 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (78 mg)to give after purification by chromatography on columns (Hex/EtOAc=2/3) of the target compound (8.5 mg).

1H NMR (300 MHz, CDCl3): δ of 7.82 (m, 2H), 7,51 (m, 1H), 7,19 (m, 3H), of 6.66 (d, 1H, J=6.6 Hz), 6,18 (d, 1H, J=17,4 Hz), 5,80 (m, 1H), 4,42 (d, 2H, J=5.4 Hz), 3,29 (m, 2H), 3,05 (m, 2H).

Example 280: [1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-but-2-ene acid

(R)-N-[4-(1-amino-ethyl)-2,6-debtor-phenyl]-methanesulfonamide, HCl salt (70 mg, 0.25 mmol) were introduced in the reaction with 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-but-2-ene acid (67 mg, 0.25 mmol)to give after purification by chromatography on columns (Hex/EtOAc=3:2), the target compound (32 mg, 24%).

1H NMR (300 MHz, CDCl3): δ 7,45 (c OSiR., 2H), PC 6.82 (m, 2H), 6,06 (c, 1H), 5,80 (t, 1H, J=7,2 Hz), 5,57 (c, 1H), equal to 4.97 (m, 1H), 3,22 (c, 3H), 2.50 each (c, 3H), of 1.76 (m, 2H), 1.55V (m, 2H), of 1.37 (d, 3H, J=6.9 Hz), of 0.93 (t, 3H, J=7,8 Hz).

Example 281 N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide

N-[4-(1-Aminomethyl)-2-ethynyl-6-fluoro-phenyl]-methanesulfonamide, HCl salt (70 mg, 0.25 mmol) were introduced in the reaction with NMM (by 0.055 ml), DMTMM (83 mg, 0.30 mmol) and 3-(2-morpholine-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (76 mg, 0.25 mmol)to give after purification by chromatography on columns (Hex/EtOAc=1/1) of the target compound (95 mg, 74%).

1H NMR (300 MHz, DMSO-d6+ CDCl3): δ 8,84 (c. user., 1H), of 8.37 (t, 1H, J=5.7 Hz), 7,76 (d, 1H, J=7.5 Hz), 7,55 (d, 1H, J=15.6 Hz), 7,33 (c, 1H), 7,18 (d, 1H, J=7.5 Hz), 7,10 (DD, 1H, J=17.1 to and 10.8 Hz), 7,01 (d, 1H, J=9.3 Hz), is 6.61 (d, 1H, J=15.6 Hz), 5,73 (d, 1H, J=17,1 Hz), 5,32 (d, 1H, J=10,8 Hz), 4,42 (d, 2H, J=5.7 Hz in), 3.75 (m, 4H), 3,24 (m, 4H), 2,90 (c, 3H).

Experimental example: Test for biological activity

1. The test flow45CA

1) Department sudnikovich spinal ganglia (DRG) newborn rats and primary cultures

Newborn (2-3 days or younger) SD rats were placed on ice for 5 minutes for anesthesia and disinfected with 70%ethanol. DRG all departments of the spinal cord was dissected (Wood et al., 1988, J. Neurosci. 8, pp3208-3220) and were placed in a medium DME/F12, to which was added 1.2 g/l sodium bicarbonate and 50 mg/l gentamicin. DRG were incubated sequentially at 37°C for 30 minutes in 200 Units/ml collagenase and 2.5 mg/ml trypsin, separately. Ganglia were washed twice with medium DME/F12, supplemented with 10%horse serum, rubbed with melted Pasteur pipette, filtered through a membrane Nitex80, obtaining a single cell suspension, and this suspension was washed again. It was subjected to centrifugation, then suspended in the medium for cell culture with a certain level of density of cells. As a medium for cell culture environment DME/F12, supplemented with 10%horse serum, diluted in the same medium, conditioned by C6 glioma cells for 2 days at the slit monomolecular layer (1:1), and NGF was added (nerve growth Factor) to a final concentration of 200 ng/ml After growing the cells for 2 days in an environment where added citizenoriented (Ara-C, 100 μm)to destroy the fissile non-neural cells, the medium was replaced by medium without Ara-C. Re-suspended cells were inoculated at a density of 1500-2000 neurons/well Terasaki plates, pre-coated with poly-D-ornithine in the amount of 10 μg/ml.

2) Experiments on the flow45CA

The nerve cells of the DRG after primary culturing for 2 days balanced by washing 4 times with HEPES buffered (10 mm, pH 7.4), containing Ca2+, Mg2+HBSS (H-HBSS). The solution in each well was removed from each well. To each well was added to the medium containing the test compound plus capsaicin (final concentration 0.5 µm) and45Ca (final concentration 10 MX/ml) in N-HBSS, and incubated at room temperature for 10 minutes. PL is nsity Terasaki washed five times with N-HBSS and were dried at room temperature. To each well was added with 0.3% SDS (10 ál)to be eluted45Ca. After adding to each well of scintillation cocktail number45Ca included in the neuron was measured by counting the radioactivity. Antagonistic activity of the test compounds against vanilloideae receptor was calculated as the percentage inhibition of the maximum response of capsaicin in a concentration of 0.5 ám.

