RU2448108C2 - Novel compounds, isomers thereof or pharmacutically acceptable salts thereof as vanilloid receptor antagonists and pharmaceutical composition containing said compounds - Google Patents

Abstract

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

Description

Technical area

The present invention relates to new compounds, their isomer or their pharmaceutically acceptable salts as an antagonist of TRPV1; and to the pharmaceutical composition containing them.

State of the art

The vanilloid receptor 1 (VR1, or transient receptor potential vanilloid-1, TRPV1) is a capsaicin receptor (8-methyl-N-vanilla-6-nonenamide), a burning ingredient in hot peppers. In 1997, molecular cloning of TRPV1 (Caterina et al., 1997, Nature, 389, pp816-824), which belongs to the TRP channel family of non-selective cation channels, was reported. TRPV1 is activated or sensitized by stimuli such as capsaicin, resiniferatoxin, heat, acid, anandamide, lipid metabolites, etc .; 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 is largely expressed in primary afferent sensory neurons, and is also reportedly expressed in various organs and tissues, such as the bladder, kidney, lung, intestines, skin, central nervous system (CNS) and non-neural tissues (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 in painful pathological conditions. Activation of TRPV1 by endogenous / exogenous stimuli leads not only to the transmission of toxic stimuli, but also to the release of neuropeptides, such as substance P, CGRP (Calcitonin Gene Associated Peptide) in neurons, thus causing neurogenic inflammation. TRPV1 knockout mice show normal responses in a variety of behavioral tests, including toxic, mechanical, and acute thermal stimuli, but show slight thermal hypersensitivity in inflammatory conditions (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 indicated above, TRPV1 knockout mice show reduced responses to thermal or toxic stimuli, as evidenced by the effects of TRPV1 antagonists in various animal pain models (Immke et al., 2006, Semin. Cell. Dev. Biol., 17 (5) , pp582-91; Ma et al., 2007, Expert Opin. Ther. Targets, 11 (3), pp307-20). The well-known TRPV1 antagonist, capsazepine, reduces the 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, the processing of the primary culture of afferent sensory neurons by the TRPV1 agonist, capsaicin, etc., leads to impaired nerve function and, in addition, to the death of nerve cells. The TRPV1 antagonist has a protective effect against such impaired nerve function and nerve cell death (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 areas 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 the sensory nerves, which in turn causes 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 gastric and duodenal ulcers (Holzer P. , 2004, Eur. J. Pharmacol. 500, pp231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp1313-1320).

TRPV1 expression of afferent nerves is abundant in the mucous membrane of the respiratory tract, and bronchial hypersensitivity is a mechanism very similar to hyperalgesia. Protons and lipoxygenase products, known as endogenous ligands for TRPV1, are known as critical factors responsible for the development of asthma and chronic obstructive pulmonary diseases (Hwang et al., 2002, Curr. Opin. Pharmacol. Pp235-242; Spina et al., 2002 , Curr. Opin. Pharmacol. Pp 264-272). In addition, it has been reported that air pollutants, which are a variety of asthma-causing substances, i.e., particles specifically act on TRPV1 and this effect is inhibited by capsazepine (Veronesi et al., 2001, NeuroToxicology, 22, pp795-810). Bladder hypersensitivity 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 bladder inflammation (Birder et al., 2001, PNAS, 98, pp13396-13401) . Further, TRPV1 knockout mice are anatomically normal, but have a higher frequency of low-amplitude, non-emptying contractions of the bladder and a decreased emptying reflex during filling of the bladder compared to wild-type mice, which thus indicates that TRPV1 affects the functions of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp856-860). TRPV1 is common in keratinocytes of the human epidermis, as well as 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 is involved in the transmission of various toxic stimuli and pain effects, such as skin irritation and pruritus, thereby finding a close correlation with the etiology of dermatological diseases and disorders such as skin inflammation 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. Pharmacol. Exp. Ther., 304, pp217-222). In recent years, evidence has been accumulated of other TRPV1 roles. TRPV1 may be involved in blood flow / pressure regulation through the release of sensory vasoactive neuropeptide and 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). Furthermore, TRPV1 knockout mice are less likely to exhibit less anxiety-related behavior than their wild-type relatives, without differences in locomotion (Marsch et al., 2007, J. Neurosci., 27 (4), pp832-9 )

Based on the above information, the development of various TRPV1 antagonists is in full swing, and several patents and patent applications have been published regarding the TRPV1 antagonists being developed (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).

The compounds of the present invention can be used for the prevention and treatment of diseases associated with TRPV1 activity (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, postherpetic neuralgia, neuralgia, headache, toothache, pelvic pain, migraine, bone cancer pain, mastalgia and visceral pain (Petersen et al., 2000 , Pain 88, pp. 125-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 3 04, 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); nerve-related diseases such as neuropathies, 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); urge to defecate; 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), gastric 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); urinary 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 diseases such as psoriasis, pruritus, prurigo and dermatitis (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp. 217-222); irritation of the skin, eyes or mucous membrane (Tominaga et al., 1998, Neuron 21 pp. 531-543); hypernormal hearing; noise in ears; vestibular hypersensitivity (Balaban et al., 2003, Hear Res. 175, pp. 165-70); heart diseases 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); hair growth disorders such as hirsutism, effluvium, baldness (Bodó et al., 2005, Am. J. Patho. 166, pp. 985-998; Biró 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).

Compounds that are associated with VR1 activities 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 relate to VR1 modulators with a partial biphenyl structure. As a result of extensive and intensive studies, the authors of the present invention synthesized new compounds having VR1 antagonistic activity by replacing one phenyl ring with a substituted heterocyclic ring. In addition, the authors of the present invention also unexpectedly identified that the replacement of one phenyl ring, as indicated above, provides an improvement in their physicochemical characteristics, such as metabolic stability or pharmacokinetic profiles.

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

Disclosure of invention

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

(I),

(I)

wherein

,

или C≡C, причем R₁₁ и R₁₂, если они присутствуют, являются независимо водородом, галогеном или C1-C10 алкилом;X is CR ₁₁ = CR ₁₂ , CHR ₁₁ CHR ₁₂ ,

,

or C≡C, wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen or C1-C10 alkyl;

Y and Z are independently CH, CR ₆ or N, so that at least one of Y and Z is N;

R ₁ is hydrogen, halogen or alkyl (preferably C1-C10 alkyl);

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), haloalkyl (preferably halogen (C1-C10) alkyl) alkenyl (preferably C2-C10 alkenyl), alkynyl (preferably C2-C10 alkynyl), carboxy, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl) or alkylthio (preferably C1-C10 alkylthio);

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), alkenyl (preferably C2-C10 alkenyl), alkynyl (preferably C2-C10 alkynyl), alkylthio (preferably C1-C10 alkylthio), alkylsulfonyl (preferably C1-C10 alkylsulfonyl), alkylcarbonyl (preferably C1-C10 alkylcarbonyl), alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), alkenyloxy (preferably C2- C10 alkenyloxy), alkoxyalkoxy (preferably C1-C10 alkoxy (C1-C10) alkoxy), alkoc alkoxyalkyl (preferably C1-C10 alkoxy (C1-C10) alkoxy (C1-C10) alkyl), piperidyl, piperazinyl, alkoxyalkylamino (preferably C1-C10 alkoxy (C1-C10) alkylamino), alkylamino (preferably C1-C10 alkylamino), dialkylamino (preferably di (C1-C10 alkyl) amino), cycloalkyl (preferably C3-C8 cycloalkyl), cycloalkylamino (preferably C3-C8 cycloalkylamino), cycloalkoxy (preferably C3-C8 cycloalkoxy), oxacycloalkyloxy (preferably C3-C8 oxacycloalkyloxy), N- alkoxyalkyl-N-alkylamino (preferably N- (C1-C10) alkoxy (C1-C10) alkyl-N- (C1-C10) alkyl lamino), 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, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl,

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or eschennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

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

and

R ₁₀ is alkyl (preferably C1-C10 alkyl), haloalkyl (preferably halogen (C1-C10) alkyl) or alkenyl (preferably C2-C10 alkenyl).

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

(I),

(I)

wherein

X is CR ₁₁ = CR ₁₂ , CHR ₁₁ CHR ₁₂ or C≡C, wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen or C1-C5 alkyl;

Y and Z are independently CH, CR ₆ or N, so that at least one of Y and Z is N, R ₁ is hydrogen, halogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1- C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino, C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, 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, prefer especially N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or eschennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

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

and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl,

and wherein in one embodiment, preferably Z is N, Y is CR ₆ , and R ₇ is C3-C6 alkyl or halogen (C1-C5 alkyl), for example trifluoromethyl, and in another embodiment, in said compounds of formula I preferably X is CR ₁₁ = CR ₁₂ or C≡C, Z is N, Y is CR ₆ , R ₆ is different from hydrogen, and R ₇ is halogen (C1-C5 alkyl), particularly preferably trifluoromethyl.

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

(I),

(I)

wherein

,

или C≡C, причем R₁₁ и R₁₂, если они присутствуют, являются независимо водородом, галогеном или C1-C5 алкилом;X is CR ₁₁ = CR ₁₂ , CHR ₁₁ CHR ₁₂ ,

,

or C≡C, wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen or C1-C5 alkyl;

Y and Z are independently CH, CR ₆ or N, so that at least one of Y and Z is N;

R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1- C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino, C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, 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, pr dpochtitelno phenyl, arylamino, preferably phenylamino, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl, or morpholinyl,

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, or unsubstituted or substituted by halogen d (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

- each piperazinyl, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl or hydroxyl;

and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

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

(I),

(I)

wherein

,

или C≡C, причем R₁₁ и R₁₂, если они присутствуют, являются независимо водородом, галогеном или C1-C5 алкилом;X is CR ₁₁ = CR ₁₂ , CHR ₁₁ CHR ₁₂ ,

,

or C≡C, wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen or C1-C5 alkyl;

Y and Z are independently CH, CR ₆ or N, so that at least one of Y and Z is N;

R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R _{9 are} independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl , halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5 ) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazinyl, 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 and morpholinyl, wherein phenyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl, and halogen (C1-C5) alkyl; and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

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

wherein

X is CR ₁₁ = CR ₁₂ , wherein R ₁₁ and R ₁₂ are independently hydrogen, halogen or C1-C3 alkyl;

R ₁ is hydrogen or C1-C3 alkyl;

R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R ₆ , R ₇ , R ₈ and R _{9 are} independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl , halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5 ) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazinyl, 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, f phenyl or morpholinyl, wherein phenyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl and halogen (C1-C5) alkyl; and

R ₁₀ is C1-C3 alkyl or C2-C3 alkenyl.

According to one embodiment of the present invention, in compounds of formula I, as described below, R ₆ is different from hydrogen, and R ₇ is halogen (C1-C5) alkyl, preferably halogen (C1-C4) alkyl, more preferably halogen (C1-C2) alkyl, such as CF ₂ Cl or CF ₂ CF ₃ , particularly preferably R ₇ is CF ₃ .

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

- Z is N;

- Y is CR ₆ ;

- X is CR ₁₁ = CR ₁₂ , CHR ₁₁ CHR ₁₂ or C≡C;

- R ₇ is C3-C6 alkyl or halogen (C1-C5) alkyl; and R _{7 is} even more preferably denotes tert-butyl, isopropyl, isobutyl or trifluoromethyl;

and

R ₆ does not mean pyridinyl, pyridinyloxy, piperazinyl, hydroxyl substituted alkylamino or substituted pyrrolidine. In some embodiments, R _{6 is} also not hydrogen. In another embodiment, R _{6 is} not hydrogen and also is not phenylthio.

Accordingly, one embodiment of the present invention relates to a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof:

(I),

(I)

wherein

- X is CR ₁₁ = CR ₁₂ or C≡C; wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen or C1-C5 alkyl;

- Z is N;

- Y is CR ₆ ;

R ₁ is hydrogen, halogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ is hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl , C2-C10 alkenyloxy, 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 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, 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, pred desirably phenyl, arylamino, preferably phenylamino, thienyl, heteroarylamino, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl, with the proviso that R _{6 is} not hydroxy substituted alkylamino;

R ₈ and R _{9 are} independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1 -C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino, C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, 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, preferred o N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or eschennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

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

R ₇ is halo (C1-C5) alkyl;

and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

In another embodiment, in the compounds of formula I, as described herein,

X is —CH = CH—, —C (CH ₃ ) = CH—, —CH = C (CH ₃ ) -, —C (CH ₃ ) = C (CH ₃ ) -, —C (C ₂ H ₅ ) = CH-, -CH = C (C ₂ H ₅ ) -, -CF = CH-, -CH = CF- or C≡C;

R ₁ is hydrogen, fluoro, methyl or ethyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R ₆ is hydroxy, fluoro, bromo, chloro, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen (C1-C6) alkyl, halogen (C1-C6) alkoxy, C2 -C6 alkenyloxy, 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 cycloalkylamino, which may be unsubstituted or substituted by one or more methyl groups, C3-C6 cycloalkoxy, C3-C6 oxacycloalkoxy , N- (C1-C2) alkoxy (C1-C3) alkyl -N- (C1-C3) alkylamino, N- (C3-C6) cycloalkyl-N- (C1-C3) alkylamino, C1-C3 alkylpiperazinyl, piperidyl, pyrrolidinyl, halophenyl, phenyl, phenoxy, phenylamino, halophenoxy, morpholinyl; C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkynyl, di (C1-C3) alkylaminoalkynyl, (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 or piperidyl;

R ₇ is halogen (C1-C5) alkyl, such as CF ₂ Cl, CF ₂ CF ₃ or, particularly preferably, CF ₃ ;

R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl; and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

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

,

,

(Ii)

wherein

R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R _{9 are} independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, halogen (C1-C5) alkyl , halogen (C1-C5) alkoxy, hydroxy (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5 ) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazinyl, 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 mo Folin, wherein phenyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl, and halo (C1-C5) alkyl;

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and

R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen.

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

,

,

(III)

wherein

R ₁ is hydrogen, halogen or C1-C10 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), haloalkyl (preferably halogen (C1-C10) alkyl) alkenyl (preferably C2-C10 alkenyl), alkynyl (C2-C10 alkynyl), carboxy, alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl) or alkylthio (preferably C1-C10 alkylthio);

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, alkyl (preferably C1-C10 alkyl), alkoxy (preferably C1-C10 alkoxy), alkenyl (preferably C2-C10 alkenyl), alkynyl (preferably C2-C10 alkynyl), alkylthio (preferably C1-C10 alkylthio), alkylsulfonyl (preferably C1-C10 alkylsulfonyl), alkylcarbonyl (preferably C1-C10 alkylcarbonyl), alkoxycarbonyl (preferably C1-C10 alkoxycarbonyl), alkenyloxy (preferably C2- C10 alkenyloxy), alkoxyalkoxy (preferably C1-C5 alkoxy (C1-C10) alkoxy), alkox alkoxyalkyl (preferably C1-C5 alkoxy (C1-C10) alkoxy (C1-C10) alkyl), piperidyl, piperazinyl, alkoxyalkylamino (preferably C1-C10 alkoxy (C1-C10) alkylamino), alkylamino (preferably C1-C10 alkylamino), dialkylamino (preferably di (C1-C10 alkyl) amino), cycloalkyl (preferably C3-C8 cycloalkyl), cycloalkylamino (preferably C3-C8 cycloalkylamino), cycloalkoxy (preferably C3-C8 cycloalkoxy), oxacycloalkyloxy (preferably C3-C8 oxacycloalkyl-hydroxy), N-alkoxyalkyl-N-alkylamino (preferably N- (C1-C10) alkoxy (C1-C10) alkyl-N- (C1-C10) alkyl amino), 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, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl,

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or substituted schennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

- each aryl or heteroaryl, also part of a group, for example, in arylamino, aryloxy, heteroaryloxy or heteroarylamino, may be independently unsubstituted or substituted with one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halogen ( C1-C5) alkyl,

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

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

R ₁₀ is alkyl (preferably C1-C10 alkyl), haloalkyl (preferably halogen (C1-C10) alkyl) or alkenyl (preferably C2-C10 alkenyl); and

R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen.

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

,

,

(III)

wherein

R ₁ is hydrogen, halogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1- C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino, C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyl-oxy, 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 especially N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or eschennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

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

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and

R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen, wherein in one embodiment, R _{6 is} preferably different from hydrogen and R ₇ is halogen (C1-C5) alkyl.

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

,

,

(III)

wherein

R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen, hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1- C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino, C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyl-oxy, 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, ol preferably phenyl, arylamino, preferably phenylamino, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl,

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, or unsubstituted or substituted by halogen d (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

- each piperazinyl, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl or hydroxyl;

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and

R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen.

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

,

,

(III)

wherein

R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halogen (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy C1-C5 alkoxycarbonyl or C1-C5 alkylthio;

R ₆ , R ₇ , R ₈ and R _{9 are} independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, halogen (C1-C5) alkyl , halogen (C1-C5) alkoxy, hydroxy (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5 ) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkylpiperazinyl, 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 mo Folin, wherein phenyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl, and halo (C1-C5) alkyl;

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and

R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen.

One preferred aspect of the present invention relates to a compound of formula (I), (II) or (III), an isomer or pharmaceutically acceptable salt thereof, as defined below, in which X is CR ₁₁ = CR ₁₂ or C≡C, particularly preferably CR _{11 =} CR ₁₂ , wherein R ₁₁ and R _{12 are} preferably hydrogen, halogen or C1-C3 alkyl, and even more preferably hydrogen or methyl.

Accordingly, one preferred aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt thereof, as defined below, wherein X is selected from —CH═CH—, —C (CH ₃ ) = CH-, -CH = C (CH ₃ ) -, -C (CH ₃ ) = C (CH ₃ ) -, -C (C ₂ H ₅ ) = CH-, -CH = C (C ₂ H ₅ ) -, -CF = CH-, -CH = CF- or C≡C, even more preferably -CH = CH-, -C (CH ₃ ) = CH- or -CH = C (CH ₃ ) - and especially preferably -CH = CH-.

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

in which R ₇ is C3-C6 cycloalkyl, which may be unsubstituted or substituted by one or more methyl groups, or C1-C5 alkyl, which may be halogenated by one or more radicals selected from chlorine, bromine or, preferably, fluorine. Examples are methylcyclopropyl, CF ₃ , isopropyl, tert-butyl and isobutyl.

In one preferred embodiment of the present invention, in the compounds of formula (III), as described, R ₇ is C3-C6 alkyl or halogen (C1-C5 alkyl), and R _{7 is} even more preferably tert-butyl, isopropyl, isobutyl or trifluoromethyl. In one preferred embodiment of the present invention, in the compounds of formula (III), as described below, R ₇ is halogen (C1-C5) alkyl or halogen (C1-C4) alkyl, such as CF ₂ Cl, CF ₂ CF ₃ or, especially preferably CF ₃ .

In another embodiment of the present invention, in the compounds of formula (III), R _{6 is} not pyridynyloxy, phenylthio or substituted pyrrolidine. In another preferred aspect of the present disclosure, R ₆ is different from hydrogen.

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

- R ₇ is C3-C6 alkyl or halogen (C1-C5 alkyl), and R _{7 is} even more preferably is tert-butyl, isopropyl, isobutyl or trifluoromethyl;

and

- R ₆ does not mean pyridinyl, pyridinyloxy, piperazinyl, hydroxyl substituted alkylamino or substituted pyrrolidine. In some embodiments, R _{6 is} also not hydrogen and / or phenylthio.

Another aspect of the present invention relates to a compound of formula (I) or (III), an isomer or pharmaceutically acceptable salt thereof, as defined above, wherein R _{6 is} selected from hydrogen, bromo, chloro, n-butyl, methoxy, isobutyloxy, sec- butyloxy, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamino, n-butylamino, phenoxy, n-butyloxy and methoxyethylamino.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt thereof, as defined above, wherein R _{3 is} selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl and cyano.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), an isomer thereof or a pharmaceutically acceptable salt thereof, as defined above, in which R ₁₀ is methyl.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), an isomer thereof or a pharmaceutically acceptable salt thereof, as defined above, in which R ₁₁ and R ₁₂ , if present, are both hydrogen. In another embodiment, one of R ₁₁ and R ₁₂ is hydrogen, and the other is selected from methyl, ethyl, and propyl. In one embodiment, R ₁₁ may be hydrogen, and R ₁₂ may be hydrogen, methyl, ethyl or propyl, preferably hydrogen.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt thereof, as defined above, in which R ₄ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyano or trifluoromethyl.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt thereof, as defined above, in which R ₁ and R _{2 are} both hydrogen.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt, as defined above, in which R ₁ , R ₂ and R ₁₁ and R ₁₂ , if present, all are hydrogen.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt, as defined above, in which R ₁ , R ₂ and R ₁₁ and R ₁₂ , if present, all are hydrogen, R ₁₀ is methyl, and R _{3 is} selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl and cyano.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt, as defined above, in which R ₁₁ and R ₁₂ , if present, are both hydrogen, R ₁₀ denotes methyl or ethyl, R ₃ selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifluoromethyl, ethenyl, ethinyl and cyano, and R ₄ selected from hydrogen, fluorine, chlorine, bromine, methyl, cyano or trifluoromethyl.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt, as defined above, in which R ₁₁ and R ₁₂ , if present, are both hydrogen, R ₁₀ is methyl or ethyl, R _{3 is} selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl and cyano, and R ₇ is cyclopropylmethyl or C1-C5 alkyl, which may optionally be halogenated by one or more radicals, selected from chlorine, bromine, or preferably fluorine.

Another aspect of the present invention relates to a compound of formula (I), (II) or (III), its isomer or pharmaceutically acceptable salt, as defined above, in which R ₁₁ and R ₁₂ , if present, are both hydrogen, R ₁₀ is methyl or ethyl, R ₂ , R ₅ and R ₈ are hydrogen, R _{3 is} selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl and cyano, and R ₇ is C1-C5 alkyl, which may optionally be halogenated with one or more radicals selected from chlorine, bromine, or preferably fluorine.

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

wherein

R ₁ is hydrogen, methyl or ethyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R ₆ , if present, is hydrogen, hydroxy, fluorine, bromine, chlorine, hydroxymethyl, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, halogen (C1-C5) alkyl, halogen ( C1-C5) alkoxy, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, di (C1-C3 alkyl) amino, C1- C3 alkylpiperazinyl, piperidyl, pyrrolidinyl, halogenphenyl, phenyl or morpholinyl, wherein R _{6 is} preferably different from hydrogen;

R ₇ is C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl, which may be unsubstituted or substituted with one or more methyl groups, C2-C5 alkenyl, with R ₇ preferably denotes halogen (C1-C4) alkyl;

R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl;

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and

R ₁₁ and R ₁₂ , if present, are independently hydrogen or methyl.

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

wherein

R ₁ , R ₂ and R ₅ are hydrogen;

R ₃ is hydrogen, fluoro, chloro, cyano, methyl, ethenyl, ethynyl or trifluoromethyl;

R ₄ is hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;

R ₆ , if present, is hydrogen, hydroxy, fluoro, bromo, chloro, methyl, hydroxymethyl, methoxy, trifluoromethyl, diethylamino, piperidyl, pyrrolidinyl, trifluorophenyl, phenyl or morpholinyl, wherein R _{6 is} preferably different from hydrogen;

R ₇ is methyl, isopropyl, tert-butyl, trifluoromethyl, chloro, bromo, cyclopropyl, methylcyclopropyl, piperidyl, pyrrolidinyl or morpholinyl, and R _{7 is} preferably trifluoromethyl;

R ₈ is hydrogen;

R ₁₁ and R ₁₂ , if present, are hydrogen;

R ₉ is hydrogen or trifluoromethyl; and

R ₁₀ is methyl.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl;

R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;

R ₆ , if present, is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, piperidyl or morpholinyl;

R ₇ is isopropyl, tert-butyl or, preferably, trifluoromethyl;

R ₈ is hydrogen;

R ₁₁ and R ₁₂ , if present, are hydrogen;

R ₉ is hydrogen or trifluoromethyl; and

R ₁₀ is methyl.

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

wherein

X is —CH = CH—, —C (CH ₃ ) = CH—, —CH = C (CH ₃ ) -, —C (CH ₃ ) = C (CH ₃ ) -, —C (C ₂ H ₅ ) = CH-, -CH = C (C ₂ H ₅ ) -, -CF = CH-, -CH = CF- or C≡C;

R ₁ is hydrogen, fluoro, methyl or ethyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R ₆ is hydrogen, hydroxy, fluoro, bromo, chloro, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen (C1-C6) alkyl, halogen (C1-C6) alkoxy , C2-C6 alkenyloxy, 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 cycloalkylamino, which may be unsubstituted or substituted by one or more methyl groups, C3-C6 cycloalkoxy, C3- C6 oxacycloalkoxy, N- (C1-C2) alkoxy (C1-C3) alkyl-N- (C1-C3) alkylamino, N- (C3-C6) cycloalkyl-N- (C1-C3) alkylamino, C1-C3 alkylpiperazinyl, piperidyl, pyrrolidinyl, halogenophenyl, phenyl, phenoxy, pyridinyloxy phenylamino, halogenophenoxy or morpholinyl;

R ₇ is C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl, which may be unsubstituted or substituted with one or more methyl groups, C2-C5 alkenyl;

R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl; and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

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

wherein

R ₁ , R ₂ and R ₅ are hydrogen;

R ₃ is hydrogen, fluoro, chloro, cyano, methyl, ethenyl, ethynyl or trifluoromethyl;

R ₄ is hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;

R ₆ is hydrogen, hydroxy, fluoro, bromo, chloro, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, trifluoromethyl, diethylamino, methoxymethylamino, methoxyethylamino, methoxypropylamino , cyclopentylamino, cyclohexylamino, ethylamino, propylamino, butylamino, pentylamino, N, N-dimethylamino, N-methyl-N-ethylamino 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-methoxymethyl amino, N-methyl-N-methoxyethylamino, N-methyl-N-methoxypropylamino, N-methyl-N-cyclobutylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino, phenoxy, halogenophenoxy, piperidyl, pyrrolidinyl, trifluorophenyl, phenyl or morpholinyl, wherein R _{6 is} preferably different from hydrogen;

R ₇ is methyl, isopropyl, tert-butyl, trifluoromethyl, chloro, bromo, cyclopropyl, methylcyclopropyl, piperidyl, pyrrolidinyl or morpholinyl, and preferably is trifluoromethyl;

R ₈ is hydrogen;

R ₁₁ and R ₁₂ are hydrogen;

R ₉ is hydrogen or trifluoromethyl; and

R ₁₀ is methyl.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl;

R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;

R ₆ is hydrogen, fluoro, chloro, bromo, methyl, n-butyl, methoxy, n-butyloxy, isobutyloxy, sec-butyloxy, methoxyethoxy, methoxyethylamino, diethylamino, n-butylamino, cyclopentylamino, phenoxy, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl, in one aspect, R ₆ is different from hydrogen;

R ₇ is isopropyl, tert-butyl or preferably trifluoromethyl;

R ₈ is hydrogen;

R ₁₁ and R ₁₂ are hydrogen;

R ₉ is hydrogen or trifluoromethyl; and

R ₁₀ is methyl.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, ethenyl or ethynyl;

R ₄ is hydrogen or fluoro;

R ₅ is hydrogen;

R ₆ is hydrogen, hydroxy, fluoro, bromo, chloro, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, trifluoromethyl, N, N-dimethylamino, N -methyl-N-ethylamino N, N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N, N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, methoxymethylamino, methoxyethylamino, methoxypropylamino, N-methyl-N-methoxymethylamino, N-methyl-N-methoxyethylamino, N-methyl-N-methoxypropylamino, cyclobutylamino, cyclopentylamino, cycle ohexylamino, N-methyl-N-cyclobutylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino, ethylamino, propylamino, butylamino, pentylamino, phenoxy, halogenophenoxy, N-piperidyl, N-pyrrolidinyl, trifluorophenyl, phenyl or N-morpholinyl,

wherein R _{6 is} in one aspect different from hydrogen;

R ₇ is isopropyl, tert-butyl or preferably trifluoromethyl;

R ₈ is hydrogen;

R ₉ is hydrogen or trifluoromethyl;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

wherein

R ₁ is hydrogen;

R ₂ is hydrogen;

R ₃ is hydrogen, ethenyl or ethynyl;

R ₄ is hydrogen or fluoro;

R ₅ is hydrogen;

R ₆ is hydrogen, bromo, chloro, n-butyl, methoxy, isobutyloxy, sec-butyloxy, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamino, n-butylamino, phenoxy, n-butyloxy, methoxyethylamino wherein R _{6 is} in one aspect different from hydrogen;

R ₇ is isopropyl, tert-butyl or preferably trifluoromethyl;

R ₈ is hydrogen;

R ₉ is hydrogen or trifluoromethyl;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

R ₁ is hydrogen or methyl, wherein if R ₁ is methyl, the compound may be a pure enantiomer or may be a mixture of (R) and (S) enantiomers; and the C atom to which R ₁ is attached is preferably in the (R) configuration;

one of R ₂ and R ₅ is hydrogen, and the other is hydrogen, methyl or halogen, preferably fluorine;

R _{3 is} selected from hydrogen, fluorine, bromine, chlorine, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl, and cyano, preferably hydrogen, fluorine, chlorine, methyl, ethyl, ethenyl, ethynyl, and cyano;

R ₄ is hydrogen, fluoro, chloro, cyano, methyl or ethyl;

R ₆ has the meanings described in various embodiments within the framework of this application;

R ₇ is C1-C5 alkyl, or more preferably C1-C4 alkyl or C1-C3 alkyl, which is halogenated by one or more radicals selected from chlorine, bromine or preferably fluorine, wherein R _{7 is} particularly preferably CF ₃ ;

one of R ₈ and R ₉ is hydrogen, and the other is halogen, CF _3, or preferably hydrogen;

R ₁₀ is methyl, ethyl or ethenyl, and preferably methyl;

R ₁₁ is hydrogen;

R ₁₂ is hydrogen, methyl, ethyl or propyl, and preferably hydrogen.