Table 1

The test results on calcium influx

2. Test for analgesic activity: test convulsions in mice with induction of phenyl-p-quinone

Male ICR mice (average weight 25 g) for the experiment was kept under controlled lighting conditions (12 hours light/12 hours dark). Animals received intraperitoneal injection of 0.3 ml of a chemical irritant phenyl-p-quinone (dissolved in saline containing 5%ethanol at a dose of 4.5 mg/kg), and 6 minutes later they were counting the number of contractions of the abdominal muscles during the subsequent period of 6 minutes. Animals (10 animals/group) received 0.2 ml of the test compounds in a carrier consisting of a mixture of ethanol/Tween 80/saline (10/10/80), int is peritoneal 30 minutes before the injection of phenyl-p-quinone. In the case of oral administration of 0.2 ml of the test compounds in a carrier consisting of a mixture of ethanol/Tween 80/saline (5/5/90), was introduced for 54 minutes before the injection of 0.2 ml of 0.02% phenyl-p-quinone. Reducing the number of convulsions in response to a medicinal product containing the test compound, relative to their numbers in the control group treated with saline solution was taken as an indicator of analgesic effect. Analgesic effect was calculated by the equation % inhibition (%inhibition=(C-T)/C × 100), where C and T denote the number of convulsions in the control and treated the connection groups, respectively. Most of the examples of the present invention have good activity in vitro was tested in different doses (ranging from 0.1 to 3 mg/kg), and all compounds tested in vivo, showed analgesic effects from 12 to 70% inhibition at each dose, respectively.

3. Metabolic stability and PK study

1) Test on metabolic stability

Diluted sample (final concentration 5 μg/ml in a buffer of 0.1 M potassium phosphate, pH 7.4) pre-incubated with co-factors (glucose-6-phosphate, 3.3 mm, 1.3 mm NADPH, MgCl20.16 mm glucose-6-phosphatedehydrogenase at a final concentration of 0.4 U/ml), and the enzymatic reaction was initiated by addition of intestinal microsomes (1 mg/ml protein or rat liver (0.5 mg/ml protein). The reaction was completed using a 2X volume of cold acetonitrile after 1 minute (initial point) or 30 minutes (the reaction of the sample) incubation. In the case of the microsomes of human intestine used, the reaction time is 2 hours. The reaction mixture was extracted with agitated in the bath for 20 minutes, after which the supernatant was separated by centrifugation. The peak area of the parent compounds were analyzed in the supernatant using the method HPLC-UV, and the extent of metabolism is shown as a reduction of the peak area of the compound (%) from the starting point.

The metabolic stability of compounds with partial structure of CF3-pyridinyl according to the present invention is generally better than the corresponding tert-butylphenyl-containing compounds, which were at least partially disclosed in the prior art, for example in WO06/101318. Details of the received data on metabolic stability are presented in Table 2.

2) PK

Pharmacokinetic properties of the compounds analyzed for rats, using the following experiment. Rats were kept without food during the night prior to the introduction until after approximately 4 hours after injection. The rats were given a single oral administration of the compounds at the same dose. The volume of injection was 10 ml/kg blood Samples were taken from retro-orbital sinus at various mo the coefficients of time in the next 7 hours. Immediately after each sampling the plasma was separated from blood cells by centrifugation and kept at -20°C until analysis. Plasma samples were analyzed using the method of high-performance chromatography (HPLC) reverse phase.

As shown in Table 3, the PK profile of compounds with partial structure of CF3-pyridinyl according to the present invention was generally better than the corresponding tert-butylphenyl-containing compounds, which were at least partially disclosed in the prior art, for example in WO 06/101318. When replacing tert-butylphenyl CF3the pyridinyl observed a significant increase absorption, and apparent half-life.

Industrial applicability

As explained above, the connection according to the present invention can be used for prevention or treatment of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), illness and Crown, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis.

More specifically, the connection according to the present invention can be used for prevention or treatment of pain, which is either associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headache.

1. The compound of formula (I), its isomer or pharmaceutically acceptable salt:

in which
- X represents CR11=CR12or C≡C bonds; and R11and R12if they are present, are independently hydrogen, halogen or C1-C5-alkyl;
- Z represents N;
- Y represents CR6;
R1denotes hydrogen Il is C1-C5 alkyl;
R2, R3, R4and R5independently represent hydrogen, halogen, cyano, C1-C5 alkyl, C2-C5 of alkenyl, C2-C5 quinil;
R6denotes hydrogen, halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10, alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10, alkylamino, di(C1-C10 alkyl)amino, C3-The C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl,
R8and R9independently represent hydrogen, halogen, C1-C10 alkyl, and
each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylcarboxylic, alkylamino may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or the two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 of the alkyl or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5) alkylamino,
each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,
each cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and
each piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;
R7denotes halogen (C1-C5) alkyl;
and
R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

2. The compound according to claim 1, its isomer or pharmaceutically acceptable salt, in which
X represents-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH 3)=C(CH3)-, -C(C2H5)=CH-, -CH=C(C2H5)-, -CF=CH-, -CH=CF -, or C≡C;
R1 denotes hydrogen, methyl or ethyl;
R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl;
R6denotes fluorine, bromine, chlorine, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 of alkenyl, C2-C6 quinil, halogen (C1-C6) alkyl, halo (C1-C6) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, di(C1-C6 alkyl)amino, C1-C6, alkylamino, C1-C3 alkoxy (C1-C5) alkylamino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cyclooctylamine, which may be unsubstituted or substituted by one or more methyl groups, C3-C6, cycloalkane, C3-C6, oxacyclobutane, piperidyl, pyrrolidinyl, halogenfree, phenyl, phenoxy, phenylamino, halogenfree, morpholinyl; C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkyl, di(C1-C3) alkylaminocarbonyl, (C1-C3) alkoxyphenyl, thienyl, (C3-C6) cycloalkyl (C1-C3) alkoxy, phenyl (C1-C3) alkoxy, C1-C5, alkylthio, phenyl (C1-C3) alkylamino, arylamino, N-phenyl-N-(C1-C3)alkylamino, or piperidyl;
R7denotes halogen (C1-C5) alkyl;
R8and R9independently represent hydrogen, halogen or trifluoromethyl; and R10denotes C1-C5 Alky is, halogen (C1-C5) alkyl or C2-C5 of alkenyl.

3. The compound according to claim 1, its isomer or pharmaceutically acceptable salt, in which
X represents CR11=CR12and R11and R12are independently hydrogen, halogen or C1-C3 alkyl;
R1denotes hydrogen or C1-C3 alkyl;
R2, R3, R4and R5independently represent hydrogen, halogen, cyano, methyl, ethyl, ethynyl, ethinyl trifluoromethyl;
R6denotes halogen, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5, alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylaryl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7, alkylamino, di(C1-C3 alkyl)amino, C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, pyrrolidinyl, phenyl or morpholinyl, and phenyl may be unsubstituted or substituted by one or more substituents selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl;
R8and R9independently represent hydrogen, halogen, C1-C5 alkyl;
R7denotes halogen (C1-C4) alkyl;
and
R10denotes a C1-C3 alkyl or C2-C3 of alkenyl.

4. The compound according to claims 1-3, its isomer or pharmaceutically acceptable salt, in which R7 represents trifluoromethyl.

5. The compound of formula (III), its isomer or pharmaceutically acceptable salt:
,
(III)
in which
R1denotes hydrogen or C1-C5 alkyl;
R2, R3, R4and R5independently represent hydrogen, halogen, cyano, C1-C5 alkyl, C2-C5 of alkenyl, C2-C5 quinil;
R6denotes hydrogen, halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10, alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinil, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10, alkylamino, di(C1-C10 alkyl)amino, C3-The C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-aryl-N-(C1-C5) alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, aaltio, preferably phenylthio, heteroaryl, preferably, thienyl, heteroallyl, aryloxy, preferably phenoxy, heteroaromatic, preferably pyridyloxy, pyrrolidinyl or morpholinyl;
R8and R9independently represent hydrogen, halogen, C1-C10 alkyl,
and
each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylcarboxylic, alkylamino may be independently unsubstituted or substituted by one or more substituents, select nimi from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two radicals of halogen and/or methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 of the alkyl or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5)alkylamino,
each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,
each cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and
each piperazinil, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;
R7denotes halogen (C1-C5) alkyl;
R10about the means C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and
R11and R12independently represent hydrogen, C1-C5 alkyl or halogen.

6. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt,
in which
R1denotes hydrogen, methyl or ethyl;
R2, R3, R4and R5independently represent hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl, trifluoromethyl;
R6denotes fluorine, bromine, chlorine, hydroxymethyl, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 of alkenyl, C2-C5 quinil, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, di(C1-C3 alkyl)amino, C1-C3 alkylpiperazine, piperidyl, pyrrolidinyl, halogenfree, phenyl or morpholinyl;
R7denotes halogen (C1-C4) alkyl;
R8and R9independently represent hydrogen, halogen or trifluoromethyl;
R10denotes a C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 of alkenyl; and
R11and R12if they are present, are independently hydrogen or stands.

7. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt,
in which
R1, R2and R5represent hydrogen;
R3denotes hydrogen, fluorine, chlorine, cyano, methyl, ethynyl, ethinyl or trifluoromethyl;
R4denotes hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;
R6oznachaet fluorine, bromine, chlorine, methyl, hydroxymethyl, methoxy, trifluoromethyl, diethylamino, piperidyl, pyrrolidinyl, tryptophanyl, phenyl or morpholinyl;
R7denotes trifluoromethyl;
R8denotes hydrogen;
R11and R12if they are present, are hydrogen;
R9denotes hydrogen or trifluoromethyl; and
R10denotes methyl.

8. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1, R2and R5represent hydrogen;
R3denotes hydrogen, fluorine, chlorine, cyano, methyl, ethynyl, ethinyl or trifluoromethyl;
R4denotes hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;
R6denotes fluorine, bromine, chlorine, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentox, methoxyethoxy, ethoxyethoxy, methoxypropane, trifluoromethyl, diethylamino, methoxyethylamine, methoxyethylamine, methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, ethylamine, Propylamine, butylamine, pentylamine, N,N-dimethylamino, N-methyl-N-ethylamine N,N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, phenoxy, halogenfree, piperidyl, pyrrolidinyl, tryptophanyl, phenyl or morpholinyl;
R7denotes trifluoromethyl;
R8means at the location;
R11and R12represent hydrogen;
R9denotes hydrogen or trifluoromethyl; and
R10denotes methyl.

9. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl;
R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl, ethyl or trifluoromethyl;
R6denotes fluorine, chlorine, bromine, methyl, n-butyl, methoxy, n-Butylochka, isobutoxy, sec-Butylochka, methoxyethoxy, methoxyethylamine, diethylamino, n-butylamino, cyclopentylamine, phenoxy, N-pyrrolidinyl, N-piperidyl or N-morpholinyl;
R7denotes trifluoromethyl;
R8denotes hydrogen;
R11and R12represent hydrogen;
R9denotes hydrogen or trifluoromethyl; and
R10denotes methyl.

10. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, ethynyl or ethinyl;
R4denotes hydrogen or fluorine;
R5denotes hydrogen;
R6denotes fluorine, bromine, chlorine, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, Penta is XI, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxyethoxy, trifluoromethyl, N,N-dimethylamino, N-methyl-N-ethylamine N,N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, methoxyethylamine, methoxyethylamine, methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, ethylamine, Propylamine, butylamine, pentylamine, phenoxy, halogenfree, N-piperidyl, N-pyrrolidinyl, tryptophanyl, phenyl or N-morpholinyl;
R7denotes trifluoromethyl;
R8denotes hydrogen;
R9denotes hydrogen or trifluoromethyl;
R10denotes methyl; and
R11and R12denote hydrogen.

11. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen;
R2denotes hydrogen;
R3denotes hydrogen, ethynyl or ethinyl;
R4denotes hydrogen or fluorine;
R5denotes hydrogen;
R6denotes bromine, chlorine, n-butyl, methoxy, isobutoxy, sec-Butylochka, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamine, n-butylamino, phenoxy, n-Butylochka, methoxyethylamine;
R7denotes trifluoromethyl;
R8denotes hydrogen;
R9denotes hydrogen or trifluoromethyl;
R10denotes methyl; and R11and R12denote hydrogen.

12. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, fluorine, methyl, ethyl, cyano, ethynyl, ethinyl or trifluoromethyl;
R4denotes hydrogen, fluorine, chlorine or methyl;
R5denotes hydrogen;
R6denotes fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethinyl, methoxypropanol, diethylaminopropyl, phenyl, halogenfree, methoxyphenyl, thienyl, pyridinyl, halogenopyrimidines, methoxy, ethoxy, propoxy, butoxy, pentox, triptoreline, cyclopentane, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenfree, benzyloxy, pyridyloxy, ethylthio, propylthio, butylthio, pentylthio, ethylamino, propylamino, butylamino, pentylamine, methoxyethylamine, amoxicillin, methoxypropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine benzylamino, phenylamino, N,N-dimethylamino, N-methyl-N-propylamino, N-methyl-N-propylamino, N,N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-pyrrolidinyl, methoxy N-pyrrolidinyl, hydroxymethyl, N-pyrrolidinyl, N-piperidyl, etoxycarbonyl N-piperidyl, Pieper is sinil or N-morpholinyl;
R7denotes trifluoromethyl;
R8denotes hydrogen;
R9denotes hydrogen or trifluoromethyl;
R10denotes methyl; and
R11and R12denote hydrogen.

13. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl; R2denotes hydrogen;
R3denotes hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, ethinyl or trifluoromethyl;
R4and R5independently represent hydrogen, fluorine, chlorine, cyano, methyl or ethyl;
R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, phenylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R7denotes trifluoromethyl;
R8denotes hydrogen or chlorine;
R9denotes hydrogen or trifluoromethyl;
R10denotes methyl; and
R11and R12denote hydrogen.

14. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R4denotes hydrogen, fluorine, chlorine or methyl;
R3oboznachaet is hydrogen, fluorine, methyl, cyano, ethynyl, ethinyl or trifluoromethyl;
R5denotes hydrogen;
R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, forfinal, thienyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3 methylbutoxy, 2,2,2-triptoreline, cyclopentane, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, phenylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, methoxyethylamine, amoxicillin, cyclopentylamine, benzylamine, phenylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, methoxy N-pyrrolidinyl, N-piperidyl or etoxycarbonyl N-piperidyl;
R7denotes trifluoromethyl;
R8denotes hydrogen or chlorine;
R9denotes hydrogen or trifluoromethyl;
R10denotes methyl; and
R11and R12denote hydrogen.

15. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, fluorine, methyl, cyano, ethynyl or ethinyl;
R4denotes hydrogen, fluorine or methyl;
R5denotes hydrogen;
R6denotes n-propyl, and propyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R7denotes trifluoromethyl;
R8and R9represent hydrogen;
R10denotes methyl; and
R11and R12denote hydrogen.

16. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, fluorine, chlorine, methyl, cyano, ethynyl or ethinyl;
R4denotes hydrogen;
R5denotes a fluorine, chlorine or methyl;
R6denotes ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, forfinal, thienyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3 methylbutoxy, 2,2,2-triptoreline, cyclopentane, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, methoxyethylamine, amoxicillin, cyclopentylamine, benzylamine, phenylamino, N-ethyl-N-phenylamino, N-m is Teal-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or etoxycarbonyl N-piperidyl;
R7denotes halogen (C1-C3) alkyl;
R8and R9independently represent hydrogen, halogen or trifluoromethyl;
R10denotes methyl; and
R11and R12denote hydrogen.

17. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R1denotes hydrogen or methyl;
R2denotes hydrogen;
R3denotes hydrogen, fluorine, chlorine, methyl, cyano, ethynyl or ethinyl;
R4denotes hydrogen;
R5denotes fluorine;
R6denotes n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, acylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamine, amoxicillin, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R7denotes trifluoromethyl;
R8denotes hydrogen or chlorine;
R9denotes hydrogen;
R10denotes methyl; and
R11and R12denote hydrogen.

18. The compound according to claim 1, its isomer or pharmaceutically acceptable salt, and a compound represented by formula VI:
,
in which
W denotes hydrogen or fluorine;
X represents-CR11=CR1 - or-C≡C-;
R1selected from hydrogen and C1-C3 alkyl;
R6denotes halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 of alkenyl, C2-C10 quinil, C1-C10, alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylaryl, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-10 alkylamino, di(C1-C10 alkyl)amino, C3-C8 cycloalkyl, C3-C8, cycloalkenyl, C3-C8, cycloalkane, C3-C8, oxacyclobutane, N-aryl-N-(C1-C5)alkylamino, preferably N-phenyl-N-(C1-C5)alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, heteroaryl, preferably thienyl, heteroallyl, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl;
R11and R12if they are present, are independently selected from hydrogen and cutting;
R7means CF3, CF2Cl or CF2CF3;
R8and R9independently selected from hydrogen, halogen or CF3;
and
each alkyl, alkenyl and quinil, as part of a group, for example, in alkoxy, alkylcarboxylic, alkylamino may be independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, unsubstituted or substituted with halogen (C1-C5) alkoxy, (C3-C8) cycloalkyl, which may be unsubstituted or substituted by one or two halogen radicals and/and and methyl groups, unsubstituted or substituted with halogen (C1-C5) alkylamino, phenyl which may be unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C3 of the alkyl or halo (C1-C3) alkyl, or unsubstituted or substituted by halogen, di(C1-C5) alkylamino,
each aryl or heteroaryl, as part of a group, for example, in arylamino, aryloxy may be independently unsubstituted or substituted by one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halo (C1-C5) alkyl,
each cycloalkyl, as part of a group, for example, in cycloalkane or cycloalkene may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and
each piperidyl or morpholinyl may be unsubstituted or substituted by one or more unsubstituted or substituted with halogen, C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl.

19. Connection p, its isomer or pharmaceutically acceptable salt, in which R8and R9both represent hydrogen.

20. Connection p, its isomer or pharmaceutically acceptable salt, in which X represents-CH=CH-.

21. Connection p, its isomer or pharmaceutical is Eski acceptable salt, in which X represents-CH=CH-, and W, R8and R9denote hydrogen.

22. Connection p, its isomer or pharmaceutically acceptable salt, in which
R6selected from C2-C6 alkyl, di(C1-C6 alkyl)amino, 2,2,2-trifter(C1-C3)alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6, alkylamino, C3-C6, cycloalkenyl, phenyl, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N-(C1-C5)alkylamino, each phenyl can be substituted by one or more halogen; and
R7means CF3.

23. Connection p, its isomer or pharmaceutically acceptable salt, in which
R6selected from C2-C5 alkyl, C1-C4, alkylamino or methoxyethylamine;
R7means CF3;
R12denotes hydrogen.