Another aspect of the present disclosure relates to a compound of formula (III), as described herein, to an isomer or pharmaceutically acceptable salt thereof, in which

R ₆ is halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2 -C10 alkenyloxy, 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 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyl-oxy, 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, preferred a phenyl, arylamino, preferably phenylamino, arylthio, preferably phenylthio, thienyl, heteroarylamino, aryloxy, preferably phenoxy, pyrrolidinyl, or morpholinyl, with the proviso that R ₆ does not denote alkylamino substituted by hydroxy, preferably

R ₆ is chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethynyl, methoxypropinyl, diethylaminopropinyl, phenyl, halogenophenyl, methoxyphenyl, thienyl, methoxy, ethoxy, propoxy, butoxy , trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenophenoxy, benzyloxy, ethylthio, propylthio, butylthio, pentylthio, methylamino, ethylamino, propylamino, butylamino, pentylamino, methoxyethylamino, iclobutylamino, cyclopentylamino, 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-N-phenylamino, N-pyrrolidinyl, N-piperidyl, ethoxycarbonyl-N-piperidyl or N-morpholinyl, preferably

R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethhenyl, phenyl, fluorophenyl, thienyl , n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3-methylbutoxy, 2,2,2-trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, n-propylamino, isopropylamino , n-butylamino, isobutylamino, sec-butylamino, methoxymethylamino, methoxyethylamino, ethoxyethylamino, cyclopentylamino, benzylamino, feni amino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or ethoxycarbonyl-N-piperidyl, and more preferably

R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, methylamino, ethylamino , n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino or N-methyl-N-phenylamino, more preferably

R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, benzylamino or N-methyl-N-phenylamino, even more preferably

R ₆ is C2-C5 alkyl, C1-C4 alkylamino or methoxyethylamino, with particular preference

R ₆ is C3-C5 alkyl or C2-C4 alkylamino, with particular preference

R ₆ is C2-C4 alkyl or C1-C3 alkylamino, with particular preference

R ₆ is linear or branched C3 alkyl, linear C4 alkyl or linear (C2-C3) alkylamino.

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

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

3- (6-tert-butyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

3- (6-tert-butyl-2-chloro-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

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

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

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

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

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

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

N- (3-Fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,

N- (4-methanesulfonylamino-3-vinyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,

N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,

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

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

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

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

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

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

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

N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide,

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

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

Particularly preferred compounds of the present invention are

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

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

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

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

3- (6-tert-butyl-2-chloro-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

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

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

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

3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

Particularly preferred compounds of the present invention are

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

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

N- (4-methanesulfonylamino-3-vinyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,

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

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

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

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

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

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

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

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide and

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

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

wherein

X is —CH = CH—, —C (CH ₃ ) = CH—, —CH = C (CH ₃ ) -, —C (CH ₃ ) = C (CH ₃ ) -, —C (C ₂ H ₅ ) = CH-, -CH = C (C ₂ H ₅ ) -, -CF = CH-, -CH = CF- or C≡C;

R ₁ is hydrogen, fluoro, methyl or ethyl;

R ₂ , R ₃ , R ₄ and R _{5 are} independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy or methoxycarbonyl;

R ₆ is C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkynyl, di (C1-C3) alkylaminoalkynyl, (C1-C3) alkoxyphenyl, thienyl, pyridinyl, halo pyridinyl, (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, piperazinyl or C1-C3 alkylpiperazinyl, wherein R _{6 is} in one embodiment different from hydrogen;

R ₇ is C1-C5 alkyl, halogen (C1-C4) alkyl, halogen, piperidyl, morpholinyl, pyrrolidinyl, C3-C6 cycloalkyl, which may be unsubstituted or substituted with one or more methyl groups, C2-C5 alkenyl, with R ₇ preferably denotes halogen (C1-C4) alkyl;

R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl; and

R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, methyl, ethyl, cyano, ethenyl, ethynyl or trifluoromethyl;

R ₄ is hydrogen, fluoro, chloro or methyl;

R ₅ is hydrogen;

R ₆ is fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethynyl, methoxypropinyl, diethylaminopropinyl, phenyl, halogenophenyl, methoxyphenyl, thienyl, pyridinyl, halo , propoxy, butoxy, pentoxy, trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenophenoxy, benzyloxy, pyridinyloxy, ethylthio, propylthio, butylthio, pentylthio, phenylthio, ethylamino, propylamino, butylamino, butylamino, amylamino, ethoxyethylamino, methoxypropylamino, cyclobutylamino, cyclopentylamino, 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-N-phenylamino, N-pyrrolidinyl, methoxy N-pyrrolidinyl, hydroxymethyl N-pyrrolidinyl, N-piperidyl, ethoxycarbonyl N-piperidyl, piperazinyl or N-morpholinyl;

R ₇ is isopropyl, tert-butyl or trifluoromethyl;

R ₈ is hydrogen;

R ₉ is hydrogen or trifluoromethyl;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl;

R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl or ethyl;

R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, phenylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R ₇ is isopropyl, tert-butyl or trifluoromethyl;

R ₈ represents hydrogen or chlorine;

R ₉ is hydrogen or trifluoromethyl;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₄ is hydrogen, fluoro, chloro or methyl;

R ₃ is hydrogen, fluoro, methyl, cyano, ethenyl, ethynyl or trifluoromethyl;

R ₅ is hydrogen;

R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, fluorophenyl, thienyl, n-propoxy , isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3-methylbutoxy, 2,2,2-trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, phenylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxymethylamino, methoxyethylamino, ethoxyethylamino, cyclopentylamino, benzylamino, phenylamino, N-ethyl-N-f nilamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, methoxy, N-pyrrolidinyl, piperidyl or N-ethoxycarbonyl-N-piperidyl;

R ₇ is isopropyl, tert-butyl or trifluoromethyl;

R ₈ represents hydrogen or chlorine;

R ₉ is hydrogen or trifluoromethyl;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, methyl, cyano, ethenyl or ethynyl;

R ₄ is hydrogen, fluoro or methyl;

R ₅ is hydrogen;

R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R ₇ is isopropyl, tert-butyl or trifluoromethyl;

R ₈ and R ₉ are hydrogen;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

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

wherein

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

when R ₄ is fluoro, R ₃ is hydrogen, fluoro, methyl or ethynyl, or when R ₄ is hydrogen,

R ₃ is methyl;

R ₅ is hydrogen;

R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R ₇ is isopropyl, tert-butyl or trifluoromethyl;

R ₈ and R ₉ are hydrogen;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

In a preferred aspect of the present invention, in compounds of formula III, as described herein, R ₇ is a CF ₃ group. Another embodiment of the present disclosure relates to compounds having the formula III as described herein, wherein R ₇ is CF ₂ Cl or CF ₂ CF ₃ .

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

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2,2,2-trifluoro-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide,

3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

N- (3-cyano-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] -acrylamide,

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

3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,

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

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

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

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

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

3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,

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

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

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

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

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

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

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

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

N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- [1- (3,5-difluoro-4-methanesulfonylamino-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-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,

including their isomers, racemic mixtures and pharmaceutically acceptable salts.

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

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

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

3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(R) -N- [1- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,

including their isomers, racemic mixtures and pharmaceutically acceptable salts.

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

(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,

3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N-1- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,

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

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

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

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

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

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

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

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

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

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

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

3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,

[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide of 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid,

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

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

3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzylamide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,

3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,

[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,

[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid and

N- (3-ethenyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-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

R ₁ is hydrogen or methyl;

R ₂ is hydrogen;

R ₃ is hydrogen, fluoro, chloro, methyl, cyano, ethenyl or ethynyl;

R ₄ is hydrogen;

R ₅ is fluoro, chloro or methyl, preferably fluoro;

R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, fluorophenyl, thienyl, n-propoxy , isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3-methylbutoxy, 2,2,2-trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxymethylamino, methoxyethylamino, ethoxyethylamino, cyclopentylamino, benzylamino, phenylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or ethoxycarbonyl N-piperidyl, and wherein R _{6 is} preferably n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino N-ethyl-N-phenylamino or N-methyl-N-phenylamino;

R ₇ is halogen (C1-C3) alkyl, preferably CF ₃ ;

R ₈ and R _{9 are} independently hydrogen, halogen or trifluoromethyl, wherein R _{8 is} preferably hydrogen or chlorine, and R ₉ is hydrogen;

R ₁₀ is methyl; and

R ₁₁ and R ₁₂ are hydrogen.

Another aspect of the present invention relates to a compound having formula IV, an isomer thereof or a pharmaceutically acceptable salt thereof:

формула IV,

formula IV

wherein

R ₁ is hydrogen, methyl or ethyl;

R ₁₂ is hydrogen or C1-C3 alkyl, preferably hydrogen or propyl;

R ₆ is C2-C6 alkyl, di (C1-C6 alkyl) amino, C1-C6 alkoxy, 2,2,2-trifluoro (C1-C3) alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6 alkylamino, C3-C6 cycloalkylamino, phenoxy, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl, N-phenyl-N- (C1-C5) alkylamino, methoxy-N-pyrrolidinyl or C1-C6 alkylthio ;

R ₇ is CF ₃ , CF ₂ Cl or CF ₂ CF ₃ ;

and

R ₈ and R ₉ independently represent hydrogen, CF ₃ or halogen.

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

R ₁ is hydrogen or methyl;

R ₆ is C2-C5 alkyl, C1-C4 alkylamino, methoxy or methoxyethylamino;

R ₇ is CF _3;

R ₈ and R ₉ are hydrogen; and

R ₁₂ is hydrogen.

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

формула V,

formula V,

wherein

R ₁ is hydrogen, methyl or ethyl;

R ₃ is hydrogen, fluoro or chloro;

R ₆ is C2-C6 alkyl, di (C1-C6 alkyl) amino, C1-C6 alkoxy, 2,2,2-trifluoro (C1-C3) alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6 alkylamino, C3-C6 cycloalkylamino, phenoxy, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N- (C1-C5) alkylamino;

R ₇ is CF ₃ , CF ₂ Cl or CF ₂ CF ₃ ;

R ₈ and R ₉ independently represent hydrogen, CF ₃ or halogen; and

R ₁₂ is 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, wherein

R ₁ is hydrogen or methyl;

R ₃ is hydrogen or fluoro;

R ₆ is C2-C5 alkyl, C1-C4 alkylamino, methoxy or methoxyethylamino;

R ₇ is CF ₃ ;

R ₈ and R _{9 are} both hydrogen; and

R ₁₂ is hydrogen.

Another aspect of the present invention relates to a compound having formula VI, an isomer or pharmaceutically acceptable salt thereof:

,

,

wherein

W is hydrogen or fluorine;

X is —CR ₁₁ = CR ₁₂ - or —C≡C—;

R ₁ selected from hydrogen and C1-C3 alkyl;

R ₆ is hydroxy, halogen, nitro, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl , C2-C10 alkenyloxy, 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 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyl-oxy, 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, pre ochtitelno phenyl, arylamino, preferably phenylamino, heteroaryl, preferably thienyl, heteroarylamino, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl;

R ₁₁ and R ₁₂ , if present, are independently selected from hydrogen and C 1 -C 3 alkyl, preferably hydrogen or propyl;

R ₇ is CF ₂ CF _3, CF ₂ Cl or preferably CF ₃ ;

R ₈ and R _{9 are} independently selected from hydrogen, halogen or CF ₃ ,

moreover

- each alkyl, alkenyl and alkynyl, also as part of a group, for example, in alkoxy, alkylsulfonyl, alkylcarbonyl, alkylamino or alkenyloxy, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or eschennym one or more substituents selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,

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

- each cycloalkyl, as well as part of a group, for example, in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halo C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and

- each piperidyl or morpholinyl may be unsubstituted or substituted with one or more unsubstituted or substituted with 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

• R ₈ and R ₉ are both hydrogen, and / or

• X is —CH = CH—, and / or

• X is —CH = CH—, and W, R ₈ and R ₉ are hydrogen, and / or

• R ₁ is hydrogen or methyl; and / or

• R _{6 is} selected from C2-C6 alkyl, di (C1-C6 alkyl) amino, 2,2,2-trifluoro (C1-C3) alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6 alkylamino, C3 -C6 cycloalkylamino, phenyl, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N- (C1-C5) alkylamino, wherein each phenyl may be substituted with one or more halogens; and / or

• R ₇ is CF ₃ .

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

• R ₁ is hydrogen or methyl; and / or

• R _{6 is} selected from C2-C5 alkyl, C1-C4 alkylamino or methoxyethylamino, preferably R ₆ is —NH- (C1-C4) alkyl or a linear or branched C2-C5 alkyl; and / or

• R ₇ is CF ₃ ; and / or

• R ₁₂ is hydrogen.

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

• W, R ₈ and R ₉ are hydrogen;

• X is —CH = CH—;

• R _{6 is} selected from C2-C5 alkyl, C1-C4 alkylamino or methoxyethylamino, preferably R ₆ is —NH- (C1-C4) alkyl or a linear or branched C2-C5 alkyl;

• R ₁ is hydrogen or methyl; and

• R ₇ is CF ₃ .

Another aspect of the present invention relates to compounds of formula I, III, IV, V or VI, as described herein, wherein R ₁ is hydrogen, methyl or ethyl, preferably hydrogen or methyl. In more particular embodiments, if R ₁ is methyl or ethyl, then the atom to which R ₁ is attached is 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 are provided only to illustrate the invention and are not intended to limit its scope.

[Scheme 1]

Scheme 1 shows a method for synthesizing an acrylamide compound with various substituents. Substituted benzylamine (1) is reacted with pyridinylacrylic acid (2) to give benzylpyridinylacrylamide (3) using DMTMM {4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium} (Tetrahedron Lett., 1999 , 40, 5327).

[Scheme 2]

Scheme 2 shows a method for the synthesis of pyridinylacrylic acid (9) with various substituents. Substituted pyridinecarboxaldehyde (7) is prepared by known methods. Substituted nicotinic acid (4) or nicotinic acid ester (5) is converted to the corresponding pyridinecarboxaldehyde (7) via pyridinyl methyl alcohol (6) . Pyridinylmethyl alcohol is converted to pyridinecarboxaldehyde (7) via oxidation according to Swern. Pyridinecarboxaldehyde (7) is converted to methylpyridinylacrylic acid ester (8) by the Wittig reaction. The methylpyridinylacrylic ester (8) is hydrolyzed with potassium hydroxide to give pyridinylacrylic acid (9) .

[Scheme 3]

Scheme 3 shows a method for synthesizing a pyridinyl acrylic acid amide (16) with a tert-butyl group. A substituted tert-butyl pyridinecarboxaldehyde group (12) is obtained by reduction followed by a radical substitution method (J. Heterocyclic Chem., 1989, 25, 45-48). The substituted nicotinic acid ester (10) is converted to the corresponding pyridin-3-methanol (11) . Pyridinyl-3-methanol is reacted with trimethylacetic acid and silver nitrate to give pyridinecarboxaldehyde (12) via Tada radical substitution. Compound (14) is synthesized from compound (12) in a manner similar to that indicated for Scheme 2. 4-tert-Butylpyridinylacrylic acid (14) is reacted with compound (15) to give compound (16) .

[Scheme 4]

Scheme 4 shows a method for the synthesis of pyridinyl acrylic acid amide (22) with a trifluoromethyl group on pyridine. The 2-chloro-6-trifluoromethyl-nicotinic acid ester (17) is reacted with a cyclic secondary amine to give compound (18) . Compound (18) is converted to compound (21) by a reaction similar to that of Scheme 2. Compound (21) is reacted with compound (15) to give compound (22) .

[Scheme 5]

Scheme 5 shows a method for the synthesis of pyridinyl acrylamide (28) . 2-Chloro-nicotinic acid (23) is reacted with N, O-dimethylhydroxylamine hydrochloride to give compound (24) . Compound (24) is reduced with LAH to give compound (25) , which is converted to methylpyridinylacrylic acid ester (26) by the Wittig reaction. Compound (26) is hydrolyzed using LiOH to give pyridinyl acrylic acid (27) , which is then reacted with compound (15) to give compound (28) .

[Scheme 6]

Scheme 6 shows a method for synthesizing a pyridinyl acrylic ester or pyridinyl acrylic acid ester (30) or (31) with a 2-alkylamino group or 2-alkoxy group on pyridine, respectively. Compound (29) is reacted with various amines or alcohols to give compound (30) or compound (31) with or without a base such as K ₂ CO ₃ or NaH.

[Scheme 7]

Scheme 7 shows a method for synthesizing pyridinylacrylamide (32) or (33) with an alkylamino (or arylamino) group or an alkoxy group on pyridine, respectively. Compound (28) is reacted with various amines or alcohols to give compound (32) or compound (33) with or without a base such as K ₂ CO ₃ or NaH.

[Scheme 8]

Scheme 8 shows a method for synthesizing pyridinyl acrylamide (40) with a 2-alkyl group on pyridine. The keto ester (34) is reacted with compound (35) to give 2-alkyl-6-trifluoromethyl-nicotinic acid alkyl ester (36) , which is reduced to the alcohol compound (37) with lithium aluminum hydride. Oxidation by Swern of compound (37) followed by a Wittig reaction gives 3- (2-alkyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (38) . 3- (2-Alkyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (39) obtained by hydrolysis of compound (38) using LiOH is reacted with an amine compound (1) to obtain pyridinyl acrylamide (40) with 2-alkyl group on pyridine.

[Scheme 9]

Scheme 9 shows a method for synthesizing pyridinyl acrylamide (44) with 2-aryl or 2-heteroaryl on pyridine. Compound (42) , obtained by a Suzuki coupling reaction from compound (41) with various boronic acids using microwave irradiation, hydrolyzes LiOH to give acrylic acid (43) . Acrylic acid (43) is then reacted with compound (1) to give pyridinyl acrylamide (44) with a 2-aryl or 2-heteroaryl group on pyridine.

[Scheme 10]

Scheme 10 shows another method for synthesizing pyridinyl acrylamide (49) with a 2-alkyl group on pyridine. Compound (46) obtained by combining Sonogashira from compound (45) with various alkynes using microwave irradiation is reduced by hydrogenation to obtain Weireb amide (47) . This amide (47) is reduced to an aldehyde, and the obtained aldehyde is subjected to a Wittig reaction followed by hydrolysis using LiOH to give acrylic acid (48) . Acrylic acid (48) is then reacted with compound (1) to give pyridinyl acrylamide (49) with a 2-alkyl group on pyridine.

[Scheme 11]

Scheme 11 shows a method for synthesizing pyridinyl acrylamide (53) with a 2-alkylsulfinyl or 2-arylsulfinyl group on pyridine. Compound (50) obtained by reacting compound (45) with various alkylthiols or arylthiols using NaH is reduced with lithium aluminum hydride to give an aldehyde, and the resulting aldehyde is subjected to a Wittig reaction to give compound (51) . Compound (51) is hydrolyzed by LiOH to give acrylic acid (54) . Acrylic acid (54) is then reacted with compound (1) to give pyridinyl acrylamide (55) with a 2-alkylthio or 2-arylthio group on pyridine.

[Scheme 12]

Scheme 12 shows a method for synthesizing pyridinyl acrylamide (56) with a 2-alkylsulfonyl or 2-arylsulfonyl group on pyridine. Compound (55) oxidizes mCPBA to give pyridinyl acrylamide (56) with a 2-alkylsulfonyl or 2-arylsulfonyl group on pyridine.

[Scheme 13]

Scheme 13 shows a method for the synthesis of pyridinylacrylamide (59) with a 2-styryl group on pyridine. Compound (57) obtained by the Heck reaction of compound (41) using microwave irradiation is hydrolyzed using LiOH to give acrylic acid (58) . Acrylic acid (58) is then reacted with compound (1) to give pyridinyl acrylamide (59) with a 2-styryl group on pyridine.

[Scheme 14]

Scheme 14 shows a method for the synthesis of pyridinyl acrylamide (64) . The 2-chloro-nicotinic acid compound (23) is reacted with various amines to produce nicotinic acid (60) with 2-alkylamino, 2-dialkylamino, 2-arylamino or 2-N-alkyl-N-aryl amino -group, which is subjected to reactions similar to those of scheme 5, obtaining pyridinylacrylic acid (63) . Pyridinyl acrylamide (64) is then prepared by reacting pyridinyl acrylic acid (63) with an amine compound (1) .

[Scheme 15]

Scheme 15 shows another method for the synthesis of 2-alkyl-6-trifluoromethyl-nicotinic acid alkyl ester (36) . 3-Amino-alk-2-enoic acid alkyl ester (65) is reacted with compound (66) to give 2-alkyl-6-trifluoromethyl-nicotinic acid alkyl ester (36) .

[Scheme 16]

Scheme 16 shows another method for the synthesis of 3- (2-alkyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (38) . 2-alkyl-6-trifluoromethyl-nicotinic acid alkyl ester (36) is treated with a base such as LiOH to give the corresponding acid, which is reacted with N, O-dimethylhydroxylamine hydrochloride to give the amide compound (67) . Compound (67) was reduced using LAH to give the corresponding aldehyde, which was converted to 3- (2-alkyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (38) by the Wittig reaction.

[Scheme 17]

Scheme 17 shows a method for the synthesis of 3-pyridin-3-yl-propinic acid benzylamide (71) . Weinreb amide (67) is reduced using LAH to give the corresponding aldehyde, which is converted to dibromide (68) . Compound (68) was treated with BuLi, then methyl chloroformate, to give 3-pyridin-3-yl-propinic acid methyl ester (69) , which was then converted to 3-pyridin-3-yl-propinic acid (70) using LiOH. 3-Pyridin-3-yl-propinic acid benzylamide (71) is prepared by reacting propinic acid (70) with an amine compound (1) .

[Scheme 18]

Scheme 18 shows a method for synthesizing pyridinyl acrylamide (76) . Diketone (72) is reacted with compound (35) to give pyridinyl ketone (73) , which is converted to pyridinyl acrylonitrile (74) by reaction with diethyl ether of cyanomethylphosphonic acid and NaH. 3- (2-Alkyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (75) obtained by hydrolysis of pyridinyl acrylonitrile with 74 KOH is reacted with an amine compound (1) to obtain pyridinyl acrylamide (76) .

[Scheme 19]

Scheme 19 shows a method for the synthesis of acrylamide with various substituents. Substituted benzylamine (77) is reacted with pyridinyl acrylic acid (2) to give benzyl pyridinyl acrylamide (78) using DMTMM.

The present invention also relates to a compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt for the prevention or treatment of a disease associated with pathological excitation and / or aberrant expression of a vanilloid receptor, said composition comprising a compound of formula (I), (II), (III), (IV), (V) or (VI), an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In one preferred aspect, the present invention relates to a compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt for treating a condition selected from the group consisting of pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, bladder hypersensitivity, including urinary incontinence, cystitis, stomach and duodenal ulcers, irritable bowel syndrome (IBS), and inflammatory bowel disease ka (IBD), urge to defecate, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic / allergic / inflammatory skin disease, psoriasis, itching, prurigo, irritation of the skin, eye or mucous membrane, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, hair growth disorders 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 a 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, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and lower back pain), migraine, other types , more bone cancer, mastalgia, and visceral pain.

The present invention also relates to a pharmaceutical composition comprising a compound of 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 a pharmaceutical composition for the prophylaxis or treatment of a disease associated with pathological arousal and / or aberrant expression of a vanilloid receptor, said composition comprising a compound of formula (I), (II), (III), (IV), (V) or (VI), an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In one preferred aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V) or (VI), an isomer thereof or a pharmaceutically acceptable salt thereof, for treating a condition, selected from the group consisting of pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, bladder hypersensitivity, including urinary incontinence, cystitis, gastric and duodenal ulcers, irritable bowel syndrome (IBS) 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 the skin, eyes or mucous membranes sheath, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, hair growth disorders such as eff lyuvium, alopecia, rhinitis, pancreatitis, vulvodynia, haemorrhagic shock, and psychiatric disorders such as anxiety or fears.

In a particularly preferred aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V) or (VI), an isomer thereof or a pharmaceutically acceptable salt thereof, for the treatment of pain, as described above, wherein 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, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial b dermal syndrome and lower back pain), migraines, other types of headache, bone cancer pain, mastalgia and visceral pain.

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

In another aspect, the present invention relates to a method for inhibiting the binding of a vanilloid ligand to a vanilloid receptor in a patient, the method comprising administering cells expressing a vanilloid receptor in a patient, in contact with a compound of 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 preventing or treating a condition selected from the group consisting of pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, hypersensitivity of the bladder, including urinary incontinence, cystitis, stomach 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 the skin, eye or mucous membrane, hearing loss, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, hair growth disorders such as effluvium, alopecia, rhinitis, pancreatitis, vulvodynia, hemorrhagic shock, and psychiatric disorders such as anxiety or fears, which includes administering to the mammal, including humans, a therapeutically effective amount of a compound 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 for treating pain by administering a compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt, as described above wherein 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, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and pain lower back), migraines, other types of headache, bone cancer pain, mastalgia and visceral pain.

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

In another aspect, the present invention relates to the use of a compound of formula (I), (II), (III), (IV), (V) or (VI), its isomer or its pharmaceutically acceptable salt in the manufacture of a medicament for the prevention or treatment of a condition which is selected from the group consisting of pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, hypersensitivity of the bladder, including urinary incontinence, cystitis, stomach and duodenal ulcers, irritable to ischemic (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 skin, eyes or mucous membranes, hypernormal hearing, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, hair growth disorders, 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 a compound of formula (I), (II), (III), (IV), (V) or (VI), an isomer thereof, for the manufacture of a medicament for the prevention or treatment of pain, as described above wherein the condition is pain that is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including I have fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches, pain associated with bone cancer, mastalgia, and visceral pain.

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

,

,

(III)

which includes introducing into the reaction a compound represented by formula (IIIa):

(IIIa),

(IIIa)

with the compound represented by formula (IIIb):

(IIIb),

(IIIb)

in which

R _1, R ₂ , R ₃ , R ₄ , R ₅ R ₆ , R ₇ , R ₈ , R ₉ , R _10, R ₁₁ and R ₁₂ are as described in any of the previous embodiments.

One preferred aspect of the present invention relates to a process for preparing a compound of formula (III), wherein the reaction is carried out in the presence of a coupling agent.

Another preferred aspect of the present invention relates to a method for producing a compound of formula (III), wherein the coupling agent is 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-triazin-2-yl) -4-methylmorpholine chloride}.

The present invention also relates to a method for producing a compound of formula (IIIc):

(IIIc),

(IIIc)

which includes a step for reducing a compound of formula (III).

One preferred aspect of the present invention relates to a process for preparing a compound of formula (IIIc), wherein the reduction step 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 producing a compound of formula (III) or (IIIc), in which R ₁ , R ₁₁ and R ₁₂ are hydrogen.

Another preferred aspect of the present invention relates to a process for preparing a compound of formula (III) or (IIIc), wherein R ₁ , R ₂ , R ₈ , R ₁₁ and R ₁₂ are hydrogen; R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl; R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl; R ₆ is hydrogen, fluoro, chloro, bromo, methyl, methoxy, diethylamino, pyrrolidinyl, piperidyl or morpholinyl; R ₇ is isopropyl, tert-butyl or trifluoromethyl; R ₉ is hydrogen or trifluoromethyl; and R ₁₀ is methyl.

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

Формула (IIId),

Formula (IIId)

wherein

W is hydrogen or fluorine;

R ₁ is hydrogen or C1-C3 alkyl, preferably methyl; and

R ₁₀ is C1-C3 alkyl, C2-C3 alkenyl or halogen C1-C3 alkyl, preferably methyl;

with the proviso that if R ₁ is hydrogen and R ₁₀ is methyl, then W is fluoro.

Particular examples of compounds of formula (IIId) are:

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

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

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

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

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

N- (4-aminomethyl-2,6-difluoro-phenyl) -ethanesulfonamide, HCl salt,

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

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

N- (4-aminomethyl-2,3,6-trifluoro-phenyl) -ethanesulfonamide, HCl salt,

(R) -N- [4- (1-amino-ethyl) -2,3,6-trifluoro-phenyl] ethenesulfonamide, an HCl salt or

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

Another aspect of the present invention relates to the use of a compound of formula (IIId) as described above as an intermediate in the preparation of a ligand compound VR1, preferably of general formula I, III or most preferably VI, as described in this application, in which W is hydrogen or fluorine.

Another embodiment of the present invention relates to a method for producing a compound of formula (IIId), in which R ₁ is C1-C3 alkyl, preferably methyl,

including:

(a) administration of a compound of formula (IIIe)

Формула (IIIe),

Formula (IIIe),

in which W has the meaning defined above,

in reaction with a compound of formula (IIIf)

Формула (IIIf),

Formula (IIIf),

in which A is I or Br, in the presence of an acid in a solvent, to obtain a compound of formula (IIIg)

Формула (IIIg),

Formula (IIIg)

in which W and A are as defined above;

(b) reacting a compound of Formula (IIIg) with a compound of formula (IIIh)

Формула (IIIh),

Formula (IIIh),

in which R ₁₃ is hydrogen or C1-C2 alkyl, preferably hydrogen, in the presence of a catalyst and a ligand in a solvent, to obtain a compound of formula (IIIi)

Формула (IIIi),

Formula (IIIi)

in which W and R ₁ are as defined above;

(c) reacting a compound of formula (IIIi) with a compound of Formula (IIIj)

Формула (IIIj),

Formula (IIIj),

in which R ₁₀ is as defined above, in the presence of a base in a solvent, then NaOH in a solvent, to obtain a compound of formula (IIIk)

Формула (IIIk),

Formula (IIIk),

in which W, R ₁ and R ₁₀ are as defined above;

(d) reacting a compound of Formula (IIIk) with (R) - (+) - 2-methyl-2-propanesulfinamide in the presence of an acid in a solvent, then NaBH ₄ in a solvent, and then HCl in a solvent, to obtain a compound of Formula (IIId ), in which W and R ₁₀ are as defined above, and R ₁ is C1-C3 alkyl, preferably methyl.

Another embodiment of the present invention relates to a method for producing a compound of formula (IIId) in which R ₁ is hydrogen,

including:

(a) administration of a compound of formula (IIIg)

Формула (IIIg),

Formula (IIIg)

in which W and A are as defined above, reacting with CuCN in a solvent to give a compound of formula (IIIm)

Формула (IIIm),

Formula (IIIm),

in which W is as defined above;

(b) reacting a compound of formula (IIIm) with a compound of formula (IIIj)

Формула (IIIj),

Formula (IIIj),

in which R ₁₀ is as defined above, in the presence of a base in a solvent, then NaOH in a solvent, to obtain a compound of formula (IIIn)

Формула (IIIn),

Formula (IIIn)

in which W and R ₁₀ are as defined above;

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

Формула (IIId),

Formula (IIId)

in which W and R ₁₀ are as defined above, and R ₁ is hydrogen.

Next will be described methods of preparation and types of excipients, but the present invention is not limited to them.

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 , thinners, etc. For example, the compounds of the present invention may be dissolved in oils, propylene glycol or other solvents that are commonly used to prepare injection compositions. Suitable examples of carriers include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc. For topical administration, the compounds of the present invention may be formulated as an ointment or cream.

The compound of 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.

The compounds of the present invention can be formulated by dissolution, suspension or emulsification in a water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, esters higher fatty acid and propylene glycol. The compositions of the invention may include any of the usual additives, such as solvents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

The preferred dose level of the compounds of the present invention depends on various factors, including the condition and body weight of the patient, the severity of the particular disease, dosage forms, and the route and period of administration, but may accordingly be selected by one skilled in the art. The compounds of the present invention are preferably administered in an amount of from 0.001 to 100 mg / kg body weight per day, and more preferably from 0.01 to 30 mg / kg body weight per day. Doses can be administered once a day or several times a day with the division of the dose into parts. The compounds of the present invention are used in the pharmaceutical composition in an amount of 0.0001 ~ 10% by weight, and preferably 0.001 ~ 1% by weight, based on the total amount of the composition.

The pharmaceutical composition of the present invention may be administered to a mammal, such as a rat, mouse, domestic animal, human, or the like, in various ways. Routes of administration include oral and rectal administration; intravenous, intramuscular, subcutaneous, intrauterine, dural and intracerebroventricular injections.

Detailed Description of the Definitions of the Invention

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

“Alkyl” includes monovalent saturated aliphatic hydrocarbon groups. The hydrocarbon chain may be straight or branched. “Alkyl” preferably has 1-15 carbon atoms (“C1-C15 alkyl”), more preferably 1-10 carbon atoms (“C1-C10 alkyl”), even 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 groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tert-amyl and the like.

“Alkoxy” includes an —OR group in which R is “alkyl” as defined above. Particular examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1,2-dimethylbutoxy and the like.

“Alkoxyalkoxy” refers to the group —OROR ′ in which R and R ′ are the same or different “alkyl” groups as defined above.

“Alkoxyalkoxyalkyl” refers to the group —ROR'OR ″, in which R, R ′ and R ″ are the same or different “alkyl” groups as defined above.

“Alkoxyalkylamino” refers to the group —NH (ROR ′) in which 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.

, в которой n означает целое число от 0 до 8, и R обозначает "алкильную" группу, как определено выше.“Alkoxyalkynyl” refers to the group

in which n is an integer from 0 to 8, and R is an "alkyl" group, as defined above.

, в которой n означает целое число от 0 до 8, и R и R' являются одинаковыми или разными "алкильными" группами, как определено выше."Dialkylaminoalkynyl" refers to the group

in which n is 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 is an “alkyl” group as defined above.

“Alkenyl” includes monovalent olefinically unsaturated hydrocarbon groups that are straight or branched and have at least 1 double bond. “Alkenyl” preferably has 2-15 carbon atoms (“C2-C15 alkenyl”), more preferably 2-10 carbon atoms (“C2-C10 alkenyl”), even more preferably 2-8 carbon atoms (“C2-C8 alkenyl” ) or 2-6 carbon atoms (“C2-C6 alkenyl”), and in some cases even more preferably 2-5 carbon atoms (“C1-C5 alkenyl”), 2-4 carbon atoms (“C2-C4 alkenyl”) or only 2-3 carbon atoms (“C2-C3 alkenyl”). Examples of alkenyl groups include ethenyl (-CH = CH ₂ ), n-propenyl (-CH ₂ CH = CH ₂ ), isopropenyl (C (CH ₃ ) = CH ₂ ), and the like. A preferred "alkenyl" group is ethenyl (vinyl).

“Alkynyl” includes acetylene unsaturated hydrocarbon groups that are straight or branched and have at least 1 triple bond. “Alkynyl” preferably has 2-15 carbon atoms (“C2-C15 alkynyl”), more preferably 2-10 carbon atoms (“C2-C10 alkynyl”), even more preferably 2-8 carbon atoms (“C2-C8 alkynyl” ) or 2-6 carbon atoms (“C2-C6 alkynyl”), and in some cases even more preferably 2-5 carbon atoms (“C1-C5 alkynyl”), 2-4 carbon atoms (“C2-C4 alkynyl”) or only 2-3 carbon atoms (“C2-C3 alkynyl”). A preferred alkynyl group is ethynyl (acetylenyl).

“Alkylamino” includes the group —NHR ′ in which R ′ is alkyl groups as defined herein.

“Dialkylamino” includes the group —NR′R ″ in which R ′ and R ″ are alkyl groups as defined herein.

“Alkylsulfonyl” includes the radical —S (O) ₂ R, in which R is alkyl groups as defined herein. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

“Alkylthio” includes the radical —S — R, in which R is alkyl groups as defined herein, which may be substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH ₂ .

“Aryl” refers to an aromatic hydrocarbon radical. Examples of “aryl” radicals are phenyl, naphthyl, indenyl, azulenyl, fluorine or anthracene, with phenyl being preferred.

“Arylamino” refers to the group —NHAr, in which Ar represents “aryl” groups as defined above.

“Aryloxy” refers to the group —OAr, in which Ar is “aryl” groups as defined above.

“Carboxy” refers to the radical —C (═O) OH.

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

“Cycloalkoxy” refers to an —OR group in which R is “cycloalkyl” groups as defined above.

“Cycloalkylamino” refers to a —NHR group in which R is “cycloalkyl” groups as defined above.

“N-Cycloalkylamino-N-alkylamino” refers to a —NRR ′ group in which R are the same or different “alkyl” groups as defined above and R ′ are “cycloalkyl” groups as defined above.

“N-aryl-N-alkylamino” refers to the group —NRAr in which Ar is “aryl” groups as defined above, and R is “alkyl” groups as defined above.

“Oxacycloalkyl” refers to cyclic saturated aliphatic hydrocarbon groups with one oxygen atom at any position in the ring. The number of C atoms indicated in connection with this oxacycloalkyl group corresponds to the number of ring carbon atoms, for example, “C3-C6 oxacycloalkyl” refers to oxacycloalkyl with the number of ring atoms C from three to six and one O atom. Examples of “oxacycloalkyl” "Are oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc. If indicated, an “oxacycloalkyl” group may be unsubstituted or substituted with one or more alkyl groups, for example, C1-C6 alkyl groups, preferably C1-C3 alkyl groups, particularly preferably methyl groups. If “oxacycloalkyl” carries more than one alkyl substituent, these substituents can be attached to the same or to different ring-forming carbon atoms.

“Oxacycloalkyl-oxy” refers to an —OR group in which R is “oxacycloalkyl” groups as defined above.

“Cyano” refers to the radical —C≡N _.

"Ethenyl" refers to -CH = CH ₂ , which is also defined in this application as "vinyl".

“Ethinyl” refers to —C≡CH.

"Halogen" refers to fluorine, chlorine, bromine and iodine. Preferred halogen groups are fluorine or chlorine.

“Haloalkyl” includes an “alkyl” group as defined above, substituted with one or more halogens, which may be the same, for example, in trifluoromethyl or pentafluoroethyl, or which may be different.

“Heteroaryl” refers to an aromatic 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, isothiazolyl, triazolyl, oxadiazol, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzothiazolinyl, quinoline, quinoline, quinoline, quinoline, carbazolyl, wherein single ring systems, and especially pyridinyl and imidazolyl, are preferred.

“Heteroarylamino” refers to the group —NHAr ′ in which Ar ′ is a “heteroaryl” group as defined above.

“Heteroaryloxy” refers to the group —OAr ′ in which Ar ′ is a “heteroaryl” group as defined above.

“Hydroxy” refers to —OH.

“Hydroxyalkyl” includes an “alkyl” group as defined above substituted with one or more hydroxyl groups.

“Nitro” refers to the radical —NO ₂ .

“Alkylpiperazinyl” refers to a piperazine ring which carries “alkyl” as a substituent, the piperazinyl ring being preferably bonded to both “alkyl” and the second attachment position via nitrogen atoms.

“Piperazinyl” includes a piperazinyl ring which can be bonded via any C atom, as well as via a nitrogen atom, with bonding via one of the nitrogen atoms being preferred.

“Pyrrolidinyl” includes a pyrrolidine ring, which may be bonded via any C atom, as well as via a nitrogen atom, with bonding through its nitrogen atom being preferred.

“Morpholinyl” includes a morpholine ring, which may be bonded via any C atom, as well as via a nitrogen atom, with bonding through its nitrogen atom being preferred.

“Pyridinyl” includes a pyridine ring, which may be bonded by any C-atom in the same way as its nitrogen atom.

Any “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “heteroaryl”, “cycloalkyl”, “piperazinyl”, “piperidyl”, “morpholinyl” or “pyrrolidinyl”, as well as parts of larger groups such as “alkoxy”, “alkylsulfonyl”, “alkenyloxy”, “aryloxy”, “heteroaryloxy”, “cycloalkylamino”, etc., may be unsubstituted or substituted with one or more groups. Suitable substituents are, for example, halogen, hydroxyl unsubstituted or substituted with halogen C1-C5 alkoxy, unsubstituted or substituted one or more times with methyl and / or halogen C3-C8 cycloalkyl, C1-C5 alkyl, halogen (C1-C5) alkyl, amino cyano or nitro. Unless expressly stated otherwise, any “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “heteroaryl”, “cycloalkyl”, “piperazinyl”, “piperidyl”, “morpholinyl” or “pyrrolidinyl” (as well as parts larger group) is preferably unsubstituted.

An “isomer” includes especially optical isomers (for example, substantially pure enantiomers, substantially pure diastereomers and mixtures thereof) as well as conformational isomers (that is, isomers that differ only in their angles of at least one chemical bond), positional isomers ( especially tautomers) and geometric isomers (e.g. cis-trans isomers).

“Essentially pure”, for example, with respect to 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 at least about 99%, and particularly preferably at least about 99.5% (weight / weight) of the compound, for example, a particular enantiomer or diastereomer.

"Pharmaceutically acceptable" means not showing significant toxic effects when used in doses usually used for medical purposes, and in a way that can be tested or preferably tested by a regulatory agency of the Federal or state government, or which is included in the US Pharmacopeia or other generally accepted pharmacopeia for use in animals, and more specifically in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts 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, cyclopentane propionic 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, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid , trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed by replacing a proton of an acid present in the parent compound.

"Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which the compound of the invention is administered.

“Prevention” or “prophylaxis” refers to a reduction in the risk of acquiring a disease or disorder (that is, preventing a person from developing who may be susceptible or predisposed to the disease, but who does not yet experience or show symptoms of the disease, at least one of the clinical symptoms of the disease to disease, but not yet experiencing or showing symptoms of the disease).

"Patient" includes a person. The terms “person,” “patient,” and “face” are used interchangeably.

“Therapeutically effective amount” means an amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat a disease. A “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and age, body weight, etc. the patient.

"Treatment" of a disease or disorder refers, in one embodiment, to an improvement in the condition of the disease or disorder (ie, arresting or attenuating the development of the disease or at least one of its clinical symptoms). In another embodiment, “treatment” refers to an improvement in respect of at least one physical parameter that may not be distinguishable by the patient. In yet another embodiment, “treatment” refers to correcting a disease or disorder physically (eg, by stabilizing a visible symptom), physiologically (eg, by stabilizing a physical parameter), or both. In yet another embodiment, “treatment” refers to delaying the onset of a disease or disorder.

The method of carrying out the invention

The present invention is more specifically explained by 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-methanesulfonylamino-benzyl) acrylamide

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

To a solution of 6-tert-butyl-pyridin-3-carboxaldehyde (1.34 g, 8.75 mmol) prepared according to a known procedure in toluene was added methyl (triphenylphosphoranilidene) acetate (2.93 g), and the resulting mixture 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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 4/1) to give an ether product (1.56 g, 81%). The resulting ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed with ether. The aqueous phase was acidified with 1N. HCl and then extracted with CHCl ₃ , and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (1.00 g, 68 %).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.78 (d, 1H, J = 2.1 Hz), 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 ( s, 9H).

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

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (50 mg, 0.20 mmol) was reacted with 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid ( 40 mg), after purification by column chromatography (Hex / EtOAc = 1/2) 3- (6-tert-butyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) -acrylamide (75 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.70 (d, 1H, J = 2.1 Hz), 7.77 (dd, 1H, J = 2.1 and 8.1 Hz), 7, 64 (d, 1H, J = 15.6 Hz), 7.48 (m, 1H), 7.38 (d, 1H, J = 8.4 Hz), 7.13 (m, 2H), 6, 77 (s, 1H), 6.51 (d, 1H, J = 15.6 Hz), 6.43 (t, 1H), 4.54 (d, 2H, J = 6.0 Hz), 3, 02 (s, 3H); 1.38 (s, 9H).

ESI [M + H] ⁺ : 406.2.

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

N- (4-Aminomethyl-2-chloro-phenyl) methanesulfonamide, HCl salt (100 mg, 0.35 mmol) was reacted 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-methanesulfonylamino-benzyl) acrylamide (110 mg, 74%) after purification by column chromatography (Hex / EtOAc = 1/2).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.66 (d, 1H, J = 2.1 Hz), 7.74 (dd, 1H, J = 2.1 and 8.1 Hz), 7, 64 (d, 1H, J = 15.6 Hz), 7.57 (d, 1H, J = 8.7 Hz), 7.41 (d, 1H, J = 2.1 Hz), 7.36 ( d, 1H, J = 8.1 Hz), 7.24 (dd, 1H, J = 2.1 and 8.7 Hz), 6.82 (s, 1H), 6.48 (d, 1H, J = 15.6 Hz), 6.42 (t, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.00 (s, 3H), 1.37 (s, 9H).

ESI [M + H] ⁺ : 422.2.

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

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (70 mg, 0.25 mmol) was reacted with 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (52 mg), obtaining after purification by column chromatography (Hex / EtOAc = 1/2) 3- (6-tert-butyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro- 4-methanesulfonylamino-benzyl) acrylamide (63 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.71 (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 (s, 1H), 7.16 (dd, 1H, J = 2 , 1 and 11.0 Hz), 6.64 (s, 1H), 6.52 (d, 1H, J = 16.0 Hz), 6.47 (t, 1H), 4.51 (d, 2H , J = 6.0 Hz), 3.45 (s, 1H), 3.24 (s, 3H), 1.38 (s, 9H).

ESI [M + H] ⁺ : 430.1.

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

N- (4-Aminomethyl-2-vinyl-phenyl) methanesulfonamide, HCl salt (70 mg, 0.28 mmol) was reacted with 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid ( 52 mg), after purification by column chromatography (Hex / EtOAc = 1/2) 3- (6-tert-butyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-vinyl-benzyl) -acrylamide (62 mg, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.36 (m, 2H), 7.23 (m, 2H), 6, 90 (dd, 1H, J = 11.0 and 17.0 Hz), 6.70 (s, 1H), 6.48 (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 Hz), 4.54 (d, 2H, J = 5.7 Hz), 2.98 (s, 3H); 1.37 (s, 9H).

ESI [M + H] ⁺ : 414.2.

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

N- (4-Aminomethyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (100 mg, 0.40 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3- yl) -acrylic acid (121 mg) obtained in accordance with the known procedure, obtaining, after purification by chromatography on columns (CH ₂ Cl ₂ / MeOH = 20/1) N- (3-fluoro-4-methanesulfonylamino-benzyl) -3 - (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (118 mg, 66%).

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 9.13 (s, 1H), 8.32 (t, 1H), 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 (m, 4H); 3.13 (s, 3H).

ESI [M + H] ⁺ : 503.1.

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

N- (4-Aminomethyl-2-vinyl-phenyl) methanesulfonamide, HCl salt (70 mg, 0.27 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (81 mg), obtained after purification by column chromatography (CH ₂ Cl ₂ / MeOH = 20/1) N- (4-methanesulfonylamino-3-vinyl-benzyl) -3- (2-morpholin-4 -yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (55 mg, 45%).

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 8.92 (s, 1H), 8.18 (s, 1H), 7.97 (d, 1H, J = 7.8 Hz) 7.83 (d, 1H, J = 16.0 Hz), 7.73 (s, 1H), 7.44 (m, 3H), 7.33 (dd, 1H, J = 11.0 and 17 0 Hz), 6.83 (d, 1H, J = 16.0 Hz), 5.93 (d, 1H, J = 17.0 Hz), 6.55 (d, 1H, J = 11.0 Hz), 4.69 (d, 2H, J = 5.1 Hz), 4.01 (m, 4H), 3.50 (m, 4H), 3.09 (s, 3H).

ESI [M + H] ⁺ : 511.1.

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

N- (4-Aminomethyl-2-chloro-phenyl) -methanesulfonamide, HCl salt (62 mg, 0.22 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (67 mg), obtained after purification by column chromatography (CH ₂ Cl ₂ / MeOH = 20/1) N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4 -yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (93 mg, 91%).

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 8.37 (s, 1H), 8.27 (t, 1H), 7.99 (d, 1H, J = 7.8 Hz) 7.86 (d, 1H, J = 15.9 Hz), 7.72 (d, 1H, J = 8.4 Hz), 7.62 (m, 1H), 7.44 (m, 2H) 6.84 (d, 1H, J = 15.9 Hz), 4.68 (d, 2H, J = 5.7 Hz), 4.04 (m, 4H), 3.52 (m, 4H) 3.19 (s, 3H).

ESI [M + H] ⁺ : 519.1.

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

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, an HCl salt (100 mg, 0.35 mmol) were reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (116 mg), obtained after purification by column chromatography (Hex / EtOAc = 1/2) N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- ( 2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide (120 mg, 74%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.76 (d, 1H, J = 7.8 Hz), 7.71 (d, 1H, J = 15.6 Hz), 7.24 (m, 3H), 6.42 (d, 1H, J = 15.6 Hz), 6.32 (s, 1H), 6.06 (t, 1H), 4.59 (d, 2H, J = 6.3 Hz), 3.85 (m, 4H), 3.34 (m, 4H), 3.05 (s, 3H), 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-methanesulfonylamino-benzyl) acrylamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (17.8 mg, 0.052 mmol) was reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 3/2), the target compound (14 mg, 61, 8%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.70 (d, 1H, J = 15.6 Hz), 7.61 (d, 1H, J = 9.3 Hz), 7.51 (m, 1H), 7.13 (m, 2H), 6.90 (d, 1H, J = 7.8 Hz), 6.84 (d, 1H, J = 15.6 Hz), 6.61 (s broad ., 1H), 6.10 (s broad, 1H), 4.54 (d, 2H, J = 6 Hz), 4.01 (s, 3H), 3.02 (s, 3H), 1, 33 (s, 9H).

ESI [M + H] ⁺ : 436.1.

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

N- (4-Aminomethyl-2-fluoro-6-vinyl-phenyl) methanesulfonamide, HCl salt (84 mg, 0.30 mmol) was reacted with 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (62 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2) 3- (6-tert-butyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino 5-vinyl-benzyl) acrylamide (34 mg, 26%).

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 8.68 (d, 1H, J = 2.4 Hz), 8.09 (s, 1H), 7.78 (dd, 1H, J = 2.1 and 8.4 Hz), 7.61 (s, 1H), 7.56 (d, 1H, J = 15.9 Hz), 7.35 (d, 1H, J = 8.4 Hz), 7.33 (s, 1H), 7.12 (dd, 1H, J = 14.8 and 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 (s, 9H).

ESI [M + H] ⁺ : 432.2.

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

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (82.4 mg, 0.30 mmol) was reacted 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, obtained after purification by column chromatography (Hex / EtOAc = 1/1) target compound (51.2 mg, 37.6%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.70 (d, 1H, J = 15.9 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.30 (s, 1H), 7.17 (m, 1H), 6.91 (d, 1H, J = 7.8 Hz), 6.69 (d, 1H, J = 15.6 Hz), 6.41 (s, 1H). 6.02 (s broad, 1H), 4.53 (d, 2H, J = 6 Hz), 4.02 (s, 3H), 3.47 (s, 1H), 3.26 (s, 3H ), 1.34 (s, 9H).

ESI [M + H] ⁺ : 460.1.

Example 12: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, an HCl salt (100 mg, 0.22 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (108 mg), after purification by chromatography on columns (Hex / EtOAc = 1/2) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- ( 2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide (190 mg, 100%).

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 9.31 (s, 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 (s, 1H), 7.18 (d, 1H, J = 10.8 Hz), 6.71 (d, 1H, J = 15.6 Hz), 4.38 (d, 2H, J = 5.7 Hz), 4.14 (s, 1H), 3 76 (m, 4H); 3.22 (m, 4H); 3.04 (s, 3H).

ESI [M + H] ⁺ : 527.2.

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

N- (4-Aminomethyl-3-fluoro-phenyl) methanesulfonamide, HCl salt (32 mg, 0.12 mmol) and NMP (0.05 ml) were added in 20 ml of THF. The mixture was stirred for 10 minutes. DMTMM (51 mg, 0.18 mmol) and 2- (2-piperid-1-yl-6-chloro-pyridin-3-yloxy) -acetic acid (20 mg, 0.092 mmol) were added to the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with ethyl acetate (30 ml × 3) and H ₂ O (30 ml). The combined organic layer was washed with sat. NaHCO ₃ (30 ml) and brine (30 ml) were dried using MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography to give a white solid (11 mg).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.87 (d, J = 15.9 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.12 (m, 2H), 6.39 (broad, 1H), 6.51 (d, J = 9.0 Hz, 1H), 6.20 (d, J = 15.6 Hz), 6.00 (br, 1H), 5.53 (d, J = 6.3 Hz, 2H), 3.60 (m, 4H), 3.01 (s, 3H ), 1.65 (m, 6H).

ESI [M + H] ⁺ : 467.1.

Example 14: 3- (6-chloro-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

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

Methyl (triphenylphosphoranilidene) acetate (708 mg, 2.12 mmol) was added to 6-chloro-pyridin-3-carboxaldehyde (300 mg, 2.12 mmol) in toluene, and the solution was heated under reflux for 6 hours. The reaction mixture was diluted with EtOAc and then washed three times with H ₂ O, brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was chromatographed on a column to give 3- (6-chloro-pyridin-3-yl) -acrylic acid methyl ester (380 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.36 (d, 1H, J = 8.4 Hz), 6.48 (d, 1H, J = 15.9 Hz), 3.83 ( s, 3H).

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

3- (6-Chloro-pyridin-3-yl) -acrylic acid methyl ester (107 mg, 0.541 mmol) in THF was added to a 0.5N solution. LiOH (2 equiv.), And the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with Et ₂ O, neutralized with 1N. HCl to pH 5 ~ 7. The resulting solid was filtered and washed with H ₂ O, and then dried in vacuo to give 3- (6-chloro-pyridin-3-yl) -acrylic acid (80 mg, 80%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.64 (s, 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-pyridin-3-yl) -N- (3-ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (78.3 mg, 0.272 mmol) was suspended in THF and treated with triethylamine (30 mg, 0.299 mmol), and then the resulting mixture was stirred within 10 minutes 3- (6-chloro-pyridin-3-yl) -acrylic acid (50 mg, 0.272 mmol) was added to the reaction mixture, 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 sequentially with water, sat. NaHCO ₃ (x2), brine and then dried over anhydrous. Na ₂ SO _{4 was} filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the desired compound (26 mg, 23%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (s, 1H), 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 (s, 3H).

ESI [M + H] ⁺ : 408.0.

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

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

To 6-bromo-pyridine-3-carboxaldehyde (300 mg, 1.61 mmol) in toluene was added methyl (triphenylphosphoranilidene) 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 with H ₂ O, brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was chromatographed on a column to give 3- (6-bromo-pyridin-3-yl) -acrylic acid methyl ester (380 mg, 97%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.47 (d, 1H, J = 2.4 Hz), 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), 6.49 (d, 1H, J = 15.9 Hz), 3.81 ( s, 3H).

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

0.5N was added to 3- (6-bromo-pyridin-3-yl) -acrylic acid methyl ester (120 mg, 0.495 mmol) in THF. LiOH solution (2 equiv.) and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H ₂ O, then washed three times with Et ₂ O and neutralized with 1N. HCl to pH 5 ~ 7. The resulting solid was filtered and washed with H ₂ O, and then dried in vacuo to give 3- (6-bromo-pyridin-3-yl) -acrylic acid (100 mg, 88%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.67 (d, 1H, J = 2.1 Hz), 8.11 (dd, 1H, J = 8.4, 2.1 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.59 (d, 1H, J = 15.9 Hz), 6.71 (d, 1H, J = 15.9 Hz).

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

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (63 mg, 0.219 mmol) was suspended in THF and treated with triethylamine (25 mg, 0.241 mmol), and then the resulting mixture was stirred for 10 min. 3- (6-Bromo-pyridin-3-yl) -acrylic acid (50 mg, 0.219 mmol) was added to the reaction mixture, 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 sequentially with water, sat. NaHCO ₃ (× 2) and brine and then dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The crude residue was recrystallized (EtOAc / n-hexane) to give the title compound (71 mg, 72%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.42 (s, 1H), 8.77 (t, 1H, J = 6.0 Hz), 8.60 (d, 1H, J = 2 4 Hz), 7.96 (dd, 1H, J = 8.1, 1.8 Hz), 7.70 (d, 1H, J = 8.1 Hz), 7.48 (d, 1H, J = 15.9 Hz), 7.28 (s, 1H), 7.27 (d, 1H, J = 8.7 Hz), 6.81 (d, 1H, J = 15.9 Hz), 4, 50 (s, 1H), 4.39 (d, 2H, J = 5.7 Hz), 3.06 (s, 3H).

ESI [M + H] ⁺ : 452.0.

Example 16: 3- (6-chloro-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (51 mg, 0.21 mmol) was suspended in THF and treated with triethylamine (23 mg, 0.22 mmol), and then the resulting mixture was stirred for 10 min. To the reaction mixture was added 3- (6-chloro-pyridin-3-yl) -acrylic acid (37 mg, 0.21 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 sequentially with water, sat. NaHCO ₃ (x2), brine and then dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give the title compound (74 mg, 96%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (s, 1H), 8.74 (t, 1H, J = 6.0 Hz), 8.62 (d, 1H, J = 2 4 Hz), 8.07 (dd, 1H, J = 6.0, 2.4 Hz), 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 (s, 3H).

ESI [M + H] ⁺ : 384.0.