24. Connection p.22, its isomer or pharmaceutically acceptable salt, in which
R6denotes-NH-(C1-C4)alkyl or linear or branched C2-C5 alkyl; and
R7means CF3.

25. Connection p, its isomer or pharmaceutically acceptable salt, in which R1denotes hydrogen or methyl.

26. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt, in which, if R1denotes methyl or ethyl, the atom that is attached to R1is in the (R)-configuration.

27. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt, when it is eaten compound selected from the group consisting of the following compounds:
3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-hydroxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-acrylic is d,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-AK is ilamed,
N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2,2,2-Cryptor-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-yl)-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-etoxycarbonyl-piperid-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-methyl-butoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-Tien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-Tr is formetal-pyridine-3-yl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-vinyl-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-styryl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-propyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide, (R)-3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
3-(2-ethylthio-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-[2-PIP the reed-1-yl-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylthio-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-trifluoromethyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-three is tormentil-pyridine-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(3-forfinal)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-m is Teal-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(35-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
(R)-N-[l-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(S)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-sec-butyl-6-tryptomer-pyridine-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-ethylamino-6-trifter ethyl-pyridine-3-yl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3,5-debtor-4-methanesulfonamido-benzylated 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid,
[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid,
N-(4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-atenololonline-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated Z-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,
3-ethinyl-5-fluoro-4-methanesulfonamido-benzylated (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,
[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (Z)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid,
[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid, and
N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide.

28. Connection item 27, its isomer or pharmaceutically acceptable salt, and a compound selected from the group consisting of the following compounds:
3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-meth is sulfonylamino-benzyl)-3-(2-methoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-cyclopentylamine-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acre shall lamed,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutoxy-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-[2-(tetrahydro-furan-3-yloxy)-6-trifluoromethyl-pyridin-3-yl]-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(4-pertenece)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(4-methanesulfonamido-3-vinyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-morpholine-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-cyano-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-cyano-5-fluoro-4-methanol is arylamino-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-[2-(methyl-phenyl-amino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
3-(2-butylamino-6-cryptomate the-pyridine-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-acrylamide,
(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-benzylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-[2-(2-methoxy-ethylamino)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-(3,5-debtor-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propyl-6-trifluoromethyl-PI is one-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-Deut-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-[2-(2-methyl-butyl)-6-trifluoromethyl-pyridin-3-yl]-acrylamide,
(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3-fluoro-4-is ethanolgasoline-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(4-methanesulfonamido-3-methyl-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-N-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-butylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isopropyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-sec-butyl-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
(R)-N-[1-(3,5-d is fluoro-4-methanesulfonamido-phenyl)-ethyl]-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide
(R)-N-[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-3-(2-isobutyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
(R)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-[1-(3-fluoro-4-methanesulfonamido-phenyl)-ethyl]-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-1-(4-methanesulfonamido-3-methyl-benzyl)-acrylamide,
N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethinyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonamido-benzyl)-acrylamide,
N-(3-chloro-4-methanesulfonamido-benzyl)-3-(2-propylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(2,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3,5-debtor-4-methanesulfonamido-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
N-(3-fluoro-4-methanesulfonamido-5-methyl-benzyl)-3-(2-ethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylamide,
[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide 3-(2-butyl-6-trifluoromethyl-pyridin-3-yl)-propanolol acid, and
[1-(3,5-debtor-4-methanesulfonamido-phenyl)-ethyl]-amide (E)-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-Gex-2-ene acid.

29. The pharmaceutical is Skye composition, having antagonistic activity against vanilloideae receptor containing the compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable carrier.

30. Pharmaceutical composition for prevention or treatment of a condition associated with pathological excitation and/or aberrant expression vanilloid receptors, and this composition contains a compound according to claim 1 or 7, its isomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to clause 29 for the treatment of a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, noise in the ears is x, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis.

32. The pharmaceutical composition according p, and the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headache.

33. The pharmaceutical composition according to clause 29, characterized in that it is adapted for oral administration.

34. The use of compounds according to claim 1 or 7, its isomer or pharmaceutically acceptable salt to obtain drugs for prevention or treatment of a condition that is associated with aberrant expression and/or aberrant activation vanilloideae receptor.

35. The use of compounds according to claim 1 or 7, its isomer or pharmaceutically acceptable salt to obtain drugs for prevention or treatment of a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, damage to era, neurodegeneration, stroke, bladder hypersensitivity including urinary incontinence, cystitis, stomach ulcers and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough,
neuropathic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, disorders associated with growth of hair, such as effluvium, alopecia, rhinitis, pancreatitis.

36. Application connection p, and the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headache.

37. The method of obtaining the compound represented by formula (III):

which includes the introduction of compounds represented by formula (IIIA):

in the reaction with the compound represented by the formula (IIIb):

in which
R1R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12have the meanings as defined in claim 5.