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

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (41.2 mg, 0.162 mmol) was reacted with 3- (6-tert-butyl-4-trifluoromethyl-pyridin-3-yl) -acrylic acid (1.0 eq., 44.2 mg), DMTMM (1.0 equiv., 44.8 mg) and NMP (1.2 equiv., 22 ml) in THF, obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (48 mg, 62.6%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.84 (s, 1H), 7.93 (d, 1H, J = 15.3 Hz), 7.57 (s, 1H), 7.52 ( t, 1H), 7.14 (m, 1H), 6.60 (s broad, 1H), 6.45 (d, 1H, J = 15.6 Hz), 6.24 (s broad, 1H ), 6.50 (s broad, 1H), 4.54 (d, 2H, J = 6.0 Hz), 3.03 (s, 3H), 1.39 (s, 9H).

ESI [M + H] ⁺ : 474.2.

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

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (11.2 mg, 0.04 mmol) was reacted 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, receiving, after purification by column chromatography (Hex / EtOAc = 3/2), the target compound (6 mg, 30.2%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.85 (s, 1H), 7.95 (d, 1H, J = 13.5 Hz), 7.58 (s, 1H), 7.32 ( c broad., 1H). 7.20 (d, 1H, J = 12.6 Hz), 6.05 (s broad, 1H), 4.54 (d, 1H, J = 6.0 Hz), 3.49 (s, 1H ), 3.27 (s, 3H), 1.40 (s, 9H).

ESI [M + H] ⁺ : 498.2.

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

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

3- (6-Bromo-pyridin-3-yl) -acrylic acid methyl ester (180 mg, 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 with H ₂ O, brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was chromatographed on a column to give 3- (6-piperid-1-yl-pyridinyl-3-yl) -acrylic acid methyl ester (60 mg, 33%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 ( s, 3H), 3.64-3.61 (m, 4H), 1.66-1.60 (m, 6H).

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

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (25.2 mg, 0.099 mmol) was suspended in THF and treated with triethylamine (11 mg, 0.108 mmol), and then the resulting mixture was stirred for 10 minutes. To the reaction mixture was added 3- (6-piperid-1-yl-pyridinyl-3-yl) -acrylic acid (23 mg, 0.099 mmol), then after 10 minutes DMTMM (30 mg, 0.108 mmol). The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed sequentially with water, sat. NaHCO ₃ (× 2), brine and then dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the title compound (15 mg, 35%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.25 (d, 1H, J = 2.7 Hz), 7.59 (dd, 1H, J = 6.0, 2.7 Hz), 7, 52 (d, 1H, J = 15.9 Hz), 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 (s, 1H, broad), 4.53 (d, 2H, J = 6.0 Hz), 3.62-3.59 (m, 4H), 3.01 (s, 3H), 1.65-1.64 (m, 6H).

ESI [M + H] ⁺ : 433.2.

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

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (183 mg, 0.719 mmol) was suspended in THF and treated with triethylamine (80 mg, 0.791 mmol), and then the resulting mixture was stirred for 10 min. (6-Chloro-pyridin-3-yloxy) -acetic acid (164 mg, 0.719 mmol) was added to the reaction mixture, 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 sequentially with water, sat. NaHCO ₃ (× 2), brine and then dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the desired compound (225 mg, 65%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (s, 1H), 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 (s, 3H).

ESI [M + H] ⁺ : 428.0.

Example 21: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, an HCl salt (50 mg, 0.22 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin- 3-yl) -acrylic acid (55 mg), obtained after purification by column chromatography (Hex / EtOAc = 1/2) N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholine- 4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide (37 mg, 39%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.78 (d, 1H, J = 8.1 Hz), 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 (s, 1H) , 6.10 (t, 1H), 4.38 (d, 2H, J = 6.6 Hz), 3.85 (m, 4H), 3.35 (m, 4H), 3.21 (s, 3H).

ESI [M + H] ⁺ : 521.1.

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

N- (4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl) methanesulfonamide, an HCl salt (80 mg, 0.25 mmol) was reacted with 3- (2-morpholin-4-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (76 mg), obtained after purification by column chromatography (Hex / EtOAc = 1/2) N- (3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzyl) -3- ( 2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide (56 mg, 39%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.71 (s, 1H), 8.21 (t, 1H), 7.65 (d, 1H, J = 7.8 Hz), 7.49 ( d, 1H, J = 15.6 Hz), 7.29 (s, 1H), 7.22 (d, 1H, J = 9.9 Hz), 7.07 (d, 1H, J = 7.8 Hz), 6.48 (d, 1H, J = 15.6 Hz), 4.36 (d, 2H, J = 6.0 Hz), 3.67 (m, 4H), 3.18 (m, 4H), 3.02 (s, 3H).

ESI [M + H] ⁺ : 571.

Example 23: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (6-morpholin-4-yl-pyridin-3-yl) -acrylamide

Stage 1: 3- (6-Morpholin-4-yl-pyridin-3-yl) -acrylic acid methyl ester

3- (6-Bromo-pyridin-3-yl) -acrylic acid methyl ester (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 with H ₂ O, brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was chromatographed on a column to give 3- (6-morpholin-4-yl-pyridin-3-yl) -acrylic acid methyl ester (40 mg, 21%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.27 (d, 1H, J = 2.4 Hz), 7.68 (dd, 1H, J = 6.0, 2.4 Hz), 7, 59 (d, 1H, J = 15.9 Hz), 6.62 (d, 1H, J = 9.3 Hz), 6.25 (d, 1H, J = 15.3 Hz), 3.82- 3.78 (m, 7H); 3.61-3.57 (m, 4H).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (6-morpholin-4-yl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (20 mg, 0.072 mmol) were suspended in THF and treated with triethylamine (11 mg, 0.108 mmol), and then the resulting mixture was stirred for 10 min. To the reaction mixture was added 3- (6-morpholin-4-yl-pyridin-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 sequentially with water, sat. NaHCO ₃ (× 2), brine and then dried over anhydrous. Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the desired compound (8 mg, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.39 (s, 1H), 8.52 (t, 1H, J = 5.4 Hz), 8.24 (s, 1H), 7, 74 (d, 1H, J = 8.7 Hz), 7.34 (d, 1H, J = 15.9 Hz), 7.22-7.19 (m, 2H), 6.84 (d, 1H , J = 9.3 Hz), 6.45 (d, 1H, J = 15.9 Hz), 4.46 (s, 1H), 4.31 (d, 2H, J = 5.7 Hz), 3.63-3.62 (m, 4H), 3.48-3.47 (m, 4H), 3.01 (s, 3 H).

ESI [M + H] ⁺ : 459.

Example 24: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 in accordance with a procedure similar to that described in the previous examples from 2-chloro-6-trifluoromethylnicotinic acid at total yield 54%.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.81 (m, 2H), 7.18 (d, 1H, J = 7.5 Hz), 6.45 (d, 1H, J = 16.2 Hz), 3.31 (m, 4H), 1.72 (m, 6H).

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

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, an HCl salt (139 mg, 0.50 mmol) were reacted with 3- (2-piperid-1-yl-6-trifluoromethyl- pyridinyl-3-yl) -acrylic acid (150 mg), obtained after purification by column chromatography (Hex / EtOAc = 1/1) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- ( 2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl) acrylamide (132 mg, 50%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.72 (m, 2H), 7.30 (s, 1H), 7.16 (m, 2H), 6.44 (s, 1H), 6, 43 (d, 1H, J = 15.6 Hz), 6.10 (s, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3, 30 (m, 4H); 3.26 (s, 3H); 1.65 (m, 6H).

ESI [M + H] ⁺ : 525.

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

3- (6-Chloro-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (15 mg, 0.413 mmol) was added to pyrrolidine (0.5 ml), and the mixture was stirred in for 12 hours at 90 ° C. The resulting residue was dissolved in EtOAc, then washed three times with H ₂ O and neutralized with 1 N. HCl to pH 5 ~ 7. The resulting solution was washed with brine and then dried over anhydrous. Na ₂ SO _{4 was} filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the desired compound (4 mg, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ, 8.41 (t, 1H, J = 6.0 Hz), 8.15 (s, 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), 6.43 (d, 1H, J = 9.3 Hz), 6.36 (d, 1H, J = 15.6 Hz ), 4.29 (d, 2H, J = 5.7 Hz), 3.85-3.75 (m, 4H), 2.92 (s, 3H), 3.48-3.47 (m, 4H).

ESI [M + H] ⁺ : 419.

Example 26: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3- il) -acrylic acid (150 mg), after purification by column chromatography (Hex / EtOAc = 1/1) N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-piperid-1-yl- 6-trifluoromethyl-pyridinyl-3-yl) acrylamide (175 mg, 70%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.70 (m, 2H), 7.50 (t, 1H, J = 8.1 Hz), 7.12 (m, 3H), 6.65 ( s, 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), 3.02 (s, 3H), 1.70 (m, 6H).

ESI [M + H] ⁺ : 501.

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

A suspension of N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (32 mg, 0.069 mmol) and 10% Pd / C (3 mg) in MeOH was reacted under a hydrogen pressure of 40 psi. The reaction mixture was filtered through celite and then concentrated under reduced pressure to obtain N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3- sludge) propionamide (22 mg, 69%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.61 (d, 1H, J = 6.9 Hz), 7.27 (d, 1H, J = 8.4 Hz), 7.10 (m, 2H), 6.51 (s, 1H), 6.21 (s, 1H), 4.42 (d, 2H, J = 5.1 Hz), 3.86 (m, 4H), 3.20 ( m, 4H), 3.07 (m, 2H), 3.03 (s, 3H), 2.63 (m, 2H), 2.22 (d, 3H, J = 2.4 Hz).

ESI [M + H] ⁺ : 519.

Example 28: 2- (2-bromo-6-tert-butyl-pyridin-3-yloxy) -N- (3-fluoro-4-methanesulfonylamino-benzyl) -acetamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (72 mg, 0.25 mmol) was reacted with (2-bromo-6-tert-butyl-pyridin-3-yloxy) -acetic acid (64 mg), DMTMM (1, 2 eq., 83 mg) and NEt ₃ (2.5 eq., 90 μl) in THF, to obtain the desired compound (71 mg, 58.2%) after purification by column chromatography (Hex / EtOAc = 1/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.56 (m, 1H), 7.24 (m, 2H), 7.11 (m, 3H), 6.48 (broad s, 1H), 4.58 (s, 2H), 4.55 (d, 2H, J = 6 Hz), 3.03 (s, 3H), 1.33 (s, 9H).

ESI [M + H] ⁺ : 488.

Example 29: 2- (6-tert-butyl-pyridin-3-yloxy) -N- (3-fluoro-4-methanesulfonylamino-benzyl) -acetamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (158 mg, 0.62 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy) -acetic acid (130 mg), DMTMM (1.2 eq., 206 mg) and NEt ₃ (2.5 eq., 220 μl) in THF, obtaining the target compound (165 mg, 65%) after purification by column chromatography (Hex / EtOAc = 1/3).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.33 (d, 1H, J = 0.6 Hz), 7.38 (m, 1H), 7.21 (s broad, 1H), 6, 96 (m, 2H), 6.88 (m, 2H), 4.71 (s, 2H), 4.52 (d, 2H, J = 6 Hz), 2.99 (s, 3H), 1, 47 (s, 9H).

ESI [M + H] ⁺ : 409.

Example 30: 2- (6-tert-butyl-2-chloro-pyridin-3-yloxy) -N- (3-fluoro-4-methanesulfonylamino-benzyl) -acetamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (21 mg, 0.08 mmol) was reacted with (6-tert-butyl-2-chloro-pyridin-3-yloxy) -acetic acid (1.0 eq., 20 mg ), DMTMM (1.2 equiv., 27 mg) and NMM (1.5 equiv., 14 μl) in THF, obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (10 mg, 28 , 2%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.55 (m, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 7.13 (m, 2H), 7, 10 (s broad, 1H), 6.50 (s broad, 1H), 4.59 (s, 2H), 4.54 (d, 2H, J = 6.3 Hz), 3.03 (s , 3H); 1.33 (s, 9H).

ESI [M + H] ⁺ : 444.

Example 31: N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (2-hydroxymethyl-6-methyl-pyridin-3-yloxy) -acetamide

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

(2-Hydroxymethyl-6-methyl-pyridin-3-yloxy) -acetic acid (200 mg) was obtained in accordance with a procedure similar to that described above from 2,6-lutidin-α ² , 3-diol with a total yield of 51% .

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.24 (d, 1H, J = 8.1 Hz), 7.10 (d, 1H, J = 8.1 Hz), 4.73 ( s, 2H); 4.54 (s, 2H); 2.40 (s, 3H).

Stage 2: Synthesis of N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (2-hydroxymethyl-6-methyl-pyridin-3-yloxy) -acetamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (270 mg, 1.00 mmol) was reacted with (2-hydroxymethyl-6-methyl-pyridin-3-yloxy) -acetic acid ( 200 mg), after purification by column chromatography (Hex / EtOAc = 10/1) N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (2-hydroxymethyl-6-methyl-pyridin-3-yloxy) -acetamide (350 mg, 88%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.69 (t, 1H), 7.29 (m, 2H), 7.09 (m, 3H), 5.10 (t, 1H), 4.66 (s, 2H), 4.60 (d, 2H, J = 5.4 Hz), 4.31 (d, 2H, J = 6.3 Hz), 2.99 (s, 3H), 2.40 (s, 3H).

ESI [M + H] ⁺ : 398.

Example 32: N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (6-trifluoromethyl-pyridin-3-yloxy) -acetamide

Stage 1: Synthesis of (6-trifluoromethyl-pyridin-3-yloxy) -acetic acid

(6-Trifluoromethyl-pyridin-3-yloxy) -acetic acid (410 mg) was obtained according to a procedure similar to that described above from 2-trifluoromethyl-5-hydroxypyridine in a total yield of 93%.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.29 (d, 1H, J = 2.7 Hz), 7.75 (d, 1H, J = 8.7 Hz), 7.34 ( dd, 1H, J = 2.7 and 8.7 Hz), 4.33 (s, 2H).

Stage 2: Synthesis of N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (6-trifluoromethyl-pyridin-3-yloxy) -acetamide

N- (4-Aminomethyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (270 mg, 1.00 mmol) was reacted with (6-trifluoromethyl-pyridin-3-yloxy) -acetic acid (221 mg), obtaining, after recrystallization from Hex / EtOAc, N- (3-fluoro-4-methanesulfonylamino-benzyl) -2- (6-trifluoromethyl-pyridin-3-yloxy) -acetamide (54 mg, 88%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.52 (s, 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 (s, 2H), 4.33 (d, 2H, J = 6.3 Hz), 2.99 (s, 3H).

ESI [M + H] ⁺ : 422.

Example 33: 2- (6-tert-butyl-5-chloro-pyridin-3-yloxy) -N- (3-fluoro-4-methanesulfonylamino-benzyl) -acetamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (192 mg, 0.751 mmol) was reacted with (6-tert-butyl-5-chloro-pyridin-3-yloxy) -acetic acid (183 mg), DMTMM (1.1 eq. ., 229 mg) and NMM (1.2 equiv., 100 μl) in THF to obtain the target compound (102 mg, 30.6%) after purification by column chromatography (Hex / EtOAc = 1/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.18 (d, 1H, J = 1.8 Hz), 7.56 (t, 1H), 7.10 (m, 2H), 7.07 ( m, 1H), 6.71 (s broad, H), 6.50 (s wide, 1H), 4.60 (s, 2H), 4.54 (d, 2H, J = 6 Hz), 3.03 (s, 3H); 1.38 (s, 9H).

ESI [M + H] ⁺ : 444.

Example 34: 2- (6-tert-butyl-pyridin-3-yloxy) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -acetamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (120 mg, 0.43 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy) -acetic acid (90 mg), DMTMM (1.1 eq., 131 mg) and NMP (1.2 eq., 60 μl) in THF, obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound ( 62 mg, 33.3%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.36 (d, 1H, J = 1.8 Hz), 7.22 (s broad, 1H), 7.18 (m, 1H), 7, 06 (m, 1H), 6.89 (tf, 1H), 6.64 (s, 1H), 4.68 (s, 2H), 4.51 (d, 2H, J = 6 Hz), 3, 46 (s, 1H), 3.23 (s, 3H), 1.47 (s, 9H).

ESI [M + H] ⁺ : 434.

Example 35: 2- (6-chloro-pyridin-3-yloxy) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -acetamide

Stage 1: (6-chloro-pyridin-3-yloxy) -acetic acid ethyl ester

To a suspension of 6-chloro-pyridin-3-ol (1000 mg, 7.72 mmol) and bromoethyl acetate (1933 mg, 11.57 mmol) in CH ₃ CN was added Cs ₂ CO ₃ (3772 mg, 11.57 mmol) . The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed three times with H ₂ O and brine, and then dried with MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was chromatographed on a column to give (6-chloro-pyridin-3-yloxy) -acetic acid ethyl ester (1.5 g, 90%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.07 (dd, 1H, J = 2.7, 0.9 Hz), 7.27-7.23 (m, 2H), 4.65 (s , 2H), 4.28 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz).

Stage 2: (6-chloro-pyridin-3-yloxy) -acetic acid

Ethyl (6-chloro-pyridin-3-yloxy) -acetic acid (800 mg, 3.71 mmol) in THF was added to a solution of 0.5 N. LiOH (2 equiv.), And the mixture was stirred for 1.5 hours at room temperature. The resulting residue was dissolved in H ₂ O, then washed three times with Et ₂ O and neutralized with 1 N. HCl to pH 5 ~ 7. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ , and concentrated in vacuo to give (6-chloro-pyridin-3-yloxy) -acetic acid (300 mg, 36%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.05 (d, 1H, J = 3.3 Hz), 7.43-7.35 (m, 2H), 4.74 (s, 2H).

Stage 3: 2- (6-chloro-pyridin-3-yloxy) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -acetamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide (74.3 mg, 0.266 mmol) was suspended in THF and treated with triethylamine (27 mg, 0.266 mmol), and then the resulting mixture was stirred for 10 min (6-Chloro-pyridin-3-yloxy) -acetic acid (50 mg, 0.266 mmol) was added to the reaction mixture, 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 sequentially with water, sat. NaHCO ₃ (× 3) and brine and then dried over anhydrous. MgSO ₄ was filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH ₂ Cl ₂ ) to give the title compound (25 mg, 25%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.13 (dd, 1H, J = 3.0, 0.9 Hz), 7.34-7.24 (m, 3H), 7.14 (dd , 1H, J = 10.5, 2.1 Hz), 6.90 (s, 1H, broad), 6.44 (s, 1H), 4.58 (s, 2H), 4.53 (s , 1H), 4.50 (d, 2H, J = 6.3 Hz), 3.26 (s, 3H).

ESI [M + H] ⁺ : 412.

Example 36: 3- (2-bromo-6-tert-butyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (116 mg, 0.454 mmol) was reacted with 3- (2-bromo-6-tert-butyl-pyridin-3-yl) -acrylic acid (1.0 eq., 129 mg ), DMTMM (1.0 equiv., 126 mg) and NMP (1.2 equiv., 60 μl) in THF, obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (72 mg, 32 ,8%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.15 (m, 2H), 6.46 (s broad, 1H), 6.36 (d, 1H, J = 15 , 3 Hz), 6.01 (s broad, 1H), 4.56 (d, 2H, J = 6.3 Hz), 3.03 (s, 3H), 1.35 (s, 9H).

Example 37: 3- (2-bromo-6-tert-butyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, an HCl salt (41.2 mg, 0.148 mmol) were reacted with 3- (2-bromo-6-tert-butyl-pyridine- 3-yl) -acrylic acid (1.0 eq., 42 mg), DMTMM (1.0 eq., 41 mg) and NMP (1.2 eq., 20 μl) in THF, obtained after purification by column chromatography (Hex / EtOAc = 3/2) target compound (42 mg, 55.8%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.90 (d, 1H, J = 15.9 Hz), 7.73 (d, 1H, J = 7.5 Hz), 7.31 (m, 1H), 7.28 (s, 1H), 7.17 (dd, 1H, J = 2.1 Hz and 1.5 Hz), 6.41 (s, 1H), 6.37 (d, 1H, J = 15.7 Hz), 6.09 (s broad, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3.27 (s, 3H), 1.35 (s, 9H).

Example 38: 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 hydrochloride (95 mg, 0.97 mmol) in CH ₂ Cl ₂ (3 ml) was added N-methylmorpholine ( 0.106 ml, 0.97 mmol). The mixture was stirred for 5 minutes, then N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (185 mg, 0.97 mmol) was added. The mixture was stirred for 3 hours at room temperature and then diluted with EtOAc and water. The organic layer was washed with 1 N. HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was dried in vacuo to give 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (220 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.86 (d, 1H, J = 7.8 Hz), 7.69 (d, 1H, J = 7.8 Hz), 3.52 (s, 3H), 3.42 (s, 3H).

Stage 2: 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 1.489 mmol) and diethylamine (0.773 ml, 7.44 mmol) in DMF (4 ml) was added K ₂ CO ₃ (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 twice with 1 N. HCl (30 ml) and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed to give 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 88%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.50 (d, 1H, J = 7.5 Hz), 6.90 (d, 1H, J = 7.5 Hz), 3.54-3, 41 (m, 7H), 3.29 (s, 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 1.0 M LiAlH ₄ (0.108 ml, 0.108 mmol) at - 78 ° C. The mixture was heated to -20 ° C for 30 minutes. The reaction mixture was diluted with Et ₂ O and washed twice with 1 N. KHSO ₄ and brine, dried over anhydrous. MgSO _{4 was} filtered and concentrated under reduced pressure. The product was dried in vacuo to give 2-diethylamino-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (43 mg, 75%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.98 (s, 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), 1.27 (t, 6H, J = 7.2 Hz).

Stage 4: 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester

To a solution of 2-diethylamino-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (39 mg, 0.147 mmol) in toluene was added methyl (triphenylphosphoranilidene) acetate (73.8 mg, 0.221 mmol), and the resulting mixture was heated at 90 ° C within 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 10/1) to give 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (40 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 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 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (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 resulting residue was dissolved in H ₂ O and then washed three times with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ , and concentrated in vacuo to give 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (33 mg, 87%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.79 (d, 1H, J = 18.0 Hz), 7.74 (d, 1H, J = 8.1 Hz), 7.09 (d, 1H, J = 7.5 Hz), 6.37 (d, 1H, J = 15.6 Hz), 3.38 (q, 4H, J = 7.2 Hz), 1.22 (t, 6H, J = 7.2 Hz).

Stage 6: 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

To a suspension of N- (4-aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (476 mg, 1.66 mmol) in THF (5 ml) was added N-methylmorpholine (0.365 ml, 3.32 mmol). The mixture was stirred for 5 minutes, then 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (434 mg, 1.51 mmol) and 4- (4,6-dimethoxy [1, 3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMTMM, 459 mg, 1.66 mmol). The mixture was stirred overnight at room temperature and 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 CH ₂ Cl ₂ to give the title compound (645 mg, 83%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H) 6.35 (d, 1H, J = 15.3 Hz), 6.10 (s, 1H), 4.51 (d, 2H, J = 5.7 Hz), 3.47 (s, 1H) 3.38 (q, 4H, J = 7.2 Hz); 3.26 (s, 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-difluoro-4-methanesulfonylamino-benzyl) acrylamide

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

To a solution of 6-tert-butyl-pyridin-3-yl-carbaldehyde (1.34 g, 8.75 mmol) prepared according to a known procedure in toluene was added methyl (triphenylphosphoranilidene) 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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 4/1) to give an ether product (1.56 g, 81%). The resulting ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed with ether. The aqueous phase was acidified with 1 N. HCl and then extracted with CHCl ₃ , and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (1.00 g , 68%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.78 (d, 1H, J = 2.1 Hz), 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 ( s, 9H).

Stage 2: 3- (6-tert-butyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (50 mg, 0.18 mmol) was reacted with 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (37 mg), after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (60 mg, 79%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): 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) 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 (s, 3H); 1.37 (s, 9H).

ESI [M + H] ⁺ : 424.

Example 40: 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 (step 3).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1.109 mg, 4.128 mmol) was reacted with 1.0 M LiAlH ₄ (0.5 eq.) To give 2-chloro-6-trifluoromethyl -pyridin-3-yl-carbaldehyde (844 mg, 97%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 10.49 (s, 1H), 8.41 (d, 1H, J = 7.8 Hz), 7.79 (d, 1H, J = 7.8 Hz).

Stage 2: 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester

The target compound was obtained according to the General procedure described in example 38 (step 4).

2-Chloro-6-trifluoromethyl-pyridin-3-yl-carbaldehyde (844 mg, 4.027 mmol) was reacted with methyl (triphenylphosphoranilidene) acetate (1.62 g, 4.83 mmol) to obtain 3- (2 -chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (900 mg, 84%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.08 (d, 1H, J = 8.1 Hz), 7.99 (d, 1H, J = 15.9 Hz), 7.67 (d, 1H, J = 8.1 Hz), 6.53 (d, 1H, J = 15.9 Hz), 3.86 (s, 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 (step 5).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (200 mg, 0.753 mmol) was reacted with 0.5 N. LiOH (2 equiv.), Yielding 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (189 mg, 99%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.56 (d, 1H, J = 8.1 Hz), 7.93 (d, 1H, J = 8.1 Hz), 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-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

The target compound was obtained according to the General procedure described in example 38 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (228 mg, 0.795 mmol) was reacted with 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (200 mg, 0.795 mmol), obtaining the target compound (340 mg, 90%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.47 (s, 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), 7.67 (d, 1H, J = 15.6 Hz), 7.31-7.27 (m, 2H), 6.90 (d, 1H, J = 15.6 Hz), 4.52 (s, 1H), 4.41 (d, 2H, J = 5.7 Hz), 3.07 (s, 3H).

ESI [M + H] ⁺ : 476.

Example 41: N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylamide

Stage 1: synthesis of methyl 6-methoxy-4-trifluoromethyl nicotinate

To a solution of 6-hydroxy-4-trifluoromethyl nicotinic acid (400 mg, 1.93 mmol) in chloroform (25 ml) was added silver carbonate (1.06 g, 3.84 mmol) and methyl iodide (2.4 ml, 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 column chromatography (EtOAc / Hexanes = 1/10 to 1/1) to give methyl 6-methoxy-4-trifluoromethyl nicotinate (300 mg, 69.9%) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.79 (s, 1 H), 7.08 (m, 1 H), 4.04 (s, 3 H), 3.93 (s, 3 H )

Stage 2: synthesis of 6-methoxy-4-trifluoromethyl-3-pyridinomethanol

To a cooled (-78 ° C) solution of methyl 6-methoxy-4-trifluoromethyl nicotinate (300 mg, 1.35 mmol) in toluene (10 ml) was added diisobutyl aluminum hydride (DIBAL, 1M / toluene, 1.35 ml). The mixture was slowly warmed to room temperature and stirred for 2 days. Additional DIBAL (1M / toluene, 2 ml) was added to complete the reaction. After stirring for 4 hours, the mixture was quenched with a saturated aqueous solution of ammonium chloride (1 ml), dried over anhydrous magnesium sulfate, filtered through celite and concentrated under reduced pressure to obtain 6-methoxy-4-trifluoromethyl-3-pyridinomethanol (220 mg, 78 , 6%). The crude product was used directly in the following Swern oxidation.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.41 (s, 1H), 7.00 (s, 1H), 4.80 (s, 2 H), 3.98 (s, 3H).

Stage 3: synthesis of 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde

To a cooled (-78 ° C) solution of dimethyl sulfoxide (DMSO) (0.15 ml, 2.13 mmol) in dichloromethane (2 ml) was added oxalyl chloride (0.14 ml, 1.60 mmol), and the mixture was stirred for 10 minutes. To the reaction mixture was added 6-methoxy-4-trifluoromethyl-3-pyridinomethanol (220 mg, 1.06 mmol) in dichloromethane (4 ml). After stirring at -40 ° C for 50 minutes, the mixture was treated with triethylamine (0.44 ml, 3.16 mmol), stirred for 90 minutes, warmed to room temperature and quenched with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (162 mg, 74.4%) as a solid. The crude product was used directly in the following Swern oxidation.

¹ H NMR (300 MHz, CDCl ₃ ): δ 10.25 ~ 10.23 (m, 1H), 8.91 (s, 1H), 7.07 (s, 1H), 4.08 (s, 3H )

Step 4: Synthesis of 3- (6-methoxy-4-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester

To a solution of 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (150 mg, 0.73 mmol) in toluene (8 ml) was added methyl (triphenylphosphoranilidene) acetate (270 mg, 0.81 mmol). The mixture was heated at 110 ° C. overnight, cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / hexanes = 1/4) to obtain 3- (6-methoxy-4-trifluoromethylpyridin-3-yl) -acrylic acid methyl ester (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 hexanes to give 60 mg in the form of a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.52 (s, 1H), 7.90 ~ 7.84 (m, 1H), 7.03 (s, 1H), 6.38 (d, 1H , J = 15.9 Hz), 4.01 (s, 3H), 3.83 (s, 3H).

Stage 5: synthesis of 3- (6-methoxy-4-trifluoromethylpyridin-3-yl) -acrylic acid

To a solution of 3- (6-methoxy-4-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (trans-isomer, 59 mg, 0.23 mmol) in THF (2 ml) was added 1N. LiOH (2 ml). The mixture was stirred at room temperature for 2 hours, acidified to pH 5 using 3 N. HCl and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3- (6-methoxy-4-trifluoromethylpyridin-3-yl) -acrylic acid (50 mg, 89.6%) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.57 (s, 1H), 7.80 ~ 7.94 (m, 1H), 7.05 (s, 1H), 6.41 (d, 1H , J = 15.9 Hz), 4.02 (s, 3H).

Step 6: Synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylamide

To a suspension of 3-ethynyl-5-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (67 mg, 0.24 mmol) in THF (2 ml) was added N-methylmorpholine (40 μl, 0.36 mmol). After stirring for 5 minutes, 3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylic acid (50 mg, 0.20 mmol) dissolved in THF (3 ml) was added, and 4- (4.6- dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride 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 EtOAc / hexane to give N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylamide (75 mg, 66.2 %) in the form of a solid.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.83 (t, 1H, J = 6 Hz), 8.70 (d, 1H, J = 0.6 Hz), 7.59 ~ 7, 54 (m, 1H), 7.28 ~ 7.24 (m, 3H), 6.71 (d, 1H, J = 15.6 Hz), 4.49 (s, 1H), 4.38 (d , 2H, J = 5.7 Hz), 3.96 (s, 3H), 3.05 (s, 3H).

ESI [M + H] ⁺ : 472

Example 42: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

To a suspension of 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (50 mg, 0.105 mmol) in CH ₃ OH (1 ml) was added dropwise at 0 ° C. 30% NaOCH ₃ in CH ₃ OH (3 equiv.). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and washed twice with 1 N. HCl and brine, dried over anhydrous. MgSO _{4 was} filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the desired compound (10 mg, 20%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 8.86 (s, 1H, broad), 8.19 (d, 1H, J = 7.5 Hz) 7.60-7.54 (m, 2H), 7.29-7.26 (m, 2H), 6.96 (d, 1H, J = 15.9 Hz), 4.51 (s, 1H ), 4.40 (d, 2H, J = 5.7 Hz), 4.01 (s, 3H), 3.07 (s, 3H).

ESI [M + H] ⁺ : 472.

Example 43: N- (3-fluoro-4-methanesulfonylaminobenzyl) -3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylamide

To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (40 mg, 0.16 mmol) in THF (4 ml) was added N-methylmorpholine (26 μl, 0.24 mmol). After stirring for 5 minutes, 3- [6-methoxy-4- (trifluoromethyl) pyridin-3-yl] acrylic acid (32 mg, 0.13 mmol) dissolved in THF (3 ml) was added, and 4- (4 , 6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride 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 EtOAc / hexane to give N- (3-fluoro-4-methanesulfonylaminobenzyl) -3- (6-methoxy-4-trifluoromethylpyridin-3-yl) acrylamide (30 mg, 42.7%) in the form solid matter.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.80 (t, 1H, J = 5.7 Hz), 8.68 (s, 1H), 7.59 ~ 7.53 (m, 1H ), 7.35 (t, 1H, J = 8.4 Hz), 7.24 (s, 1H), 7.22 ~ 7.18 (m, 1H), 7.14 ~ 7.11 (m, 1H), 6.70 (d, 1H, J = 15.6 Hz), 4.38 (d, 2H, J = 5.7 Hz), 3.96 (s, 3H), 3.00 (s, 3H).

ESI [M + H] ⁺ : 448.

Example 44: 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

The target compound was obtained according to the General procedure described in example 38 (step 6).

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (467 mg, 1.84 mmol) was reacted with 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (420 mg, 1.67 mmol) to obtain the target compound (737 mg, 98%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s, 1H), 8.92 (t, 1H, J = 5.7 Hz), 8.41 (d, 1H, J = 8 , 1 Hz), 8.02 (d, 1H, J = 8.1 Hz), 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 (d, 1H, J = 15.9 Hz) 4.40 (d, 2H, J = 5.4 Hz); 3.00 (s, 3H).

ESI [M + H] ⁺ : 452.

Example 45: N- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide (35 mg, 0.077 mmol) and methoxyethylamine (5 equiv.) DMF (0.5 ml) was added K ₂ CO ₃ (5 equiv.). The mixture was stirred for 12 hours at 110 ° C. The reaction mixture was diluted with EtOAc and then washed twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give the title compound (10 mg, 26%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.67 (m, 3H), 7.13 (t, 2H, J = 9.3 Hz), 6.92 (d, 1H, J = 7.8 Hz), 6.57 (s, 1H), 6.37 (d, 1H, J = 15.3 Hz), 6.11 (s, 1H, broad), 5.25 (s, 1H, broad. ), 4.55 (d, 2H, J = 6.0 Hz), 3.74-3.69 (m, 2H), 3.65-3.58 (m, 2H), 3.38 (s, 3H), 3.01 (s, 3H).

ESI [M + H] ⁺ : 491.

Example 46: missing

Example 47: 3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

The target compound was obtained according to the General procedure described in example 45 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (27 mg, 0.06 mmol) was reacted with diethylamine (5 eq. .), obtaining the target compound (14 mg, 48%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.75 (d, 1H, J = 15.9 Hz), 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 (s, 1H), 6, 35 (d, 1H, J = 15.3 Hz), 6.04 (t, 1H, J = 5.7 Hz), 4.55 (d, 2H, J = 6.0 Hz), 3.38 ( q, 4H, J = 7.2 Hz), 3.02 (s, 3H), 1.19 (t, 6H, J = 7.2 Hz).

ESI [M + H] ⁺ : 489.

Example 48: missing

Example 49: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-pyridin-3-yl) -acrylamide

Stage 1: synthesis of 2-morpholin-4-yl-pyridin-3-carbaldehyde

To a solution of 2-chloro-pyridin-3-yl-carbaldehyde (0.5 g, 3.53 mmol) in DMF was added morpholine (0.37 ml, 1.2 equiv.), And the reaction mixture was stirred at 90 ° C. within 6 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 4/1) to give the product (0.38 g, 56.1%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 10.04 (s, 1H), 8.40 (m, 1H), 8.01 (m, 1H), 6.96 (m, 1H), 3, 88 (m, 4H); 3.47 (m, 4H).

Stage 2: synthesis of 3- (2-morpholin-4-yl-pyridin-3-yl) -acrylic acid

To a solution of 2-morpholin-4-yl-pyridin-3-yl-carbaldehyde (0.38 g, 1.98 mmol) in toluene was added methyl (triphenylphosphoranilidene) acetate (0.793 g, 1.2 eq.), And the resulting mixture 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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 4/1) to give an ethereal product (0.35 g, 71.2%). The resulting ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed with ether. The aqueous phase was acidified with 1 N. HCl and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 3- (6-tert-butyl-pyridin-3-yl) -acrylic acid (0.25 g, 75.7%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.33 (m, 1H), 7.90 (d, 1H, J = 15.9 Hz), 7.77 (m, 1H), 6.97 ( m, 1H), 6.42 (d, 1H, J = 15.9 Hz), 3.86 (m, 4H), 3.27 (m, 4H).

Stage 3: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (96 mg, 0.35 mmol) was reacted with 3- (2-morpholin-4-yl-pyridin-3- il) -acrylic acid (81 mg, 1.0 equiv.), obtained after purification by column chromatography (Hex / EtOAc = 1/10) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3 - (2-morpholin-4-yl-pyridin-3-yl) -acrylamide (105 mg, 63.6%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.29 (m, 1H), 7.80 (d, 1H, J = 15.3 Hz), 7.30 (s broad, 1H), 7, 18 (m, 1H), 6.94 (m, 1H), 6.43 (s broad, 1H), 6.40 (d, 1H, J = 15.3 Hz), 5.99 (s broad. , 1H), 4.54 (d, 1H, J = 6.0 Hz), 3.88 (m, 4H), 3.49 (s, 1H), 3.27 (s, 3H), 3.26 (m, 4H).

ESI [M + H] ⁺ : 459.

Example 50: N- (5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (57 mg, 0.22 mmol) was reacted with 3- (2-morpholin-4-yl-pyridin-3-yl) -acrylic acid (52 mg, 1.0 equiv.), after purification by column chromatography (Hex / EtOAc = 1/7) N- (5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4- yl-pyridin-3-yl) acrylamide (67 mg, 69.5%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s broad, 1H), 6.40 (d, 1H, J = 15.6 Hz), 5.92 (s broad, 1H), 4.56 (d, 1H, J = 6.0 Hz), 3.88 (m, 4H), 3.26 (m, 4H), 3.03 (s , 3H).

ESI [M + H] ⁺ : 435.

Example 51: 3- (6-tert-butyl-2-chloro-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (30 mg, 0.11 mmol), was reacted with 3- (6-tert-butyl-2-chloro-pyridine -3-yl) -acrylic acid (30 mg, 1.0 equiv.), Obtained after purification by column chromatography (Hex / EtOAc = 2/3) 3- (6-tert-butyl-2-chloro-pyridin-3 -yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (19 mg, 37.9%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.93 (d, 1H, J = 15.6 Hz), 7.23 (m, 3H), 7.00 (m, 1H), 6.42 ( c broad., 1H), 6.41 (d, 1H, J = 15.6 Hz), 6.08 (c broad., 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H); 3.26 (s, 3H); 1.36 (s, 9H).

ESI [M + H] ⁺ : 464.

Example 52: 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 equiv.), NMM (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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 4/1) to give the product (0.824 g, 76.9%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.53 (s, 1H), 7.63 (s, 1H), 3.47 (s, 3H), 3.38 (s, 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, 3.07 mmol) was dissolved in anhydrous THF and cooled to -78 ° C and added in a syringe 1.0 M LAH (1.54 ml), and then the resulting mixture was stirred for 30 minutes. 1 M NaOH (2 ml) and H ₂ O (2 ml) were carefully added to the reaction mixture, and then the resulting solution was stirred for 30 minutes. The mixture was dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo to give 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, 3.07 mmol) in toluene was added methyl (triphenylphosphoranilidene) acetate (1.13 g, 1.1 eq.), And the resulting mixture 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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 8/1) to give an ether product (0.56 g, 68.4%). The resulting ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed with ether. The aqueous phase was acidified with 1 N. HCl and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -acrylic acid (0.43 g, 81.4%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.77 (s, 1H), 7.97 (m, 1H), 7.65 (s, 1H), 6.52 (d, 1H, J = 15 9 Hz).

Step 3: Synthesis of 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (123 mg, 0.40 mmol) was reacted with 3- (6-chloro-4-trifluoromethyl-pyridin-3- il) -acrylic acid (105 mg, 1.0 equiv.), after purification by chromatography on columns (Hex / EtOAc = 3/2) 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N - (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (136 mg, 73.3%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.70 (s, 1H), 7.90 (m, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 7, 18 (m, 1H), 6.46 (d, 1H, J = 15.3 Hz), 6.14 (s broad, 1H), 4.54 (d, 2H, J = 6.0 Hz), 3.49 (s, 1H); 3.27 (s, 3H).

ESI [M + H] ⁺ : 476.

Example 53: 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (56 mg, 0.22 mmol) was reacted with 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -acrylic acid (54 mg, 1.0 equiv.), after purification by column chromatography (Hex / EtOAc = 3/2) 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N- (5- fluoro-4-methanesulfonylamino-benzyl) acrylamide (66 mg, 65.7%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.69 (s, 1H), 7.89 (m, 1H), 7.57 (d, 1H, J = 15.3 Hz), 7.54 ( m, 1H), 7.15 (m, 2H), 6.53 (s broad, 1H), 6.46 (d, 1H, J = 15.3 Hz), 6.13 (s broad, 1H ), 4.56 (d, 2H, J = 5.7 Hz), 3.03 (s, 3H).

ESI [M + H] ⁺ : 452.

Example 54: missing

Example 55: N- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) -acrylamide (40 mg, 0.088 mmol) in pyrrolidine (0.4 ml) DMF (0.5 ml) was added. The mixture was stirred for 12 hours at 110 ° C. The reaction mixture was diluted with EtOAc and then washed twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give the title compound (40 mg, 93%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.95 (s, 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), 7.13-7.08 (m, 2H), 6.43 (d, 1H, J = 15.3 Hz), 4.37 (d, 1H, J = 6.0 Hz), 3, 48-3.41 (m, 4H), 3.00 (s, 3H), 1.88-1.86 (m, 4H).

ESI [M + H] ⁺ : 487.

Example 56: N- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) -acrylamide (40 mg, 0.088 mmol) in pyrrolidin-3-ol (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 twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give the title compound (40 mg, 91%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.72 (t, 1H, J = 5.7 Hz), 7.80 (d, 1H, J = 7.5 Hz), 7.68 ( d, 1H, J = 15.3 Hz), 7.34 (t, 1H, J = 8.1 Hz), 7.19 (d, 1H, J = 11.1 Hz), 7.12-7, 08 (m, 2H), 4.98 (d, 1H, J = 2.7 Hz), 4.37 (d, 2H, J = 6.0 Hz), 4.31 (s, 1H, broad) 3.74-3.64 (m, 4H); 3.00 (s, 3H); 1.98-1.84 (m, 2H).

ESI [M + H] ⁺ : 503.

Example 57: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (137 mg, 0.49 mmol) was reacted with 3- (6-trifluoromethyl-pyridin-3-yl) -acrylic acid (107 mg, 1.0 equiv.), after purification by column chromatography (Hex / EtOAc = 2/3) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (6- trifluoromethyl-pyridin-3-yl) -acrylamide (105 mg, 48.5%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.44 (s broad, 1H), 8.97 (s, 1H), 8.84 (m, 1H), 8.28 (m, 1H ), 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 (s, 1H), 3.02 (s, 3H).

ESI [M + H] ⁺ : 442.

Example 58: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (59 mg, 0.23 mmol) was reacted with 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -acrylic acid (50 mg, 1.0 equiv.), after purification by column chromatography (Hex / EtOAc = 4/5) 3- (6-chloro-4-trifluoromethyl-pyridin-3-yl) -N- (3- fluoro-4-methanesulfonylamino-benzyl) acrylamide (47 mg, 49.0%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s broad, 1H), 8.97 (s, 1H), 8.83 (m, 1H), 8.28 (m, 1H ), 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), 4.41 (d, 2H, J = 6.0 Hz), 3.00 (s, 3H).

ESI [M + H] ⁺ : 418.

Example 59: 3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Stage 1: synthesis of 3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -acrylic acid

3- (6-tert-butyl-2-chloro-pyridin-3-yl) -acrylic acid methyl ester (0.281 g, 1.11 mmol) was dissolved in DMF and morpholine (0.15 ml), NEt ₃ ( 0.31 ml) and palladium reagent (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 MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 8/1) to give 3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -acrylic acid methyl ester (76 mg, 0 25 mmol, 22.5%). Methyl ether was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and then washed with ether. The aqueous phase was acidified with 1 N. HCl and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) - acrylic acid (67 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.88 (d, 1H, J = 15.9 Hz), 7.68 (d, 1H, J = 8.1 Hz), 6.97 (d, 1H, J = 8.1 Hz), 6.38 (d, 1H, J = 15.9 Hz), 3.87 (m, 4H), 3.30 (m, 4H), 1.33 (s, 9H).

Step 2: Synthesis of 3- (6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (59 mg, 0.23 mmol) was reacted with 3- (6-tert-butyl-2-morpholin-4- yl-pyridin-3-yl) -acrylic acid (67 mg), obtained after purification by column chromatography (Hex / EtOAc = 3/2) 3- (6-tert-butyl-2-morpholin-4-yl-pyridin- 3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (60 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.78 (d, 1H, J = 15.9 Hz), 7.61 (m, 1H), 7.25 (m, 2H), 6.93 ( m, 1H), 6.41 (s broad, 1H), 6.35 (d, 1H, J = 15.9 Hz), 5.91 (s broad, 1H), 4.53 (d, 2H , J = 6.3 Hz), 3.86 (m, 4H), 3.48 (s, 1H), 3.29 (m, 4H), 3.26 (s, 3H), 1.32 (s , 9H).

ESI [M + H] ⁺ : 515.

Example 60: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

The target compound was obtained according to the General procedure described in example 42 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (40 mg, 0.088 mmol) was reacted with 30% NaOCH ₃ in CH ₃ OH to afford the title compound (39 mg, 98%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s, 1H), 8.82 (s, 1H, broad), 8.17 (d, 1H, J = 7.5 Hz) 7.59-7.54 (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), 6.95 (d, 1H, J = 15.9 Hz), 4.39 (d, 2H, J = 5.4 Hz), 4.00 (s, 3H), 3.00 (s, 3H).

ESI [M + H] ⁺ : 448.

Example 61: N- (3-fluoro-4-methanesulfonylamino-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 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (40 mg, 0.088 mmol) was reacted with 2-aminoethanol (excess) receiving the target compound (10 mg, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s, 1H), 8.72 (s, 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 (s, 1H), 6.98 (d, 1H, J = 7.2 Hz), 6.63 (d, 1H, J = 15.3 Hz), 4.68 (s, 1H), 4.40 (d, 2H, J = 4.5 Hz), 3.55-3.54 (m, 2H), 3.42-3.40 (m , 2H); 3.00 (s, 3H).

ESI [M + H] ⁺ : 477.

Example 62: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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

To a suspension of 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 twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give 3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylic acid (100 mg, 91%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 3.64-3.60 (m, 4H), 1.96-1.92 (m, 4H )

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (94 mg, 0.327 mmol) was reacted with 3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin- 3-yl) -acrylic acid (78 mg, 0.272 mmol) to obtain the target compound (110 mg, 80%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.44 (s, 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), 6.43 (d, 1H, J = 15.9 Hz), 4.52 (s, 1H), 4.38 (d, 2H, J = 5.7 Hz), 3.51-3.47 (m , 4H); 3.07 (s, 3H); 1.88-1.86 (m, 4H).

ESI [M + H] ⁺ : 511.

Example 63: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

To a suspension of 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (40 mg, 0.088 mmol) in 1-butanol (0.5 ml) K ₂ CO ₃ (5 equiv.) was added. The mixture was stirred for 12 hours at 110 ° C. The reaction mixture was diluted with EtOAc and then washed twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was recrystallized from CH ₂ Cl ₂ / n-hexane to give the title compound (40 mg, 93%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (s, 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) 4.42-4.38 (m, 4H), 3.00 (s, 3H), 1.83-1.73 (m, 2H), 1.47-1.40 (m, 2H), 0 94 (d, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 490.

Example 64: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-methyl-piperazin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (70 mg, 0.057 mmol) was reacted with N- methylpiperazine (30 μl), as in example 46, obtaining after recrystallization from a mixture of Hex / EtOAc the target compound (13 mg, 15%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.75 (d, 1H, J = 7.2 Hz), 7.72 (d, 1H, J = 15.3 Hz), 7.29 (s, 1H), 7.18 (m, 2H), 6.44 (d, 1H, J = 15.3 Hz), 6.12 (t, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3.39 (m, 4H), 3.26 (s, 3H), 2.59 (m, 4H), 2.35 (s, 3H).

ESI [M + H] ⁺ : 540.

Example 65: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

A mixture of 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 with 2 N. HCl solution. The aqueous phase was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 2/3) to give the desired compound (4.0 mg, 12%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (d, 1H, J = 15.6 Hz), 7.59 (d, 1H, J = 7.2 Hz), 7.21 (s, 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 (s, 1H), 4.47 (d, 2H, J = 5.7 Hz), 3.71 (m, 2H), 3.61 (m, 2H), 3.44 (s, 1H), 3.37 (s, 3H), 3.28 (s, 3H).

ESI [M + H] ⁺ : 515.

Example 66: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 NaH (19 mg, 0.47 mmol) was added. The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with 1 N. HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (21 mg, 92%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (d, 1H, J = 16.2 Hz), 4.49 (t, 2H, J = 6.6 Hz), 1.86-1.79 ( m, 2H), 1.53-1.47 (m, 2H), 1.00 (t, 3H, J = 7.5 Hz).

Stage 2: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

The target compound was obtained according to the General procedure described in example 38 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (25 mg, 0.087 mmol) was reacted with 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (21 mg, 0.73 mmol), obtaining the target compound (24 mg, 54%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.44 (s, 1H), 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 (s, 1H), 4.42-4.37 (m, 2H), 3.06 (s, 3H), 1.83 -1.73 (m, 2H), 1.50-1.42 (m, 2H), 0.94 (d, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 514.

Example 67: N- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide (70 mg, 0.155 mmol) was reacted with methoxyethanol to give the title compound ( 50 mg, 66%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (s, 1H), 8.82 (t, 1H, J = 5.7 Hz), 8.19 (d, 1H, J = 7 5 Hz), 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), 4.52 (t, 2H, J = 4.5 Hz), 4, 40 (d, 2H, J = 5.7 Hz), 3.74 (t, 2H, J = 4.5 Hz), 3.31 (s, 3H), 3.00 (s, 3H).

ESI [M + H] ⁺ : 492.

Example 68: N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide

To a solution of 2-methyl-6-trifluoromethylnicotinic acid (500 mg, 2.44 mmol) and N, O-dimethylhydroxylamine hydrochloride (285 mg, 2.92 mmol) in dichloromethane (10 ml) was added N-methylmorpholine (0.32 ml, 2.92 mmol) and N- (3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (EDC, 560 mg, 2.92 mmol). The mixture was stirred at room temperature for 2 hours and washed with 1 N HCl and water. Organic layer dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain an amount of N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide but in the form of an oil The crude product was used directly in the next reaction.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.77 (d, 1H, J = 7.5 Hz), 7.56 (d, 1H, J = 7.8 Hz), 3.44 (s broad ., 3H), 3.39 (s broad, 1H), 2.63 (s, 3H).

Stage 2: synthesis of 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde

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 aluminum hydride (LAH, 1M / THF, 1.23 ml). The mixture was stirred for 15 minutes and then heated to -10 ° C. After further stirring for 30 minutes, the mixture was quenched with saturated potassium hydrogen sulfate solution (1 ml) and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde quantitatively in the form of an oil. The crude product was used directly in the next reaction.

¹ H NMR (300 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 8.29 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.1 Hz), 2.61 (s, 3H).

Stage 3: synthesis of 3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylic acid

To a solution of 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde (440 mg, 2.32 mmol) in toluene (10 ml) was added methyl (triphenylphosphoranilidene) acetate (855 mg, 2.56 mmol). The mixture was heated at 110 ° C. overnight, cooled to room temperature, and 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 column chromatography (EtOAc / hexanes = 1/4) to give 3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylic acid methyl ester (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 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 EtOAc / hexanes to give 3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylic acid (trans-isomer, 200 mg, 56.4%) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.05 ~ 7.97 (m, 2H), 7.58 (d, 1H, J = 8.1 Hz), 6.47 (d, 1H, J = 15.9 Hz), 2.75 (s, 3H).

Step 5: Synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide

To a suspension of 3-ethynyl-5-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (73 mg, 0.26 mmol) in THF (5 ml) was added N-methylmorpholine (43 μl, 0.39 mmol). After stirring for 5 minutes, 3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylic acid (60 mg, 0.26 mmol) and 4- (4,6-dimethoxy [1,3,5] triazine were added -2-yl) -4-methylmorpholinium chloride 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 by recrystallization from EtOAc / hexane to give N- (3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide (89 mg, 75.5 %) in the form of a solid.

¹ H NMR (300 MHz, CDCl ₃ + DMSO-d ₆ ): δ 8.22 (s, 1H), 8.16 (t, 1H, J = 5.7 Hz), 7.94 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 15.6 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.33 (s, 1H), 7 19 (dd, 1H, J = 10.5, 1.8 Hz), 6.61 (d, 1H, J = 15.3 Hz), 4.50 (d, 2H, J = 5.7 Hz) 3.18 (s, 3H); 2.72 (s, 3H).

ESI [M + H] ⁺ : 456.

Example 69: N- (3-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide

Stage 1: synthesis of N- (3-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide

To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (67 mg, 0.26 mmol) in THF (5 ml) was added N-methylmorpholine (43 μl, 0.39 mmol). After stirring for 5 minutes, 3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylic acid (60 mg, 0.26 mmol) and 4- (4,6-dimethoxy [1,3,5] triazine were added -2-yl) -4-methylmorpholinium chloride 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 by recrystallization from EtOAc / hexane to give N- (3-fluoro-4-methanesulfonylaminobenzyl) -3- (2-methyl-6-trifluoromethylpyridin-3-yl) acrylamide (66 mg, 58.8%) in the form solid matter.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.95 ~ 7.88 (m, 2H), 7.56 ~ 7.51 (m, 2H), 7.18 ~ 7.11 (m, 2H) 6.51 (broad s, 1H), 6.41 (d, 1H, J = 15.6 Hz), 6.07 (t broad, 1H), 4.57 (d, 2H, J = 6 Hz), 3.03 (s, 3H), 2.72 (s, 3H.)

ESI [M + H] ⁺ : 432.

Example 70: 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Stage 1: synthesis of 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

60% NaH (24 mg, 3.0 equiv.) Was placed in a flask and 2-propanol (30 μl) in DMF (1 ml) was added in a syringe, stirred for a while, and finally 3- (2 -chloro-6-trifluoromethyl-4-yl-pyridin-3-yl) -acrylic acid (50 mg). The reaction mixture was stirred for 18 hours. After completion of the reaction according to the TLC test, the mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain crude 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (23 mg, 42%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.86 (m, 2H), 7.24 (m, 1H), 6.71 (d, 1H, J = 15.9 Hz), 5.49 ( m, 1H); 1.43 (m, 6H).

Step 2: Synthesis of 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (23 mg, 0.084 mmol) was reacted with 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (23 mg), after purification by column chromatography (Hex / EtOAc = 3/2) 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5- fluoro-4-methanesulfonylamino-benzyl) acrylamide (19 mg, 45%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.81 (m, 1H), 7.75 (d, 1H, J = 15.9 Hz), 7.29 (s, 1H), 7.20 ( m, 2H), 6.73 (d, 1H, J = 15.9 Hz), 6.44 (s, 1H), 6.12 (s broad, 1H), 5.48 (m, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.47 (s, 1H), 3.26 (s, 3H), 1.43 (m, 6H).

ESI [M + H] ⁺ : 500.

Example 71: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-benzyloxycarbonyl-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

L-Proline benzyl ester hydrochloride (96 mg, 2.0 equiv.) In DMF was placed in a flask and K ₂ CO ₃ (132 mg, 2.0 equiv.) Was added, stirred for some time and 3- (2 -chloro-6-trifluoromethyl-4-yl-pyridin-3-yl) -acrylic acid (50 mg). The reaction mixture was stirred for 18 hours. After completion of the reaction according to the TLC test, the mixture was diluted with EtOAc, washed with 1 N. HCl solution. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give crude 6-trifluoromethyl-pyridin-2-yl} -pyrrolidin-2-yl-carboxylic acid benzyl ester (45 mg). N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (30 mg, 0.11 mmol) was reacted with 6-trifluoromethyl-pyridin-2-yl} -pyrrolidin- benzyl ether 2-yl-carboxylic acid (45 mg) to obtain 1- {3- [2- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylcarbamoyl) vinyl] -6-trifluoromethyl-pyridin-2-yl benzyl ester } -pyrrolidin-2-yl-carboxylic acid (3.2 mg, 4.5%) after purification by column chromatography (EtOAc / MeOH = 10/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.81 (d, 1H, J = 15.6 Hz), 7.67 (m, 1H), 7.29 (s, 1H), 7.19 ( m, 5H), 6.92 (m, 1H), 6.86 (s broad, 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 (s, 1H), 3.26 (s, 3H), 2.38 (m, 2H); 2.25 (m, 2H); 2.02 (m, 3H).

Example 72: 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (30 mg, 0.057 mmol) was reacted with n- butylamine (500 μl), as in example 65, obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (3.6 mg, 12%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (d, 1H, J = 15.3 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.23 (s, 1H), 7.12 (dd, 1H, J = 1.8 and 10.8 Hz), 6.89 (d, 1H, J = 7.8 Hz), 6.64 (s, 1H), 6, 35 (d, 1H, J = 15.3 Hz), 6.24 (t, 1H), 5.04 (s, 1H), 4.48 (d, 2H, J = 6.0 Hz), 3, 50 (m, 2H), 3.46 (s, 1H), 3.27 (s, 3H), 1.61 (m, 2H), 1.36 (m, 2H), 0.95 (t, 3H , J = 7.2 Hz).

ESI [M + H] ⁺ : 513.

Example 73: 3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (30 mg, 0.057 mmol) was reacted with cyclopentylamine ( 500 μl), as in example 65, obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (2.5 mg, 8%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (d, 1H, J = 15.0 Hz), 7.58 (d, 1H, J = 7.5 Hz), 7.29 (s, 1H), 7.17 (dd, 1H, J = 2.1 and 10.8 Hz), 6.90 (d, 1H, J = 7.5 Hz), 6.46 (s, 1H), 6, 35 (d, 1H, J = 15.0 Hz), 6.07 (t, 1H), 4.82 (s, 1H), 4.53 (d, 2H, J = 6.3 Hz), 4, 41 (m, 1H), 3.49 (s, 1H), 3.27 (s, 3H), 2.17 (m, 2H), 1.70-1.30 (m, 6H).