38. The method according to clause 37, in which the reaction is carried out in the presence of the agent combinations selected from the group consisting of DCC (N,N-dicyclohexylcarbodiimide), EDCI {1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)} and DMTMM {4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride}.

39. The compound of formula (IIId)

in which
W denotes hydrogen or fluorine;
R1denotes hydrogen or C1-C3 alkyl, preferably methyl; and
R10denotes a C1-C3 alkyl, C2-C3 of alkenyl or halo C1-C3 alkyl, preferably methyl;
provided that if R1denotes hydrogen and R10denotes methyl, then W denotes fluorine.

40. The use of the compounds of formula (IIId) § 39 as intermediate compounds in obtaining ligand receptor VR1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new thiophene derivatives of formula (I) where A is represented by *-CO-CH2CH2-, *-CO-CH=CH, where the asterisks indicate the link through which the formula (I) thiophene group is bound; R1 is represented by C2-5alkyl; R2 is represented by hydrogen, methyl or ethyl; R3 is represented by hydrogen; R4 is represented by C1-4alkyl; R5 is represented by a hydroxy group, 2,3-di-hydroxypropoxygroup or -OCH2-CH(OH)-CH2-NHCOR52; R52 is represented by hydroxymethyl, and R6 is represented by C1-4alkyl; and to its salt. The invention also refers to the pharmaceutical composition that is agonistic in relation to S1P1/EDG1 receptor on the basis of the mentioned compounds.

EFFECT: new compounds and a composition based on them that may find their application in medicine as immunomodulating agents.

17 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I) where A denotes *-CO-CN=CH-, *-CO-CH2CH2-, or where the sign * indicates the thiophene bonding site in formula (I), R1 denotes hydrogen or methyl, R2 denotes n-propyl or isobutyl, R3 denotes hydrogen, methyl, ethyl, n-propyl, isopropyl or isobutyl, R4 denotes hydrogen or methoxy, R5 denotes hydrogen, C1-C4alkyl, C1-C4alkoxy or hydrogen, R6 denotes -(CH2)k-(CHR65)p-CHR66-CONR61R62 hydroxy, hydroxy(C2-C4)alkoxy, di(hydroxy(C1-C4)alkyl)(C1-C4)alkoxy, 2,3-dihydroxypropoxy, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -OCH2- CH(OH)-CH2-NHCOR64 or -OCH2-CH(OH)-CH2-NHSO2R63, R61 denotes hydrogen, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, carboxymethyl or C1-C4alkylcarboxymethyl, R62 denotes hydrogen, R63 denotes methyl or ethyl, R64 denotes hydroxymethyl, methyl aminomethyl or 2-methyl aminoethyl, R65 denotes hydrogen, R66 denotes hydrogen, m equals 1 or 2, k equals 0, p equals 1, R67 denotes hydrogen, C1-C4alkyl or halogen, and to a salt thereof. The invention also relates to a pharmaceutical composition for preventing or treating diseases or disorders associated with an activated immune system based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as immunodepressants.

31 cl, 2 tbl, 114 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing 1,3-oxathiolane nucleosides, which involves reaction of (5-acetyloxy-1,3-oxathiolan-2-yl)methyl butanoate with a silylated pyrimidine or purine base in the presence of TiCl3(isopropoxide). Said reaction enables to obtain a product mainly containing β anomer.

EFFECT: efficient method of producing 1,3-oxathiolane nucleosides.

13 cl, 3 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of splitting a racemic mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane to obtain an optically active mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane, involving the following steps: a) dissolving and heating said racemic mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane in a solvent in the presence of (1R)-(-)-10-camphorsulphonic acid and achiral acid to form a solution containing the following two diastereoisomeric salts: (-)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane• (1R)-(-)-10- camphorsulphonate and (+)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane•(1R)-(-)-10- camphorsulphonate; b) cooling the solution to facilitate crystallisation of diastereomeric salts; c) extraction of crystals of the optically active mixture of said two diastereomeric salts obtained at step b), which contains excess (-)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane• (1R)-(-)-10- camphorsulphonate over (+)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane•(1R)-(-)-10- camphorsulphonate, and d) treating said optically active mixture of said two diastereomeric salts to remove (1R)-(-)-10- camphorsulphonic acid in order to obtain an optically active mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane.

EFFECT: improved method.