ESI [M + H] ⁺ : 525.

Example 74: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

Mixture of 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 were stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and then acidified with 2 N. HCl solution. The aqueous phase was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 1/2) to give the desired compound (12 mg, 40%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.97 (d, 1H, J = 7.8 Hz), 7.83 (m, 2H), 7.71 (s, 1H), 7.31 ( m, 2H), 7.22 (dd, 1H, J = 1.8 and 10.5 Hz), 6.94 (d, 1H, J = 15.9 Hz), 4.54 (d, 2H, J = 6.0 Hz), 4.22 (d, 2H, J = 6.6 Hz), 3.64 (s, 1H), 3.18 (s, 3H), 2.18 (m, 1H), 1.04 (d, 6H, J = 6.6 Hz).

ESI [M + H] ⁺ : 514.

Example 75: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (86.6 mg, 0.344 mmol) was reacted with methoxyethanol to give 3- [2- (2-methoxy-ethoxy) -6 trifluoromethyl-pyridin-3-yl] acrylic acid (100 mg, 99%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 3H).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (45 mg, 0.156 mmol) was reacted with 3- [2- (2-methoxy-ethoxy) -6-trifluoromethyl- pyridin-3-yl] -acrylic acid (38 mg, 0.13 mmol) to obtain the target compound (47 mg, 70%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.44 (s, 1H), 8.85 (t, 1H, J = 6.0 Hz), 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), 4.40 (d, 2H, J = 6.0 Hz), 3.97 (s , 1H), 3.76-3.73 (m, 2H), 3.31 (s, 3H), 3.07 (s, 3H).

ESI [M + H] ⁺ : 516.

Example 76: 3- (2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Stage 1: 3- (2-butyl-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 -butyl lithium (2 equiv.). The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with 1 N. HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographed on a column to give 3- (2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl) acrylic acid (14 mg, 17%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.83 (d, 1H, J = 16.5 Hz), 7.51 (s, 1H), 6.35 (d, 1H, J = 16.5 Hz), 2.79-2.66 (m, 2H), 1.66-1.50 (m, 2H), 1.50-1.44 (m, 2H), 0.98 (t, 3H, J = 7.5 Hz).

Stage 2: 3- (2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

The target compound was obtained according to the General procedure described in example 38 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (13 mg, 0.044 mmol) was reacted with 3- (2-butyl-5-chloro-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (14 mg, 0.036 mmol) to give the desired compound (18 mg, 86%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 8.92 (t, 1H, J = 6.0 Hz), 7.92 (s, 1H), 7, 50 (d, 1H, J = 15.6 Hz), 7.30-7.29 (m, 2H), 6.55 (d, 1H, J = 15.9 Hz), 4.52 (s, 1H ), 4.41 (d, 2H, J = 5.7 Hz), 3.02 (s, 3H), 2.80-2.75 (m, 2H), 1.59-1.49 (m, 2H), 0.88 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 532.

Example 77: 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Stage 1: 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

2-Butanol (70.1 mg, 0.945 mmol) and sodium hydride (70 mg, 1.8 mmol) were added to DMF. The reaction mixture was stirred for 10 minutes and then 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (67 mg, 0.266 mmol) was added to the reaction mixture. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 1/1) to obtain the desired product (52 mg).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (hour, 1H, J = 6.0 Hz), 1.79 (m, 2H), 1.26 (m, 3H); 1.02 (m, 3H).

Stage 2: 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-ethenyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (35 mg, 0.13 mmol) was reacted with 3- (2-sec-butoxy-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (22 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (10 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.82 (d, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 15.6 Hz), 7.27 (d, 1H, J = 15.9 Hz), 7.21 (m, 3H), 6.73 (d, 1H, J = 15.6 Hz), 6.44 (s, 1H), 6.11 (t, 1H), 5.33 (hour, 1H, J = 6.3 Hz), 4.53 (d, 2H, J = 6.3 Hz), 3.48 (s, 1H), 3.26 (s, 3H), 1.37 (d, 3H, J = 6.0 Hz), 0.98 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 514.

Example 78: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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, 0.60 mmol) and sodium hydride (32 mg, 0.8 mmol) were added to DMF (15 ml). The reaction mixture was stirred for 10 minutes and then 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70 mg, 0.27 mmol) was added to the reaction mixture. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 1/1) to obtain the desired product (15 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.07 (d, 1H, J = 15.9 Hz), 8.04 (d, 1H, J = 7.5 Hz), 7.43 (m, 3H), 7.21 (m, 2H), 6.79 (d, 1H, J = 15.9 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-ethenyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (35 mg, 0.13 mmol) was reacted with 3- (2-phenoxy-6-trifluoromethyl-pyridin-3- il) -acrylic acid (17 mg), obtaining the target compound (22 mg, 75%) after purification by column chromatography (Hex / EtOAc = 1/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 6.37 ( t, 1H), 4.43 (d, 2H, J = 6.0 Hz), 3.32 (s, 1H), 3.22 (s, 3H).

ESI [M + H] ⁺ : 534.

Example 79: 3- [2- (tetrahydro-furan-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (50 mg, 0.11 mmol) and 3-hydroxytetrahydrofuran (18 μl, 0.22 mmol) was introduced into the reaction, as in example 72, to obtain the target compound (23 mg, 21%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 7.18 (dd, 1H, J = 2.1 and 10.8 Hz), 6.77 (d, 1H, J = 15 , 9 Hz), 6.51 (s, 1H), 6.41 (t, 1H), 5.74 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz), 4, 05 (m, 3H), 3.91 (m, 1H), 3.46 (s, 1H), 3.25 (s, 3H), 2.35 (m, 1H), 2.30 (m, 1H )

ESI [M + H] ⁺ : 528.

Example 80: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2-pyrazol-1-yl-6-trifluoromethyl-pyridin-3-yl] acrylamide

Stage 1: 3- (5-chloro-2-pyrazol-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

The target compound was obtained according to the General procedure described in example 66 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (100 mg, 0.397 mmol) was reacted with pyrazole to give 3- (5-chloro-2-pyrazol-1-yl-6 trifluoromethyl-pyridin-3-yl) -acrylic acid (100 mg, 99%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.84 (d, 1H, J = 0.6 Hz), 7.64 (d, 1H, J = 8.1 Hz), 5.52 (d, 1H, J = 2.7 Hz), 6.42 (d, 1H, J = 15.9 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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 (step 6).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (8.5 mg, 0.029 mmol) was reacted with 3- (5-chloro-2-pyrazol-1-yl- 6-trifluoromethyl-pyridin-3-yl) -acrylic acid (7 mg, 0.025 mmol) to obtain the target compound (9 mg, 70%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H) , 7.15-7.11 (m, 1H), 6.59-6.49 (m, 3H), 6.38 (d, 1H, J = 15.9 Hz), 4.46 (d, 2H , J = 6.0 Hz), 3.44 (s, 1H), 3.24 (s, 3H).

ESI [M + H] ⁺ : 534.

Example 81: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (pyridin-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-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 overnight. The reaction mixture was extracted with ethyl acetate (30 ml × 2) and water (30 ml). The combined organic layer was washed with H ₂ O (30 ml × 4) and brine (40 ml), dried with MgSO ₄ and then concentrated in vacuo. The residue was purified by column chromatography (hexane / ethyl acetate = 1/4) to obtain the target compound (46 mg, 82%).

¹ H NMR (300 MHz, acetone d ₆ ): δ 8.53 (d, 1H, J = 2.4 Hz), 8.45 (dd, 1H, J = 4.5, 1.2 Hz), 8 31 (d, 1H, J = 7.8 Hz), 8.00 (t broad, 1H), 7.83 (d, 1H, J = 15.9 Hz), 7.71 (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 (s, 3H).

Example 82: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluorophenoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Stage 1: 3- [2- (4-fluorophenoxy) -6-trifluoromethyl-pyridin-3-yl] acrylic acid

4-Fluorophenol (116 mg, 1.03 mmol) and sodium hydride (53 mg, 1.3 mmol) were added in DMF (7 ml). The reaction mixture was stirred for 10 minutes, and then 3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (132 mg, 0.52 mmol) was added to the reaction mixture. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex / EtOAc = 1/1) to obtain the desired product (57 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.00 (d, 1H, J = 15.9 Hz), 7.99 (d, 1H, J = 7.8 Hz), 7.36 (d, 1H, J = 7.8 Hz), 7.08 (m, 3H), 6.73 (d, 1H, J = 15.9 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluorophenoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-ethenyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (32 mg, 0.13 mmol) was reacted with 3- [2- (4-fluorophenoxy) -6-trifluoromethyl- pyridin-3-yl] -acrylic acid (25 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (42 mg, 67%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 7.03 (m, 4H), 6.79 (d, 1H, J = 15.6 Hz), 6.64 (t broad , 1H), 6.57 (s, 1H), 4.41 (d, 2H, J = 6.0 Hz), 3.37 (s, 1H), 3.16 (s, 3H).

Example 83: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-hydroxymethyl-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (17 mg, 0.06 mmol) was reacted with 2- (2-hydroxymethyl-pyrrolidin-1-yl) -6 -trifluoromethyl-pyridin-3-yl) -acrylic acid (19 mg, 0.06 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (15 mg, 46%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.88 (d, 1H, J = 15.6 Hz), 7.68 (m, 1H), 7.30 (s, 1H), 7.18 ( m, 1H), 7.03 (m, 1H), 6.44 (s, 1H), 6.20 (d, 1H, J = 15.0 Hz), 6.05 (s broad, 1H), 4.52 (d, 1H, J = 6.3 Hz), 3.79 (m, 6H), 3.41 (m, 3H), 3.27 (s, 3H).

Example 84: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2,2,2-trifluoro-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (69 mg, 0.25 mmol) was reacted with 2- (2,2,2-trifluoro-ethoxy) -6 trifluoromethyl-pyridin-3-yl-acrylic acid (78 mg, 0.26 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (73 mg, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 6.03 (s broad ., 1H), 4.90 (d, 2H, J = 8.1 Hz), 4.55 (d, 2H, J = 5.7 Hz), 3.89 (s, 1H), 3.26 ( s, 3H).

Example 85: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-pyrrolidin-1-yl) -4-trifluoromethyl-phenyl] acrylamide

Step 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-methoxypyrrolidine (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 twice with 1 N. HCl and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed to give 3- [2- (3-methoxy-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid (59 mg, 98%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 4.05 (t, 1H, J = 2.1 Hz), 3.89-3.58 ( m, 2H), 3.69-3.58 (m, 2H), 3.37 (s, 3H), 2.18-2.11 (m, 1H), 2.05-1.94 (m, 1H).

Stage 2: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-pyrrolidin-1-yl) -4-trifluoromethyl-phenyl] acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (16.6 mg, 0.057 mmol) was reacted with 3- [2- (3-methoxy-pyrrolidin-1-yl ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (15.2 mg, 0.048 mmol), after purification by recrystallization from N- (3-ethynyl-5-fluoro-4-methanesulfonylamino n-hexane / EtOAc mixture) -benzyl) -3- [2- (3-methoxy-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (18 mg, 58%).

¹ H NMR (300 MHz, DMSO): δ 9.45 (s, 1H, broad), 8.75 (t, 1H, J = 6.0 Hz), 7.83 (d, 1H, J = 7 8 Hz), 7.67 (d, 1H, J = 15.6 Hz), 7.28 (s, 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 (s, 1H), 4.38 (d, 2H, J = 5.7 Hz), 4.00 (d, 1H, J = 1.8 Hz), 3.71-3.12 (m, 7H), 3.06 (s, 3H), 2.00-1.92 (m , 2H).

Example 86: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) propionamide.

To a suspension of 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide (19.3 mg, 0.039 mmol) in 5% Pd / C (6 mg) CH ₃ OH (1.0 ml) was added. The mixture was purged three times with hydrogen gas (50 psi) and shaken for 40 minutes at room temperature. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude residue was chromatographed to give 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) propionamide (19 mg, 98%).

¹ H NMR (300 MHz, DMSO): δ 9.49 (s, 1H, broad), 8.43 (s, 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), 6.96 (d , 1H, J = 9.0 Hz), 4.31 (t, 2H, J = 3.3 Hz), 4.21 (d, 2H, J = 5.7 Hz), 2.87 (s, 3H ), 2.85 (t, 2H, J = 8.2 Hz), 2.51-2.47 (m, 2H), 1.77-1.68 (m, 2H), 1.50-1, 37 (m, 2H); 0.93 (t, 3H, J = 7.5 Hz).

Example 87: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2,2,2-trifluoro-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (41 mg, 0.16 mmol) was reacted with 2- (2,2,2-trifluoro-ethoxy) -6-trifluoromethyl-pyridine -3-yl-acrylic acid (50 mg, 0.16 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (53 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 7.15 (m, 2H), 6.78 (d, 1H, J = 16.2 Hz) 6.50 (s broad, 1H), 6.03 (s broad, 1H), 4.90 (q, 2H, J = 7.8 Hz), 4.57 (d, 2H, J = 5 7 Hz), 3.03 (s, 3H).

Example 88: 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (53 mg, 0.19 mmol) was reacted with 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (10 mg, 0.036 mmol), after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (12 mg, 69%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.68 (d, 1H, J = 15.0 Hz), 7.57 (d, 1H, J = 7.5 Hz), 7.48 (t, 1H, J = 8.4 Hz), 7.10 (m, 2H), 6.89 (d, 1H, J = 7.5 Hz), 6.80 (s, 1H), 6.37 (d, 1H, J = 15.0 Hz), 6.12 (t, 1H, J = 6.0 Hz), 6.95 (t, 1H, J = 5.4 Hz), 4.54 (d, 2H, J = 6.0 Hz), 3.50 (m, 2H), 3.03 (s, 3H), 1.61 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J = 7.5 Hz).

Example 89: 3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (53 mg, 0.19 mmol) was reacted with 3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (10 mg, 0.034 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (6.3 mg, 38%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (d, 1H, J = 15.3 Hz), 7.56 (m, 2H), 7.13 (m, 2H), 6.89 ( d, 1H, J = 7.8 Hz), 6.60 (s, 1H), 6.35 (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), 4.40 (m, 1H), 3.03 (s, 3H), 2.14 ( m, 2H), 1.67 (m, 4H), 1.44 (m, 2H).

Example 90: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (14.5 mg, 0.057 mmol) was reacted with 3- [2- (3-methoxy-pyrrolidin-1-yl) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (15 mg, 0.047 mmol), after purification by recrystallization from a mixture of n-hexane / CH ₂ Cl ₂ N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [ 2- (3-methoxy-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (22 mg, 76%).

¹ H NMR (300 MHz, DMSO): δ 9.55 (s, 1H, broad), 8.71 (t, 1H, J = 5.7 Hz), 7.81 (d, 1H, J = 7 5 Hz), 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), 4.38 (d, 1H, J = 6.0 Hz), 4.01 (s, 1H), 3.71-3.16 (m , 7H), 2.99 (s, 3H), 2.00-1.93 (m, 2H).

Example 91: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) propionamide

To a suspension of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (15 mg, 0.029 mmol) in 5% Pd / C (5 mg), CH ₃ OH (1.0 ml) was added. The mixture was purged three times with hydrogen gas (50 psi) and then shaken for 40 minutes at room temperature. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude residue was chromatographed to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) -propionamide (15 mg, 98%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.33 (d, 1H, J = 7.2 Hz), 7.12 (s, 1H), 6.96 (dd, 1H, J = 10.5 , 1.8 Hz), 6.89 (d, 1H, J = 7.8 Hz), 6.39 (s, 1H), 5.78 (s, 1H, broad), 4.27 (d, 2H, J = 6.0 Hz), 3.89 (s, 1H), 3.50-3.42 (m, 4H), 3.20 (s, 3H), 3.05 (t, 2H, J = 7.5 Hz), 2.41 (t, 2H, J = 7.5 Hz), 1.91-1.86 (m, 4H).

Example 92: 3- (2-cyclopentoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (41 mg, 0.15 mmol) was reacted with 3- (2-cyclopentoxy-6-trifluoromethyl-pyridin-3- il) -acrylic acid (40 mg, 0.13 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (50 mg, 73%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 6.02 (t, 1H), 5.58 (m, 1H), 4.54 ( d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3.26 (s, 3H), 1.82 (m, 8H).

Example 93: 3- (2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (41 mg, 0.15 mmol) was reacted with 3- (2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3- il) -acrylic acid (10 mg, 0.036 mmol), obtaining, after crystallization from EtOAc / Hex, the target compound (48 mg, 72%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.81 (m, 2H), 7.26 (m, 3H), 6.80 (d, 1H, J = 15.6 Hz), 6.40 ( s, 1H), 6.00 (t, 1H), 4.55 (d, 2H, J = 6.3 Hz), 4.31 (d, 2H, J = 7.5 Hz), 3.48 ( s, 1H), 3.27 (s, 3H), 1.39 (m, 1H), 0.63 (m, 2H), 0.40 (m, 2H).

Example 94: 3- (2-dimethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (33 mg, 0.12 mmol) was reacted with 3- (2-dimethylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (26 mg, 0.10 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (42 mg, 87%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.77 (d, 1H, J = 15.6 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.30 (s, 1H), 7.18 (d, 1H, J = 10.8 Hz), 7.10 (d, 1H, J = 7.8 Hz), 6.41 (s, 1H), 6.35 (d, 1H, J = 15.6 Hz), 5.96 (t, 1H), 4.54 (d, 2H, J = 6.0 Hz), 3.46 (s, 1H), 3.27 (s, 3H), 3.01 (s, 6H).

Example 95: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (60 mg, 0.24 mmol) was reacted with 3- [2- (4-ethoxycarbonyl-piperid-1-yl) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (50 mg, 0.16 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (34 mg, 25%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.74 (d, 1H, J = 7.8 Hz), 7.69 (d, 1H, J = 15.6 Hz), 7.54 (m, 1H), 7.18 (m, 2H), 6.51 (s, 1H), 6.47 (d, 1H, J = 15.9 Hz), 6.04 (s broad, 1H), 4, 57 (d, 2H, J = 6.0 Hz), 4.16 (d, 2H, J = 7.2 Hz), 3.72 (m, 2H), 3.03 (s, 3H), 2, 99 (m, 2H), 2.50 (m, 1H), 1.96 (m, 4H), 1.28 (t, 3H, J = 7.2 Hz).

Example 96: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-benzyloxy 6-trifluoromethyl-pyridin-3-yl ) -acrylic acid (87 mg, 0.21 mmol), obtaining the target compound (75 mg, 66%) after purification by column chromatography (Hex / EtOAc = 2/3).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.83 (m, 1H), 7.75 (d, 1H, J = 15.9 Hz), 7.49 (m, 2H), 7.35 ( m, 5H), 7.15 (m, 1H), 6.74 (d, 1H, J = 15.6 Hz), 6.39 (s, 1H), 5.93 (s broad, 1H), 5.54 (s, 2H), 4.51 (d, 2H, J = 6.3 Hz), 3.48 (s, 1H), 3.26 (s, 3H).

Example 97: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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, 0.118 mmol) was reacted with 3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin- 3-yl) -acrylic acid (33 mg, 0.118 mmol), obtained after purification by recrystallization from Et ₂ O N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1- il-6-trifluoromethyl-pyridin-3-yl) acrylamide (33 mg, 55%).

¹ H NMR (300 MHz, DMSO): δ 10.07 (s, 1H, broad), 8.77 (t, 1H, J = 6.0 Hz), 7.82 (d, 1H, J = 7 8 Hz), 7.70 (d, 1H, J = 15.6 Hz), 7.76-7.60 (m, 2H), 7.10 (d, 1H, J = 7.8 Hz), 6.43 (d, 1H, J = 15.6 Hz), 4.44 (d, 1H, J = 6.0 Hz), 3.51-3.34 (m, 4H), 3.11 (s , 3H), 1.88-1.84 (m, 4H).

Example 98: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-cyano-6-fluoro-phenyl) methanesulfonamide, HCl salt (33 mg, 0.118 mmol) was reacted with 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (34 mg, 0.118 mmol), obtained after purification by recrystallization from Et ₂ O 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4- methanesulfonylamino-benzyl) acrylamide (32 mg, 53%).

¹ H NMR (300 MHz, DMSO): δ 10.07 (s, 1H, broad), 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), 4.45 (d, 2H, J = 5.4 Hz), 4.40 (t, 2H, J = 6.3 Hz), 3.10 (s, 3H), 1.83-1.73 (m, 2H), 1.47-1.40 (m, 2H) 0.94 (t, 3H, J = 7.5 Hz).

Example 99: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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, 0.118 mmol) was reacted with 3- [2- (2-methoxy-ethoxy) -6-trifluoromethyl- pyridin-3-yl] -acrylic acid (34 mg, 0.118 mmol), after purification by recrystallization from Et ₂ O N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2 -methoxy-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide (38 mg, 62%).

¹ H NMR (300 MHz, DMSO): δ 10.08 (s, 1H, broad), 8.89 (t, 1H, J = 5.4 Hz), 8.20 (d, 1H, J = 7 5 Hz), 7.64-7.53 (m, 3H), 6.93 (d, 1H, J = 15.9 Hz), 4.54-4.44 (m, 4H), 3.74 (t, 2H, J = 4.5 Hz), 3.31 (s, 3H), 3.09 (m, 4H).

Example 100: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (58 mg, 0.21 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (48 mg, 0.18 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 3/5), the target compound (40 mg, 45%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 8.40 (broad s, 1H), 8.20 (t, 1H, J = 5.7 Hz), 7.59 (m, 2H), 7.32 (s, 1H), 7.19 (dd, 1H, J = 2.1 and 10.5 Hz), 6.88 (d, 1H, J = 7.8 Hz), 6, 53 (d, 1H, J = 15.3 Hz), 5.01 (d, 1H, J = 7.2 Hz), 4.48 (d, 2H, J = 6.0 Hz), 4.33 ( m, 1H), 3.48 (s, 1H), 3.17 (s, 3H), 1.25 (d, 6H, J = 6.3 Hz).

ESI [M + H] ⁺ : 499.

Example 101: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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, 0.60 mmol) was reacted with 3- [2- (2-methoxyethylamino) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (145 mg, 0.50 mmol), obtaining the desired compound (189 mg, 73%) after crystallization from MeOH / EtOAc / Hex.

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 9.90 (broad s, 1H), 8.63 (t, 1H, J = 6.0 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.58 (d, 1H, J = 15.3 Hz), 7.45 (s, 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), 6.52 (d, 1H, J = 15.3 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.52 (m, 4H), 3.27 (s, 3H), 3.04 (s, 3H).

Example 102: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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) was reacted with a mixture (120 mg) of 3- (2-dimethylamino-6-trifluoromethyl -pyridin-3-yl) -acrylic acid and 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid, obtained after purification by column chromatography (Hex / EtOAc = 1/1 ) followed by recrystallization from EtOAc / hexane N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-dimethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide (59 mg) .

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6.05 (m, 1H), 4.59 (d, 2H , J = 6.3 Hz), 3.33 (s, 3H), 3.02 (s, 6H).

Example 103: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-6-cyano-2-fluoro-phenyl) methanesulfonamide, HCl salt (130 mg, 0.46 mmol) was reacted with a mixture (120 mg) of 3- (2-dimethylamino-6-trifluoromethyl -pyridin-3-yl) -acrylic acid and 3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid, obtained after purification by column chromatography (Hex / EtOAc = 1/1 ) followed by recrystallization from EtOAc / hexane N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (7 mg).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (d, 1H, J = 7.8 Hz), 6.75 (t, 1H, J = 6 Hz), 6.55 (d, 1H, J = 15.3 Hz), 4.56 (d, 2H, J = 6 Hz), 3.85 ~ 3.82 (m, 4H), 3.35 ~ 3.32 (m, 4H), 3.23 (s, 3H )

Example 104: 3- [2- (tetrahydro-furan-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (76 mg, 0.30 mmol) was reacted with 3- [2- (tetrahydro-furan-3-yloxy) -6-trifluoromethyl- pyridin-3-yl] -acrylic acid (60 mg, 0.20 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (70 mg, 70%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 6.46 (t, 1H, J = 6.0 Hz), 5.76 (m, 1H), 4.54 (d, 2H, J = 6.0 Hz) 4.05 (m, 2H); 3.91 (m, 2H); 3.02 (s, 3H); 2.35 (m, 1H); 2.20 (m, 1H).

Example 105: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-cyano-phenyl) methanesulfonamide, HCl salt (48.5 mg, 0.173 mmol) were reacted with NMM (0.07 ml), DMTMM (55 mg) and 3 - (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (50 mg, 0.16 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (66 mg, 76%).

¹ H NMR (300 MHz, CD ₃ OD): δ 8.20 (d, 1H, J = 7.5 Hz), 7.83 (d, 1H, J = 16.2 Hz), 7.45 (m , 4H), 7.15 (m, 2H), 6.99 (d, 1H, J = 15.9 Hz), 4.47 (s, 2H), 3.05 (s, 3H).

Example 106: 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-cyano-phenyl) methanesulfonamide, HCl salt (46.1 mg, 0.165 mmol) were reacted with NMM (0.2 ml), DMTMM (60.1 mg) and 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (43 mg, 0.15 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (57 mg, 75%).

¹ H NMR (300 MHz, CD ₃ OD): 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 (d, 1H, J = 15.9 Hz), m, 2H), 5.27 (m, 1H), 4.89 (s, 1H), 3.07 (s, 3H), 1.33 (d, 3H, J = 6, 0 Hz), 0.95 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 515.

Example 107: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Stage 1: synthesis of 3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (100 mg, 0.376 mmol), phenylboronic acid (2 equiv.), Cs ₂ CO ₃ (3 equiv. ), Pd (PPh ₃ ) ₂ Cl ₂ (0.08 equiv.), DME (1 ml) and ethanol (0.25 ml). The ampoule was irradiated in a microwave synthesizer at 140 ° C for 20 min. The contents of the ampoule were filtered through celite, which was then washed thoroughly with methanol. The filtrate was evaporated and the residue was purified by column chromatography to give 3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (96 mg, 80%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.07 (d, 1H, J = 7.5 Hz), 7.73 (d, 1H, J = 16.2 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.57-7.53 (m, 2H), 7.47-7.43 (m, 3H), 6.45 (d, 1H, J = 16.3 Hz ), 4.21 (q, 2H, J = 7.2 Hz), 1.26 (t, 3H, J = 7.2 Hz).

Stage 2: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

An aqueous solution of 0.5 N was added to a suspension of 3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (20 mg, 0.062 mmol) in THF (1 ml). LiOH (0.3 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ and concentrated in vacuo to give 3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (19 mg, 96%). To a suspension of N- (4-aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, an HCl salt (21 mg, 0.074 mmol) in THF (3 ml), N-methylmorpholine (0.015 ml, 0.148 mmol) was added. The mixture was stirred for 5 minutes, then 3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (19 mg, 0.065 mmol) and 4- (4,6-dimethoxy [1,3, 5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMTMM 19 mg, 0.068 mmol). The mixture was stirred overnight at room temperature and 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 Et ₂ O to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (18 mg , 56%).

¹ H NMR (300 MHz, DMSO): δ 9.46 (s, 1H, broad), 8.85 (t, 1H, J = 5.7 Hz), 8.39 (d, 1H, J = 8 , 1 Hz), 7.98 (d, 1H, J = 8.1 Hz), 7.61-7.54 (m, 5H), 7.45 (d, 1H, J = 15.9 Hz), 7.26 (m, 2H), 6.84 (d, 1H, J = 15.9 Hz), 4.52 (s, 1H), 4.36 (d, 2H, J = 5.7 Hz), 3.06 (s, 3H).

Example 108: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (46 mg, 0.18 mmol) was reacted with 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (50 mg, 0.18 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/1), the target compound (34 mg, 25%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 6.03 (s broad, 1H), 5, 48 (septet, 1H, J = 6.0 Hz), 4.57 (d, 2H, J = 6.3 Hz), 3.03 (s, 3H), 1.41 (d, 6H, J = 7 , 2 Hz).

Example 109: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-cyano-2-fluoro-phenyl) -methanesulfonamide, HCl salt (51 mg, 0.18 mmol) was reacted with 3- (2-isopropoxy-6-trifluoromethyl-pyridin-3- il) -acrylic acid (50 mg, 0.18 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (44 mg, 51%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.08 (broad s, 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), 4.44 (d, 2H, J = 5.7 Hz), 3.08 (s, 3H), 1, 38 (d, 6H, J = 6.0 Hz).