16 cl, 3 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which have formula (1a):

, where R1 represents hydrogen, (C1-C4)alkyl or halogen; R2 represents hydrogen, halogen, amino, (C1-C4)alkyl, heterocyclyl, (C6-C10)aryl-(C1-C4)alkylheterocyclyl, (C3-C6)cycloalkylheterocyclyl, -NR11R12, NHR16; R3 represent hydrogen, NR11R12 or NHR16; R4 and R5 each are independently selected from: hydrogen, halogen, (C1-C4)alkyl; R6 and R8 are each independently selected from: hydrogen, (C1-C4)alkyl or halogen; R7 is hydroxy-(C1-C4)alkyl, formyl, -(CH2)nC(O)OR10 or CONHR16; R10 is hydrogen, (C1-C4)alkyl; R11 and R12 each are independently selected from hydrogen, (C1-C4)alkyl, hydroxy-(C1-C4)alkyl, halogen-(C1-C4)alkyl, amino-(C1-C4)alkyl; or R11 and R12, together with N atom, to which they are bound, form 6- or 7-member heterocycle, optionally having one or more additional heteroatoms N or O; R16 is formyl, (C1-C4)alkyl, halogen-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkylcarbonyl, halogen-(C1-C4)alkylcarbonyl, hydroxy-(C1-C4)alkylcarbonyl, (C1-C4)alkylcarbonyloxy-(C1-C4)alkylcarbonyl or heterocyclyl-(C1-C4)alkylcarbonyl; n is 0, 1 or 2; where (C1-C4)alkyl is not substituted or is substituted with two similar or different groups, selected from: halogen, hydroxy-group and (C6-C10)aryl; heterocyclyl represents 6- or 7-member saturated monocyclic ring, containing one or two heteroatoms selected from nitrogen and oxygen, and which is not substituted or is substituted with one or two similar or different groups, which are selected from oxogroup, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, hydroxy-(C1-C4)alkyl, (C6-C10)aryl-(C1-C4)alkyl, formyl, (C1-C4)alkylcarbonyl, (C6-C10)aryl-(C1-C4)alkylcarbonyl, (C6-C10)arylcarbonyl, (C3-C6)cycloalkylcarbonyl, -SH, -S-(C1-C4)alkyl and -S(O)2-(C1-C4)alkyl; (C6-C10)aryl is not substituted or is substituted with (C1-C4)alkyl; W represents S(O)m; m equals 0, 1 or 2; and to their pharmaceutically acceptable salts. Invention also relates to compounds of formula (1a'), to methods of obtaining compounds of formula (1a), to methods of obtaining compounds of formula (1a'), to method of obtaining compounds of formula E2, to pharmaceutical compositions, as well as to application of compounds.

EFFECT: obtaining novel biologically active compounds which demonstrate inhibiting effect with respect to activity of tumour necrosis factor-α.

30 cl, 46 ex, 4 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

The invention relates to a method of separating a mixture of enantiomers of CIS-2-hydroxymethyl-5-(5-fertilizin-1-yl)-1,3-oxathiolane: by passing through the associated with cyclodextrin chiral column; selective hydrolysis of 5’-O-acyl derivative of the nucleoside with the help of enzymes; selective deamination of a mixture of enantiomers using titidindezaminaza

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to a diastereoselective process for obtaining optically active analogues CIS-nucleosides and their derivatives

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds inhibiting activity of hormone-sensitive lipase and represented by structure of the formula: (XXXXIVa)

and the formula (XXXXIVb): wherein R1ap and R2ap are chosen independently from (C1-C6)-alkyl, aryl wherein each (C1-C6)-alkyl and aryl can be substituted optionally with one or some substitutes chosen independently from halogen atom, (C1-C6)-alkyl under condition that if R1ap and R2ap are similar then they are not methyl or ethyl, and wherein between substitutes R1ap and R2ap can be a covalent bond optionally, and wherein R5ap, R6ap and R7ap are chosen independently from hydrogen atom and fluorine atom (F), and R4ap is chosen from hydrogen atom, sulfanyl, halogen atom, amino-, nitro-group, (C1-C6)-alkyl, heteroaryl, (C3-C8)-heterocyclyl wherein each among sulfanyl, amino-group, (C1-C6)-alkyl, heteroaryl, (C3-C8)-heterocyclyl can be substituted optionally with one or some substitutes chosen independently from hydroxy-, oxo-group, halogen atom, (C1-C6)-alkyl, aryl, heteroaryl wherein each among (C1-C6)-alkyl, aryl, heteroaryl can be substituted optionally with one or some substituted chosen independently from oxo-group, halogen atom, amino-group, (C1-C6)-alkyl, (C3-C8)-heterocyclyl wherein each among amino-group, (C1-C6)-alkyl, (C3-C8)_heterocyclyl can be substituted optionally with one or some substitutes chosen independently from oxo-group, (C1-C6)-alkyl wherein (C1-C6)-alkyl can be substituted optionally with one or some substitutes chosen independently from oxo-group under condition that R4ap is not methyl. Also, invention relates to a pharmaceutical composition and using these compounds for preparing a medicinal agent used for inhibition of lipolytic activity of hormone-sensitive lipase. Invention describes compounds that can be useful in treatment and prophylaxis of clinical disorders wherein decrease of activity of hormone-sensitive lipase is desirable.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 602 ex

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