Example 110: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (75 mg, 0.27 mmol) was reacted with 3- [2- (4-ethoxycarbonyl-piperid-1-yl ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (100 mg, 0.27 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (111 mg, 69%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.72 (m, 2H), 7.31 (broad s, 1H), 7.19 (m, 2H), 6.45 (d, 2H, J = 15.6 Hz), 6.41 (s broad, 1H), 6.00 (s broad, 1H), 4.54 (d, 2H, J = 6.3 Hz), 4.15 (q , 2H, J = 7.2 Hz), 3.71 (m, 2H), 3.49 (s, 1H), 3.27 (s, 3H), 3.01 (m, 2H), 2.51 (m, 1H), 1.96 (m, 4H), 1.27 (t, 3H, J = 7.2 Hz).

Example 111: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-ethoxycarbonyl-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) was reacted with 3- [2- (4-ethoxycarbonyl-piperid-1-yl ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (52 mg, 0.14 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (63 mg, 75%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.77 (m, 1H), 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 (s broad, 1H), 4.59 (d, 2H, J = 6.6 Hz), 4, 16 (q, 2H, J = 7.2 Hz), 3.72 (m, 2H), 3.32 (s, 3H), 3.02 (m, 2H), 2.52 (m, 1H), 1.96 (m, 4H); 1.28 (t, 3H, J = 7.2 Hz).

Example 112: 3- (2-benzyloxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (21 mg, 0.083 mmol) was reacted with 3- (2-benzyloxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ( 35 mg, 0.083 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (18 mg, 41%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 5.92 (s broad, 1H), 5.54 (s, 2H), 4.54 (d, 2H, J = 6.3 Hz), 3.02 (s, 3H).

Example 113: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (31 mg, 0.11 mmol) was reacted with 3- (2-phenylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (19 mg, 0.06 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (10 mg, 17%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.57 (d, 1H, J = 16.2 Hz), 7.43 (m, 5H), 7.23 (m, 3H), 7.06 ( m, 1H), 6.49 (d, 1H, J = 15.9 Hz), 6.45 (s broad, 1H), 6.29 (s broad, 1H), 4.34 (d, 2H , J = 6.6 Hz), 3.46 (s, 1H), 3.31 (s, 3H).

Example 114: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-ethoxycarbonyl-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) was reacted with 3- [2- (3-ethoxycarbonyl-piperid-1-yl ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (100 mg, 0.27 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 4/5), the target compound (75 mg, 46%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.79 (d, 1H, J = 7.2 Hz), 7.67 (d, 1H, J = 16.2 Hz), 7.32 (s broad ., 1H), 7.21 (m, 2H), 6.82 (s broad, 1H), 6.54 (d, 1H, J = 16.2 Hz), 6.39 (s, 1H), 4.54 (t, 2H, J = 6.6 Hz), 4.10 (m, 2H), 3.48 (s, 1H), 3.43 (m, 4H), 3.26 (s, 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-methanesulfonylamino-benzyl) -3- [2- (3-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-3-cyano-5-fluoro-phenyl) methanesulfonamide, HCl salt (23 mg, 0.081 mmol) was reacted with 3- [2- (3-ethoxycarbonyl-piperid-1-yl) - 6-trifluoromethyl-pyridin-3-yl] -acrylic acid (30 mg, 0.081 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (35 mg, 72%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.10 (broad s, 1H), 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), 4.45 (d, 2H, J = 5.7 Hz), 4.03 (q, 2H, J = 6.9 Hz), 3.72 (m, 1H), 3.09 (s, 3H), 2.94 (m, 4H), 1.81 (m, 4H ), 1.12 (t, 3H, J = 7.2 Hz).

Example 116: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-piperaz-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide, HCl salt

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (192 mg, 0.70 mmol) was reacted with 3- (2-piperaz-1-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (230 mg, 0.57 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-Boc-piperaz- 1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide. This acrylamide was treated with 4 M HCl in dioxane to obtain the title compound after purification using MeOH (90 mg, 28%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 9.57 (s broad, 2H), 9.08 (s, 1H), 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 (s, 1H), 7.12 (dd, 1H, J = 2.1 and 10.2 Hz), 6.75 (d, 1H, J = 15.9 Hz), 4.37 ( d, 2H, J = 5.7 Hz), 3.68 (s, 1H), 3.51 (m, 4H), 3.25 (m, 4H), 3.03 (s, 3H).

Example 117: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (84 mg, 0.30 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (70 mg, 0.24 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (75 mg, 63%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 9.40 (broad s, 1H), 8.71 (t, 1H), 7.74 (d, 1H, J = 7.8 Hz), 7.64 (d, 1H, J = 15.3 Hz), 7.26 (m, 2H), 6.87 (d, 1H, J = 7.8 Hz), 6.68 (d, 1H, J = 8.1 Hz), 6.59 (d, 1H, J = 15.3 Hz), 4.39 (d, 2H, J = 6.0 Hz), 4.38 (s, 1H) , 4.09 (m, 1H), 3.05 (s, 3H), 1.55 (m, 2H), 1.14 (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-methanesulfonylamino-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, 0.062 mmol) was reacted with 3- [2- (3-methyl-butoxy) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (15.7 mg, 0.052 mmol), obtained after purification by chromatography (Hex / EtOAc = 1/2) N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl ) -3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) acrylamide (22 mg, 80%).

¹ H NMR (300 MHz, DMSO): δ 10.08 (s, 1H, broad), 8.83 (t, 1H, J = 5.7 Hz), 8.12 (d, 1H, J = 7 5 Hz), 7.59-7.45 (m, 4H), 6.86 (d, 1H, J = 16.2 Hz), 4.49-4.35 (m, 4H), 3.02 (s, 3H), 1.73-1.60 (m, 3H), 0.87 (d, 6H, J = 6.0 Hz).

Example 119: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Stage 1: Synthesis of 3- (2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester

3- (2-Thien-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester was prepared according to the general procedure described in Example 107 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (100 mg, 0.357 mmol) was reacted with 3-thienylboronic acid (2 equiv.) To give 3- (2 ethyl ester thien-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (80 mg, 68%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.99 (d, 1H, J = 6.0 Hz), 7.91 (d, 1H, J = 16.5 Hz), 7.61 (dd, 1H, J = 2.7, 1.2 Hz), 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), 6.43 (d, 1H, J = 15.9 Hz), 4.24 (q, 2H, J = 7.2 Hz ), 1.30 (t, 3H, J = 7.2 Hz).

Stage 2: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-thiophen-3-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide was prepared according to the general procedure described in Example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (19 mg, 0.068 mmol) was reacted with 3- (2-thien-3-yl-6-trifluoromethyl-pyridin- 3-yl) -acrylic acid (17 mg, 0.057 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-thien-3-yl-6-trifluoromethyl-pyridine -3-yl) acrylamide (12 mg, 34%).

¹ H NMR (300 MHz, DMSO): δ 9.39 (s, 1H, broad), 8.80 (t, 1H, J = 6.0 Hz), 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 (s, 1H), 7, 22 (d, 1H, J = 7.5 Hz), 6.75 (d, 1H, J = 15.6 Hz), 4.45 (s, 1H), 4.33 (d, 2H, J = 5 4 Hz), 3.00 (s, 3H).

Example 120: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Step 1: Synthesis of 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ethyl ester

3- [2- (3-Fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ethyl ester was prepared according to the general procedure described in Example 107 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (110 mg, 0.393 mmol) was reacted with 3-fluorophenylboronic acid (2 equiv.) To give 3- [2 - (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid (70 mg, 53%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.51-7.43 (m, 1H), 7.38-7.33 (m, 2H), 7.27-7.16 (m, 1H), 6 50 (d, 1H, J = 15.6 Hz), 4.26 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz).

Stage 2: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide was prepared according to the general procedure described in Example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (71.45 mg, 0.255 mmol) was reacted with 3- [2- (3-fluorophenyl) -6-trifluoromethyl- pyridin-3-yl] acrylic acid (53 mg, 0.170 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl -pyridin-3-yl] -acrylamide (52 mg, 57%).

¹ H NMR (300 MHz, DMSO): δ 9.45 (s, 1H, broad), 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 (s, 1H), 7.26 (d, 1H, J = 8.7 Hz), 6.83 (d, 1H, J = 15.9 Hz), 4.51 (s, 1H), 4.36 (d, 2H, J = 6.0 Hz); 3.06 (s, 3H).

Example 121: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (95 mg, 0.37 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (84 mg, 0.31 mmol), after obtaining, after purification by crystallization from methylene chloride, the target compound (125 mg, 84%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (broad s, 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), 6.96 (d, 1H, J = 7.5 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.61 (d, 1H, J = 15.6 Hz), 4.39 (d, 2H, J = 5.7 Hz), 4.21 (m, 1H), 3, 00 (s, 3H), 1.18 (d, 6H, J = 6.6 Hz).

Example 122: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-5-cyano-2-fluoro-phenyl) methanesulfonamide, HCl salt (104 mg, 0.37 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (84 mg, 0.31 mmol), after obtaining, after purification by crystallization from methylene chloride, the target compound (115 mg, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.1 (broad s, 1H), 8.79 (t, 1H, J = 5.7 Hz), 7.80 (d, 1H, J = 7.5 Hz), 7.63 (m, 2H), 6.96 (d, 1H, J = 7.5 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6, 61 (d, 1H, J = 15.6 Hz), 4.39 (d, 2H, J = 5.7 Hz), 4.21 (m, 1H), 3.10 (s, 3H), 1, 18 (d, 6H, J = 6.6 Hz).

ESI [M + H] ⁺ : 500.

Example 123: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (325 mg, 1.27 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (306 mg, 1.06 mmol), obtaining, after purification by crystallization from ether, the target compound (490 mg, 95%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (broad s, 1H), 8.70 (t, 1H, J = 6.0 Hz), 7.77 (d, 1H, J = 7.8 Hz), 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), 4.40 (d, 2H, J = 6.0 Hz), 4.07 (m, 1H), 3, 00 (s, 3H), 1.55 (m, 2H), 1.14 (d, 3H, J = 6.6 Hz), 0.86 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 489.

Example 124: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-5-cyano-2-fluoro-phenyl) -methanesulfonamide, HCl salt (104 mg, 0.37 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (100 mg, 0.34 mmol), obtaining, after purification by crystallization from ether, the target compound (130 mg, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.1 (broad s, 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 (s, 3H), 1, 55 (m, 2H), 1.14 (d, 3H, J = 6.6 Hz), 0.85 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 514.

Example 125: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Step 1: Synthesis of 3- [2- (3-methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ethyl ester

3- [2- (3-Methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ethyl ester was prepared according to the general procedure described in Example 107 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-methoxyphenylboronic acid (2 equiv.) To give 3- [2 - (3-methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid (70 mg, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.09 (d, 1H, J = 8.4 Hz), 7.79 (d, 1H, J = 15.9 Hz), 7.68 (d, 1H, J = 7.8 Hz), 7.39 (dd, 1H, J = 7.2, 1.5 Hz), 7.51-7.12 (m, 2H), 7.04-7.00 (m, 1H), 6.47 (d, 1H, J = 15.9 Hz), 4.25 (q, 2H, J = 7.2 Hz), 3.85 (s, 3H), 1.31 (t, 3H, J = 7.2 Hz).

Step 2: Synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxyphenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide was prepared according to the general procedure described in Example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, an HCl salt (15.6 mg, 0.056 mmol) were reacted with 3- [2- (3-methoxyphenyl) -6-trifluoromethyl- pyridin-3-yl] acrylic acid (15 mg, 0.046 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxyphenyl) -6-trifluoromethyl pyridin-3-yl] acrylamide (15 mg, 60%).

¹ H NMR (300 MHz, DMSO): δ 9.44 (s, 1H, broad), 8.84 (t, 1H, J = 6.0 Hz), 8.37 (d, 1H, J = 8 , 1 Hz), 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 (s, 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), 6.82 (d, 1H, J = 15.9 Hz), 4.51 (s, 1H), 4.37 (d, 2H , J = 5.7 Hz), 3.79 (s, 3H), 3.06 (s, 3H).

Example 126: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Step 1: Synthesis of 3- (2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester

3- (2-Pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester was prepared according to the general procedure described in Example 107 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-pyridineboronic acid (2 eq.) To give 3- (2 -pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (60 mg, 50%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.84 (d, 1H, J = 1.8 Hz), 8.74 (d, 1H, J = 4.8 Hz), 8.14 (d, 1H, J = 8.1 Hz), 7.79 (dd, 1H, J = 6.3, 1.8 Hz), 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), 6.54 (d, 1H, J = 15.9 Hz), 4, 26 (q, 2H, J = 7.2 Hz), 1.32 (t, 3H, J = 7.2 Hz).

Step 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide.

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide was prepared according to the general procedure described in Example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (68 mg, 0.24 mmol) was reacted with 3- (2-pyridin-3-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (60 mg, 0.20 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyridin-3-yl-6 trifluoromethyl-pyridin-3-yl) -acrylamide (60 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.97 (dd, 1H, J = 4.2, 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 (s, 1H), 3.24 (s, 3H).

Example 127: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-3-fluoro-phenyl) methanesulfonamide, HCl salt (74 mg, 0.29 mmol) was reacted with 3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (90 mg, 0.29 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (100 mg, 67%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.57 (s, 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 (d, 1H, J = 15.6 Hz), 4.41 (d, 2H, J = 5.1 Hz), 2.99 (s, 3H).

Example 128: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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 mmol) was reacted with 3- (2-phenylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (90 mg, 0.29 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/3), the target compound (95 mg, 61%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.09 (s, 1H), 9.01 (s, 1H), 8.88 (m, 1H), 8.04 (d, 1H, J = 7.5 Hz), 7.82 (m, 1H), 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 (s, 3H).

Example 129: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (86 mg, 0.32 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (90 mg, 0.31 mmol), after obtaining, after purification by crystallization from ether, the target compound (106 mg, 68%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.76 (t, 1H, J = 6.0 Hz), 7.79 (d, 1H, J = 7.5 Hz), 7.65 ( d, 1H, J = 15.3 Hz), 7.11 (d, 2H, J = 8.4 Hz), 6.95 (d, 1H, J = 7.8 Hz), 6.78 (d, 1H, J = 7.8 Hz), 6.62 (d, 1H, J = 15.3 Hz), 4.41 (d, 2H, J = 6.0 Hz), 4.07 (m, 1H) , 3.03 (s, 3H), 1.55 (m, 2H), 1.14 (d, 3H, J = 6.6 Hz), 0.86 (t, 3H, J = 7.5 Hz) .

Example 130: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, HCl salt (99 mg, 0.37 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (100 mg, 0.34 mmol), obtaining the target compound (140 mg, 82%) after purification by crystallization from ether.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.1 (broad s, 1H), 8.64 (t, 1H, J = 5.7 Hz), 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), 4.40 (d, 2H, J = 5.7 Hz), 4.06 ( m, 1H), 2.97 (s, 3H), 2.20 (d, 3H, J = 2.4 Hz), 1.55 (m, 2H), 1.14 (d, 3H, J = 6 6 Hz), 0.85 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 503.

Example 131: N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, an HCl salt (50 mg, 0.19 mmol) were reacted with 3- (2-piperid-1-yl-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (56 mg, 0.19 mmol), after purification by recrystallization from EtOAc / hexane N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2 piperid-1-yl-6-trifluoromethyl-pyridinyl-3-yl) acrylamide (66 mg, 69%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.26 (s, 1H), 8.72 (t, 1H, J = 5.7 Hz), 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), 4.41 (d, 2H, J = 5.7 Hz), 3.20 ~ 3.17 (m, 4H), 2.98 (s, 3H), 2.21 (d, 3H, J = 2.1 Hz) 1.62 (br. 6H).

Example 132: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (41.7 mg, 0.162 mmol) were reacted with NMM (0.07 ml), DMTMM (44.7 mg) and 3- ( 2-phenoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (45 mg, 0.15 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (63 mg, 85% )

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 7.15 (m, 4H), 6.87 (d, 1H, J = 15.6 Hz), 6.53 (s, 1H), 6.13 (t, 1H), 4.56 (d, 2H, J = 6.0 Hz), 3.01 (s, 3H).

Example 133: N- (3-fluoro-4-methanesulfonylamino-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 reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (69 mg, 53% )

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6.88 (d, 1H, J = 15.6 Hz), 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), 4.57 (d, 2H, J = 6.0 Hz), 3.37 (s, 1H), 3.07 (s, 3H).

Example 134: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (pyridin-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Stage 1: 3- [2- (pyridin-3-yloxy) -4-trifluoromethyl-phenyl] -acrylic acid

3-Hydroxypyridine (69.1 mg) and sodium hydride (65 mg, 1.6 mmol) were added to THF. 3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (156 mg, 0.620 mmol) was added to the reaction mixture. The reaction mixture was purified, obtaining the target compound (15 mg) after purification by column chromatography (Hex / EtOAc = 1/4).

¹ H NMR (300 MHz, CD ₃ OD): δ 8.48 (m, 1H), 8.32 (d, 1H, J = 7.8 Hz), 8.03 (s, 1H), 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-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (pyridin-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-6-ethynyl-phenyl) -methanesulfonamide, HCl salt (50.5 mg, 0.198 mmol) were reacted with NMM (0.08 ml), DMTMM (57.8 mg) and 3- [2- (pyridin-3-yloxy) -4-trifluoromethyl-phenyl] acrylic acid (40.5 mg), to obtain, after purification by column chromatography (Hex / EtOAc = 1/4), the target compound (29 mg )

¹ H NMR (300 MHz, CD ₃ OD): δ 8.52 (d, 1H, J = 2.7 Hz), 8.45 (ppm, 1H), 8.30 (d, 1H, J = 7, 2 Hz), 7.88 (d, 1H, J = 15.9 Hz), 7.77 (m, 1H), 7.55 (m, 2H), 7.33 (s, 1H), 7.21 (dd, 1H, J = 1.2 and 10.2 Hz), 7.02 (d, 1H, J = 15.9 Hz), 4.49 (s, 2H), 3.31 (s, 1H) 3.11 (s, 3H).

Example 135: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Step 1: Synthesis of 3- [2- (4-fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid ethyl ester

3- [2- (4-Fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ethyl ester was prepared according to the general procedure described in Example 107 (step 1).

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (110 mg, 0.393 mmol) was reacted with 2-fluoro-5-pyridine boronic acid (2 eq.) To give ethyl 3- [2- (4-fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid ester (40 mg, 30%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.45 (d, 1H, J = 2.4 Hz), 8.16-8.08 (m, 2H), 7.76 (d, 1H, J = 8.4 Hz), 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), 1.33 (t, 3H, J = 7.2 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (4'-fluoro-6-trifluoromethyl- [2,3 '] bipyridinyl-3-yl) acrylamide was prepared according to the general procedure described in example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (29.5 mg, 0.107 mmol) was reacted with 3- [2- (4-fluoro-pyridin-3-yl ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (22 mg, 0.070 mmol) to obtain N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4- fluoro-pyridin-3-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (14 mg, 39%).

¹ H NMR (300 MHz, DMSO): δ 9.46 (s, 1H, broad), 8.88 (t, 1H, J = 6.0 Hz), 8.43 (d, 1H, J = 8 , 1 Hz), 8.41 (s, 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 (s, 1H), 7.26 (d, 1H, J = 4.8 Hz), 6.83 (d, 1H, J = 15.6 Hz), 4.52 (s, 1H), 4.37 (d, 2H, J = 5.7 Hz), 3.06 (s, 3H).

Example 136: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-cyano-6-fluoro-phenyl) -methanesulfonamide, HCl salt (18 mg, 0.065 mmol) was reacted with 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin- 3-yl] -acrylic acid (17 mg, 0.054 mmol), obtaining, after purification by recrystallization from a mixture of n-hexane / EtOAc N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- ( 3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (21 mg, 62%).

¹ H NMR (300 MHz, DMSO): δ 8.90 (t, 1H, J = 6.0 Hz), 8.41 (d, 1H, J = 8.1 Hz), 8.02 (d, 1H , J = 8.1 Hz), 7.62-7.57 (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 (s, 3H).

Examples 137 and 138 are absent

Example 139: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylthio-6-trifluoromethyl-pyridin-3-yl) acrylamide

Stage 1: 3- (2-phenylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

3- (2-Phenylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (80 mg) was hydrolyzed with a 1 M solution (3 mmol) of LiOH at room temperature to give the desired compound (63 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.13 (d, 1H, J = 15.6 Hz), 7.81 (m, 1H), 7.53 (m, 2H), 7.38 ( m, 3H), 6.48 (d, 1H, J = 15.9 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylthio-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-ethynyl-phenyl) -methanesulfonamide, HCl salt (43 mg, 0.154 mmol) were reacted with NMM (0.1 ml), DMTMM (46 mg) and 3- ( 2-phenylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (41 mg, 0.126 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (25.6 mg, 37% )

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.88 (d, 1H, J = 15.6 Hz), 7.76 (d, 1H, J = 8.1 Hz), 7.48 (m, 2H), 7.32 (m, 4H), 7.21 (s, 1H), 7.08 (d, 1H, J = 10.5 Hz), 6.45 (d, 1H, J = 15.3 Hz), 6.43 (s, 1H), 4.44 (d, 2H, J = 6.3 Hz), 3.40 (s, 1H), 3.20 (s, 3H).

Example 140: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (21 mg, 0.082 mmol) were reacted with NMM (0.1 ml), DMTMM (26 mg) and 3- (2-phenylthio- 6-trifluoromethyl-pyridin-3-yl) -acrylic acid (21 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (18 mg, 53%).

¹ H NMR (300 MHz, CDCl ₃ ): 7.88 (d, 1H, J = 15.6 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.48 (m, 2H ), 7.32 (m, 4H), 7.11 (s, 1H), 6.91 (m, 2H), 6.43 (d, 1H, J = 15.3 Hz), 6.42 (s , 1H), 4.52 (d, 2H, J = 6.3 Hz), 3.00 (s, 3H).

Example 141: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Stage 1: 2-phenethyl-4-trifluoromethyl-nicotinic acid methyl ester

To a solution of β-ketoester (2.43 g, 17.5 mmol) in toluene (30 ml) was added 4-amino-1,1,1-trifluorobuten-2-one (3.60 g, 17.5 mmol) and trifluoroacetic acid (1.30 ml, 17.5 mmol), and the resulting mixture was stirred at 90 ° C for 60 hours. This mixture was washed with an aqueous 20% solution of Na ₂ CO ₃ and dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EtOAc = 10: 1) to give 2-phenethyl-4-trifluoromethyl-nicotinic acid methyl ester (1.84 g, 41%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.30 (d, 1H, J = 8.1 Hz), 7.59 (d, 1H, J = 8.1 Hz), 7.24 (m, 5H), 3.92 (s, 3H), 3.53 (m, 1H), 3.07 (m, 1H).

Stage 2: 2-phenethyl-4-trifluoromethyl-pyridin-3-ylmethyl alcohol

To a suspension of 2-phenethyl-4-trifluoromethyl-nicotinic acid methyl ester (1.84 g, 5.95 mmol) in THF (50 ml) was added dropwise at 0 ° C. 1.0 M LiAlH ₄ (6.0 ml, 6.0 mmol). After stirring at 0 ° C for 1 hour, the reaction was stopped by adding 10% potassium sodium tartrate (50 ml), and the resulting mixture was vigorously stirred for 1 hour. The two phases were separated, and the aqueous phase was extracted with ether. The combined organic layer was washed with brine, dried over anhydrous. MgSO _{4 was} filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex / EtOAc = 10: 1) to give an alcohol product (1.55 g, 93%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 4H).

Stage 3: 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid, methyl ester

To a solution of oxalyl chloride (540 ml, 6.06 mmol) in CH ₂ Cl ₂ (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 in the above Step 2 (1.55 g, 5.51 mmol) in CH ₂ Cl ₂ (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 warmed to room temperature. Water (40 ml) was added to the reaction mixture, and the two phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous. MgSO _{4 was} filtered and concentrated under reduced pressure to obtain an aldehyde product, which was used without further purification.

To a solution of the aldehyde product obtained above in toluene (20 ml) was added methyl (triphenylphosphoranilidene) 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 MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by column chromatography (Hex / EtOAc = 10/1) to obtain 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (1.46 g, 79% 2 steps) .

¹ H NMR (300 MHz, CDCl ₃ ): 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 (d, 1H, J = 15.9 Hz), 3.82 (s, 3H), 3.29 (m, 2H), 3.07 (m, 2H).

Stage 4: 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

To a suspension of 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (1.46 g, 4.35 mmol) in THF (3 ml) was added 1N. LiOH solution (6.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H ₂ O and then washed with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. MgSO ₄ , and concentrated in vacuo to give 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (1.37 g, 98%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.91 (m, 2H), 7.58 (d, 1H, J = 7.8 Hz), 7.20 (m, 5H), 6.31 ( d, 1H, J = 15.9 Hz), 3.31 (m, 2H), 3.09 (m, 2H).

Step 5: Synthesis of N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (153 mg, 0.60 mmol) was reacted with 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (160 mg, 0.50 mmol), after purification by crystallization from a Hex / EtOAc mixture of N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl ) -acrylamide (174 mg, 67%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 8.70 (broad s, 1H), 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), 3.08 (m, 2H), 3.00 (s, 3H).

ESI [M + H] ⁺ : 528.

Example 142: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, an HCl salt (167 mg, 0.60 mmol) was reacted with 3- (2-phenethyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (160 mg, 0.50 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (175 mg, 64%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 8.20 (broad s, 1H), 8.11 (t, 1H), 7.92 (d, 1H, J = 8.1 Hz), 7.72 (d, 1H, J = 15.3 Hz), 7.55 (d, 1H, J = 8.1 Hz), 7.33 (s, 1H), 7.20 (m, 6H), 6.52 (d, 1H, J = 15.3 Hz), 4.49 (d, 2H, J = 6.0 Hz), 3.47 (s, 1H), 3.29 (m, 2H), 3.18 (s, 3H), 3.08 (m, 2H).

ESI [M + H] ⁺ : 546.

Example 143: 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (153 mg, 0.60 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (137 mg, 0.50 mmol), obtained by a method similar to that described above, obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (160 mg, 68%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s broad, 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), 4.40 (d, 2H, J = 6.3 Hz), 2.99 (s , 3H), 2.94 (m, 2H), 1.60 (m, 2H), 1.35 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz).

Example 144: 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (167 mg, 0.60 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (137 mg, 0.50 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (158 mg, 64%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (broad s, 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), 4.52 (s, 1H), 4.40 (d, 2H, J = 5.7 Hz), 3.06 (s, 3H), 2, 94 (m, 2H), 1.60 (m, 2H), 1.35 (m, 2H), 0.90 (t, 3H, J = 6.9 Hz).

ESI [M + H] ⁺ : 498.

Example 145: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethynyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Step 1: Synthesis of 3- (6-trifluoromethyl-2-trimethylsilanylethinyl-pyridin-3-yl) -acrylic acid ethyl ester

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (103 mg, 0.368 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.06 equiv.) Was charged into a microwave ampoule. CuI (0.06 equiv.), PPh ₃ (0.2 equiv.), Et ₃ N (15 equiv.), (Trimethylsilyl) acetylene and DMF (0.25 ml). The ampoule was irradiated in a microwave synthesizer at 120 ° C for 25 min. The contents of the ampoule were filtered through a pad of celite, which was washed thoroughly with EtOAc. The filtrate was evaporated and the residue was purified by column chromatography to give 3- (6-trifluoromethyl-2-trimethylsilanylethylenyl-pyridin-3-yl) -acrylic acid ethyl ester (58 mg, 46%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.08 (d, 1H, J = 16.4 Hz), 8.0 (d, 1H, J = 8.1 Hz), 6.55 (d, 1H, J = 8.1 Hz), 6.54 (d, 1H, J = 16.4 Hz), 4.25 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz), 0.27 (s, 9H).

Stage 2: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethynyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

To a suspension of 3- (6-trifluoromethyl-2-trimethylsilanylethinyl-pyridin-3-yl) -acrylic acid ethyl ester (68 mg, 0.169 mmol) in THF (1 ml) and CH ₃ OH (0.5 ml) was added 1 n . NaOH solution (0.5 ml), and the mixture was stirred for 50 minutes at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ , and concentrated in vacuo to give 3- (2-ethynyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (48 mg, 99%).

To a suspension of N- (4-aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (83 mg, 0.298 mmol) in THF (3 ml) was added N-methylmorpholine (0.066 ml, 0.597 mmol). The mixture was stirred for 5 minutes, then 3- (2-ethynyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (48 mg, 0.065 mmol) and 4- (4,6-dimethoxy [1,3, 5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMTMM 71.4 mg, 0.258 mmol). The mixture was stirred overnight at room temperature and 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 CH ₂ Cl ₂ to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethynyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (30 mg, 32%).

¹ H NMR (300 MHz, DMSO): δ 9.46 (s, 1H, broad), 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 (s, 1H), 7.28 ( d, 1H, J = 7.8 Hz), 6.97 (d, 1H, J = 15.9 Hz), 4.94 (s, 1H), 4.51 (s, 1H), 4.41 ( d, 2H, J = 5.7 Hz), 3.06 (s, 3H).

Example 146: missing

Example 147: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (153 mg, 0.60 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (137 mg, 0.50 mmol) obtained by a method similar to that described above, after obtaining the target compound after purification by crystallization from a Hex / EtOAc mixture (151 mg, 64%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (broad s, 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), 4.40 (d, 2H, J = 5.7 Hz), 3.00 (s, 3H), 2, 83 (d, 2H, J = 6.9 Hz), 2.01 (m, 1H), 0.89 (t, 6H, J = 6.6 Hz).

Example 148: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (167 mg, 0.60 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (137 mg, 0.50 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (153 mg, 62%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (broad s, 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 (m, 2H), 6, 74 (d, 1H, J = 15.3 Hz), 4.50 (s, 1H), 4.41 (d, 2H, J = 5.7 Hz), 3.07 (s, 3H), 2, 83 (d, 2H, J = 7.2 Hz), 2.01 (m, 1H), 0.89 (t, 6H, J = 6.6 Hz).

ESI [M + H] ⁺ : 498.

Example 149: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-amino-ethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (78 mg, 0.29 mmol) was reacted with 3- (2-phenylamino-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (90 mg, 0.29 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (120 mg, 80%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (d, 1H, J = 8.1 Hz), 8.12 (s, 1H), 7.72 (m, 5H), 7, 40 (m, 1H), 7.29 (m, 2H), 7.15 (m, 3H), 7.01 (m, 1H), 6.66 (d, 1H, J = 15.6 Hz), 5.16 (q, 1H, J = 6.6 Hz), 2.93 (s, 3H), 1.51 (d, 3H, J = 6.9 Hz).

Example 150: 3- (2-ethyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethinyl-nicotinamide

N-Methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide was prepared according to the general procedure described in Example 145 (step 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1.2 g, 4.52 mmol) was reacted with (trimethylsilyl) acetylene (0.689 ml, 4.97 mmol) to obtain N-methoxy -N-methyl-6-trifluoromethyl-2-trimethylsilanylethinyl-nicotinamide (896 mg, 60%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.83 (d, 1H, J = 7.8 Hz), 7.66 (d, 1H, J = 7.8 Hz), 3.51 (s, 3H), 3.39 (s, 3H), 0.26 (s, 9H).

Stage 2: synthesis of 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethinyl-nicotinamide (148 g, 0.449 mmol) in THF (1 ml) and CH ₃ OH (0.5 ml) was added 1N NaOH solution (0.5 ml), and the mixture was stirred for 50 minutes at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ , and concentrated in vacuo to give 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (116 mg, 99%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.82 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 7.8 Hz), 3.69 (s, 3H), 3.45 (s, 3H).

Stage 3: synthesis of 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide

To a suspension of 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (145 mg, 0.561 mmol) in 5% Pd / C (30 mg) was added CH ₃ OH (4 ml). The mixture was purged three times with hydrogen gas (50 psi) and shaken for 2 hours at room temperature. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude residue was chromatographed to give 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (112 mg, 76%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.75 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 7.8 Hz), 3.43 (s, 3H), 3.39 (s, 3H), 2.89 (q, 2H, J = 7.5 Hz), 1.33 (t, 3H, J = 7.5 Hz).

Stage 4: 3- (2-ethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester

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 aluminum hydride (1M LAH in THF 0.22 ml). The mixture was stirred for 15 minutes and then heated to -10 ° C. After further stirring for 30 minutes, the mixture was quenched with saturated potassium hydrogen sulfate solution (1 ml) and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2-ethyl-6-trifluoromethyl-pyridin-3-carbaldehyde quantitatively in the form of an oil. The crude product was used directly in the next reaction.

To a solution of 2-ethyl-6-trifluoromethyl-pyridin-3-carbaldehyde in toluene (10 ml) was added methyl (triphenylphosphoranilidene) acetate (172 mg, 0.516 mmol). The mixture was heated at 110 ° C. overnight, cooled to room temperature, and 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 column chromatography (EtOAc / hexanes = 1/4) to give 3- (2-ethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (89 mg, 80%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 3H), 3.02 (q, 2H, J = 7.5 Hz) 1.31 (t, 3H, J = 7.5 Hz).

Step 5: 3- (2-ethyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3- (2-Ethyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide was prepared according to the general procedure described in example 107 (step 2) .

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (74 mg, 0.263 mmol) was reacted 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-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -acrylamide ( 45 mg, 37%).

¹ H NMR (300 MHz, DMSO): δ 9.45 (s, 1H, broad), 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 (s, 1H), 7.28 ( d, 1H, J = 8.4 Hz), 6.74 (d, 1H, J = 15.6 Hz), 4.51 (s, 1H), 4.40 (d, 2H, J = 5.7 Hz), 3.00 (s, 3H), 2.96 (q, 2H, J = 7.5 Hz), 1.21 (t, 3H, J = 7.5 Hz).

Example 151: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (153 mg, 0.60 mmol) was reacted with 3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridine- 3-yl] -acrylic acid (144 mg, 0.50 mmol), obtained by a method similar to that described above, obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (176 mg, 72%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (broad s, 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), 4.40 (d, 2H, J = 5.7 Hz), 3.00 (s, 3H), 2, 97 (m, 1H), 2.70 (m, 1H), 1.80 (m, 1H), 1.30 (m, 2H), 0.87 (t, 3H, J = 7.2 Hz), 0.81 (d, 3H, J = 6.6 Hz).

Example 152: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (167 mg, 0.60 mmol) was reacted with 3- [2- (2-methyl-butyl) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (144 mg, 0.50 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (175 mg, 68%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (broad s, 1H), 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), 4.52 (s, 1H), 4.41 (d, 2H, J = 6.0 Hz), 3.07 (s, 3H), 2, 97 (m, 1H), 2.70 (m, 1H), 1.80 (m, 1H), 1.30 (m, 2H), 0.87 (t, 3H, J = 7.2 Hz), 0.81 (d, 3H, J = 6.6 Hz).

ESI [M + H] ⁺ : 512.

Example 153: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Stage 1: synthesis of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethinyl-nicotinamide

N-Methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide was prepared according to the general procedure described in Example 145 (step 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (128 mg, 0.457 mmol) was reacted with 3-methoxypropine (0.042 mg, 0.504 mmol) to give 3- [2- (3-) ethyl ester methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid (89 mg, 62%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 4.44 (s, 2H), 4.30 (d, 2H, J = 7.2 Hz) 3.53 (s, 3H); 1.36 (t, 3H, J = 7.2 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide was prepared according to the general the procedure described in example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (59 mg, 0.21 mmol) was reacted with 3- [2- (3-methoxy-prop-1-ynyl) ) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (40 mg, 0.14 mmol) to obtain N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- ( 3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (35 mg, 33%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, 1H, J = 7.2 Hz), 8.00 (d, 1H, J = 16.5 Hz), 7.62 (d, 1H, J = 8.1 Hz), 7.22 (s, 1H), 7.09 (dd, 1H, J = 10.8, 1.8 Hz), 6.73 (d, 1H, J = 15 , 9 Hz), 6.68 (d, 1H, J = 5.7 Hz), 6.61 (s, 1H), 4.47 (d, 2H, J = 5.7 Hz), 4.40 ( s, 2H), 3.47 (s, 3H), 3.24 (s, 3H).

Example 154: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (19.1 mg, 0.075 mmol) was reacted with 3- [2- (3-methoxy-prop-1-ynyl) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (18 mg, 0.063 mmol) to obtain N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-prop-1-ynyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (35 mg, 33%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (d, 1H, J = 15 6 Hz), 6.56 (s, 1H), 6.22 (t, 1H, J = 6.0 Hz), 4.56 (d, 2H, J = 6.0 Hz), 4.42 ( s, 2H), 3.48 (s, 3H), 3.03 (s, 3H).

Example 155: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

Stage 1: synthesis of N-methoxy-2- (3-methoxy-prop-1-ynyl) -N-methyl-6-trifluoromethyl-nicotinamide

N-Methoxy-2- (3-methoxy-prop-1-ynyl) -N-methyl-6-trifluoromethyl-nicotinamide was prepared according to the general procedure described in Example 145 (step 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1000 mg, 3.72 mmol) was reacted with 3-methoxypropine (0.345 ml, 4.09 mmol) to give N-methoxy-2- (3-methoxy-prop-1-ynyl) -N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 22%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.87 (d, 1H, J = 7.8 Hz), 7.68 (d, 1H, J = 7.8 Hz), 4.35 (s, 3H), 3.51 (s, 3H), 3.44 (s, 3H), 3.41 (s, 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-ynyl) -N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 0.817 mmol) in 5% Pd / C (50 mg) was added ₃ OH (6 ml). The mixture was purged three times with hydrogen gas (50 psi) and shaken for 2 hours at room temperature. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude residue was chromatographed to give N-methoxy-2- (3-methoxypropyl) -N-methyl-6-trifluoromethyl-nicotinamide (160 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.74 (d, 1H, J = 7.8 Hz), 7.68 (d, 1H, J = 7.8 Hz), 3.46-3, 34 (m, 8H), 3.32 (s, 3H), 2.93 (t, 2H, J = 7.8 Hz), 2.12-2.03 (m, 2H).

Stage 3: Synthesis of 3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid methyl ester

3- [2- (3-Methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylic acid methyl ester was prepared according to the general procedure described in Example 150 (step 4).

N-Methoxy-2- (3-methoxypropyl) -N-methyl-6-trifluoromethyl-nicotinamide (156 mg, 0.509 mmol) was reacted with 1M LAH in a THF solution to give 2- (3-methoxypropyl) -6-trifluoromethyl -pyridin-3-carbaldehyde quantitatively in the form of an oil. The crude product was used directly in the next reaction. 2- (3-Methoxypropyl) -6-trifluoromethyl-pyridin-3-carbaldehyde was reacted with methyl (triphenylphosphoranilidene) acetate (204 mg, 0.61 mmol) to give 3- [2- (3-methoxypropyl) - methyl ester 6-trifluoromethyl-pyridin-3-yl] acrylic acid (124 mg, 80%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.98 (d, 1H, J = 15.9 Hz), 7.93 (d, 1H, J = 7.8 Hz), 7.53 (d, 1H, J = 7.8 Hz), 6.43 (d, 1H, J = 15.9 Hz), 3.84 (s, 3H), 3.43 (t, 2H, J = 6.0 Hz) 3.33 (s, 3H); 3.09-3.04 (m, 2H); 2.09-1.99 (m, 2H).

Stage 4: synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide was prepared according to the general procedure described in Example 107 (stage 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, an HCl salt (57.9 mg, 0.207 mmol) were reacted with 3- [2- (3-methoxypropyl) -6-trifluoromethyl- pyridin-3-yl] acrylic acid (40 mg, 0.138 mmol) to give N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl -pyridin-3-yl] -acrylamide (18 mg, 17%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.92 (d, 1H, J = 15.9 Hz), 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 ( d, 1H, J = 11.7 Hz), 6.41-6.36 (m, 2H), 4.51 (d, 2H, J = 5.7 Hz), 3.47-3.42 (m , 3H), 3.31 (s, 3H), 3.26 (s, 3H), 3.09-3.04 (m, 2H), 2.07-1.98 (m, 2H).

Example 156: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (3-Fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide was prepared 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) was reacted with 3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] -acrylic acid (20 mg, 0.096 mmol) to obtain N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxypropyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide ( 18 mg, 17%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 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 (s, 3H ), 3.09-3.04 (m, 2H), 3.02 (s, 3H), 2.07-1.98 (m, 2H).

Example 157: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) acrylamide

Step 1: Synthesis of 3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester

3- (2-Chloro-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (100 mg, 0.357 mmol), Pd (OAc) ₄ (0.05 equiv.), NaHCO ₃ ( 2 eq.), PPh ₃ (0.5 eq.), Styrene (5 eq.) And DMF (1 ml). The ampoule was irradiated in a microwave synthesizer at 135 ° C for 3 hours. The contents of the ampoule were filtered through a pad of celite, which was washed thoroughly with EtOAc. The filtrate was evaporated and the residue was purified by column chromatography to give 3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid ethyl ester (37 mg, 20%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.10 (d, 1H, J = 15.6 Hz), 7.95 (d, 1H, J = 15.6 Hz), 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), 6.45 (d, 1H, J = 15.9 Hz), 4.32 (q, 2H, J = 7.2 Hz), 1.36 (t, 3H, J = 7.2 Hz).

Step 2: Synthesis of N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (36 mg, 0.127 mmol) was reacted with 3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (37 mg, 0.115 mmol) to obtain N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) -acrylamide ( 38 mg, 55%).

¹ H NMR (300 MHz, DMSO): δ 9.45 (s, 1H, broad), 8.91 (t, 1H, J = 6.0 Hz), 8.23 (d, 1H, J = 8 , 1 Hz), 7.97 (d, 1H, J = 15.9 Hz), 7.82-7.74 (m, 4H), 7.61 (d, 1H, J = 15.9 Hz), 7.46-7.29 (m, 5H), 6.75 (d, 1H, J = 15.6 Hz), 4.51 (s, 1H), 4.42 (d, 2H, J = 5, 7 Hz), 3.07 (s, 3H).

Example 158: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- [2- (methyl-propyl-amino) -6-trifluoromethyl-pyridine- 3-yl] -acrylic acid (50 mg, 0.18 mmol), obtaining the target compound (62 mg, 71%) after purification by column chromatography (Hex / EtOAc = 2/3).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.56 (broad s, 1H), 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 (s, 3H), 2.91 (s, 3H), 1.63 (m, 2H ), 0.81 (t, 3H, J = 4.8 Hz).

Example 159: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (N-methyl-N-propyl-amino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (93 mg, 0.33 mmol) was reacted with 3- [2- (methyl-propyl-amino) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (80 mg, 0.28 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (96 mg, 57%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (broad s, 1H), 8.78 (t, 1H, J = 5.3 Hz), 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 (s, 1H), 4.40 (d, 2H, J = 5.7 Hz), 3.21 (m, 2H), 3.07 (s, 3H), 2.91 (s, 3H), 1.63 (m, 2H); 0.81 (t, 3H, J = 7.5 Hz).

Example 160: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (53 mg, 0.21 mmol) was reacted with 3- (2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (52 mg, 0.19 mmol) obtained by a method similar to that described above, obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (53 mg, 59%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): 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), 6.64 (d, 1H, J = 15.3 Hz), 4.77 (s, 2H) 4.52 (d, 2H, J = 5.7 Hz), 3.66 (q, 2H, J = 6.9 Hz), 3.01 (s, 3H), 1.25 (t, 3H, J = 6.9 Hz).

Example 161: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethoxymethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (140 mg, 0.50 mmol) was reacted with 3- (2-ethoxymethyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (125 mg, 0.45 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (141 mg, 63%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 8.41 (s, 1H), 8.20 (t, 1H), 8.01 (d, 1H, J = 7.8 Hz) 7.94 (d, 1H, J = 15.6 Hz), 7.61 (d, 1H, J = 8.1 Hz), 7.27 (s, 1H), 7.14 (d, 1H, J = 10.2 Hz), 6.51 (d, 1H, J = 15.6 Hz), 4.71 (s, 2H), 4.4 (d, 2H, J = 5.7 Hz), 3 60 (q, 2H, J = 6.9 Hz), 3.11 (s, 3H), 1.19 (t, 3H, J = 6.9 Hz).

Example 162: 3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, the HCl salt (43 mg, 0.156 mmol) were reacted with NMM (0.1 ml), DMTMM (44 mg) and 3- (2-sec. butoxy-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (42 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (52.7 mg, 75%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.80 (d, 1H, J = 7.8 Hz), 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), 6.19 (s, 1H), 5.95 (t, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.02 (s, 3H), 2.32 (s, 3H), 1.75 (m, 2H), 1.36 ( d, 3H, J = 6.0 Hz), 0.97 (t, 3H, J = 7.2 Hz).

Example 163: N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-cyano-2-fluoro-phenyl) methanesulfonamide, an HCl salt (101 mg, 0.36 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (82 mg, 0.30 mmol), obtaining, after purification by crystallization from methylene chloride, the target compound (102 mg, 68%).

¹ H NMR (300 MHz, DMSO-d ₆ ): 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 (s, 1H), 7.47 (d, 1H, J = 10.2 Hz), 6.67 (d, 1H, J = 15 6 Hz), 4.51 (d, 2H, J = 5.4 Hz), 3.12 (s, 3H), 2.86 (d, 2H, J = 7.5 Hz), 2.15 ( m, 1H), 0.93 (d, 6H, J = 6.6 Hz).

Example 164: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (82 mg, 0.30 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (116 mg, 79%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.30 (broad s, 1H), 8.78 (t, 1H), 8.15 (d, 1H, J = 8.4 Hz), 7.79 (d, 1H, J = 8.1 Hz), 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 (s, 3H), 2.82 (d, 2H, J = 7.2 Hz), 2, 20 (d, 3H, J = 2.1 Hz), 2.10 (m, 1H), 0.88 (d, 6H, J = 6.6 Hz).

ESI [M + H] ⁺ : 488.

Example 165: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (methyl-phenylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (46 mg, 0.17 mmol) was reacted with 2-methyl-phenylamino-6-trifluoromethyl-pyridin-3 -yl-acrylic acid (55 mg, 0.17 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 3/2), the target compound (45 mg, 49%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (m, 1H), 7.53 (m, 1H), 7.23 (m, 4H), 7.03 (m, 4H), 6, 89 (d, 1H, J = 15.9 Hz), 6.47 (s broad, 1H), 6.03 (d, 1H, J = 16.2 Hz), 5.16 (d, 1H, J = 7.5 Hz), 5.00 (q, 1H, J = 7.2 Hz), 3.53 (s, 3H), 3.04 (s, 3H), 1.40 (d, 3H, J = 6.9 Hz).

Example 166: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (methyl-phenylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (47 mg, 0.17 mmol) was reacted with 3- (2-methyl-phenylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (55 mg, 0.17 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (30 mg, 32%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (m, 1H), 7.20 (m, 4H), 7.00 (m, 5H), 6.43 (broad s, 1H), 6.02 (d, 1H, J = 16.2 Hz), 5.31 (s broad, 1H), 4.32 (d, 2H, J = 6.0 Hz), 3.52 (s, 3H ), 3.48 (s, 1H), 3.29 (s, 3H).

ESI [M + H] ⁺ : 547.

Example 167: N- (4-methanesulfonylamino-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) was reacted with 3- (2-methyl-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (55 mg, 0.17 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (32 mg, 36%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (m, 1H), 7.42 (m, 1H), 7.08 (m, 9H), 6.18 (broad s, 1H), 6.05 (d, 1H, J = 16.2 Hz), 5.25 (s broad, 1H), 4.31 (d, 2H, J = 5.7 Hz), 3.51 (s, 3H ), 3.04 (s, 3H), 2.33 (s, 3H).

Example 168: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl) methanesulfonamide, HCl salt (68 mg, 0.21 mmol) was reacted 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- (3-fluoro-4-methanesulfonylamino-5-trifluoromethylbenzyl ) -acrylamide (80 mg, 68%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.82 (d, 1H, J = 7.5 Hz), 7.76 (d, 1H, J = 15.9 Hz), 7.40-7, 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 ), 4.48-4.44 (m, 2H), 3.27 (s, 3H), 1.83-1.76 (m, 2H), 1.51-1.44 (m, 2H), 0.97 (t, 3H, J = 7.5 Hz).

Example 169: (R) -3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (57 mg, 0.21 mmol) was reacted with 3- (2-butoxy-6-trifluoromethyl-pyridine- 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-methanesulfonylamino-phenyl) ethyl] acrylamide (57 mg, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H) 5.87 (d, 1H, J = 7.5 Hz), 5.24-5.19 (m, 1H), 4.46 (t, 2H, J = 6.9 Hz), 3.02 ( s, 3H), 1.86-1.76 (m, 2H), 1.56-1.45 (m, 5H), 0.9 (t, 3H, J = 7.5 Hz).

Example 170: 3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (58 mg, 0.21 mmol) was reacted 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-methanesulfonylamino-3-methyl-benzyl) acrylamide (58 mg, 57 %).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.76 (d, 1H, J = 9.9 Hz), 7.71 (d, 1H, J = 16.5 Hz), 7.35 (dd, 1H, J = 5.7, 2.4 Hz), 7.21-7.11 (m, 3H), 6.68 (dd, 1H, J = 13.4, 2.7 Hz), 6.28 (s, 1H), 6.00 (s, 1H), 4.49-4.38 (m, 4H), 2.96 (s, 3H), 2.26 (s, 3H), 1.79- 1.74 (m, 2H), 1.47-1.40 (m, 2H), 0.92 (t, 3H, J = 7.2 Hz).

Example 171: 3- (2-ethylthio-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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) were added to the microwave ampoule. The ampoule was irradiated in a Biotage synthesizer at 200 ° C for 10 min. The reaction mixture was purified, obtaining the target compound (15 mg) (Hex / EtOAc = 5/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.92 (d, 1H), 7.75 (d, 1H), 7.25 (d, 1H), 6.38 (d, 1H), 3, 23 (q, 2H); 1.37 (t, 3H).

Stage 2: 3- (2-ethylthio-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-ethynyl-phenyl) methanesulfonamide, HCl salt (67 mg, 0.240 mmol) were reacted with NMM (0.2 ml), DMTMM (65 mg) and 3- ( 2-ethylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (56 mg, 0.200 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (22 mg, 21%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.92 (d, 1H, J = 7.5 Hz), 7.75 (d, 1H, J = 15.3 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.28 (d, 1H, J = 7.8 Hz), 7.08 (m, 1H), 6.44 (d, 1H, J = 15.6 Hz) 6.37 (t, 1H), 4.44 (d, 2H, J = 5.7 Hz), 3.40 (s, 1H), 3.21 (t, 2H, J = 7.2 Hz) 3.02 (s, 3H); 1.32 (t, 3H, J = 7.2 Hz).

Example 172: N- (4-methanesulfonylamino-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 reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (61.5 mg, 57% )

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 6.25 (d, 1H, J = 15.3 Hz), 5.99 (t, 1H), 4.51 (d, 2H, J = 6.0 Hz), 3.28 (t, 2H, J = 8.4 Hz) 3.06 (t, 2H, J = 8.4 Hz); 3.01 (s, 3H).

ESI [M + H] ⁺ : 518.

Example 173: N- (3-fluoro-4-methanesulfonylamino-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 reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (62 mg, 56% )

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, 1H), 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 (s, 3H); 2.23 (d, 3H, J = 2.1 Hz).

Example 174: 3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (47 mg, 0.17 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (41 mg, 0.15 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (68 mg, 96%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.05 (broad s, 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 (s, 3H), 2.83 (d, 2H, J = 6 , 9 Hz), 2.29 (s, 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-methanesulfonylamino-phenyl) ethyl] -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (44 mg, 0.17 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (41 mg, 0.15 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (47 mg, 64%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.56 (broad s, 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), 7.67 (d, 1H, J = 15.6 Hz), 7.17 (m, 3H), 6, 74 (d, 1H, J = 15.6 Hz), 5.03 (t, 1H, J = 7.2 Hz), 3.00 (s, 3H), 2.81 (d, 2H, J = 7 , 2 Hz), 2.01 (m, 1H), 1.41 (d, 3H, J = 7.2 Hz), 0.88 (dd, 6H, J = 2.1 and 6.6 Hz).

ESI [M + H] ⁺ : 488.

Example 176: 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (60 mg, 0.22 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (58 mg, 0.20 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (85 mg, 88%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.04 (broad s, 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), 6.61 (d, 1H, J = 15.3 Hz), 4.35 (d, 2H, J = 5.7 Hz), 4.07 ( m, 1H), 2.94 (s, 3H), 2.28 (s, 3H), 1.55 (m, 2H), 1.14 (d, 3H, J = 6.6 Hz), 0, 85 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 485.

Example 177: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylthio-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-ethynyl-phenyl) methanesulfonamide, HCl salt (53 mg, 0.190 mmol) were reacted with NMM (0.15 ml), DMTMM (62 mg) and 3- ( 2-isopropylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (51 mg, 0.175 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (65 mg, 72%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 10.8 Hz), 6.45 (d, 1H, J = 15 , 9 Hz), 6.42 (s, 1H), 6.16 (t, 1H), 4.52 (d, 2H, J = 6.3 Hz), 4.14 (m, 1H), 3, 48 (s, 1H), 3.27 (s, 3H), 1.43 (d, 6H, J = 6.6 Hz).

Example 178: N- (3-fluoro-4-methanesulfonylamino-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-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (245 mg, 0.974 mmol) was reacted with 2-propanethiol (240 mg, 3.15 mmol) and sodium hydride (143 mg, 3.56 mmol) to obtain, after purification by column chromatography (Hex / EtOAc = 2.5 / 1), of the target compound (103 mg).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 1.44 (d, 6H, J = 6.9 Hz) .

Stage 2: N- (3-fluoro-4-methanesulfonylamino-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 reacted with NMM (0.15 ml), DMTMM (39 mg) and 3- (2-isopropylthio- 6-trifluoromethyl-pyridin-3-yl) -acrylic acid (31 mg, 0.106 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (49 mg, 94%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 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 (s, 3H), 1.43 (d, 6H, J = 6.9 Hz).

Example 179: N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (49 mg, 0.19 mmol) was reacted with 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3- yl] -acrylic acid (50 mg, 0.16 mmol) to obtain N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl ] -acrylamide (58 mg, 71%).

¹ H NMR (300 MHz, DMSO): δ 9.57 (s, 1H, broad), 8.84 (t, 1H, J = 5.7 Hz), 8.38 (d, 1H, J = 7 8 Hz), 8.02 (d, 1H, J = 7.8 Hz), 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 = 5.7Hz), 3.00 (s, 3H).

Example 180: N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, an HCl salt (51 mg, 0.19 mmol) were reacted with 3- [2- (3-fluorophenyl) -6-trifluoromethyl- pyridin-3-yl] acrylic acid (50 mg, 0.16 mmol) to give N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- [2- (3-fluorophenyl) -6 trifluoromethyl-pyridin-3-yl] acrylamide (47 mg, 56%).

¹ H NMR (300 MHz, DMSO): δ 9.28 (s, 1H, broad), 8.80 (t, 1H, J = 6.0 Hz), 8.36 (d, 1H, J = 8 4 Hz), 8.01 (d, 1H, J = 8.4 Hz), 7.59 (dd, 1H, J = 7.8, 5.7 Hz), 7.43-7.34 (m , 4H), 7.19-7.09 (m, 2H), 6.83 (d, 1H, J = 15.6 Hz), 4.37 (d, 2H, J = 5.4 Hz), 2 98 (s, 3H); 2.20 (s, 3H).

Example 181: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (51 mg, 0.19 mmol) was reacted with 3- [2- (3-fluorophenyl) -6- trifluoromethyl-pyridin-3-yl] -acrylic acid (50 mg, 0.16 mmol) to give (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2 - (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide (54 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.07 (d, 1H, J = 8.1 Hz), 7.72 (d, 1H, J = 15.3 Hz), 7.70 (d, 1H, J = 8.1 Hz), 7.56-7.41 (m, 2H), 7.35-7.30 (m, 2 H), 7.19-7.15 (m, 3H), 6.48 (s, 1H), 6.45 (d, 1H, J = 15.3 Hz), 5.87 (d, 1H, J = 7.5 Hz), 5.20-5.15 (m , 1H), 3.02 (s, 3H), 1.54 (d, 3H, J = 7.2 Hz).

Example 182: 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (53 mg, 0.19 mmol) was introduced into the reaction 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl ] -acrylic acid (50 mg, 0.16 mmol) to give 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide (48 mg, 59%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.06 (d, 1H, J = 8.1 Hz), 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 (s, 1H), 5.93 (s, 1H), 4.51 (d, 2H, J = 5.7 Hz), 3.03 (s, 3H), 2.31 (s , 3H).

Example 183: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (54 mg, 0.19 mmol) was reacted 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-methanesulfonylamino-phenyl) ethyl] -3- (2 piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide (54 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 7.17-7.12 (m, 3H), 6.56 (s, 1H), 6.42 (d, 1H, J = 15.6 Hz), 5, 92 (d, 1H, J = 7.5 Hz), 5.24-5.19 (m, 1H), 3.29-3.26 (m, 4H), 3.03 (s, 3H), 1 70-1.64 (m, 6H); 1.54 (d, 3H, J = 7.2 Hz).

Example 184: N- (4-methanesulfonylamino-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) was reacted with 3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3- yl) -acrylic acid (50 mg, 0.16 mmol) to give 3-N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3 -yl) -acrylamide (33 mg, 40%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.72-7.67 (m, 2H), 7.41 (d, 1H, J = 8.4 Hz), 7.21-7.12 (m , 3H), 6.43 (d, 1H, J = 15.6 Hz), 6.24 (s, 1H), 5.96 (t, 1H, J = 5.7 Hz), 4.53 (d , 2H, J = 5.7 Hz), 3.30-3.25 (m, 4H), 3.03 (s, 3H), 2.32 (s, 3H), 1.71-1.63 ( m, 6H).

Example 185: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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) was reacted with propantiol (229 mg, 3.01 mmol) and sodium hydride (145 mg, 3, 62 mmol) to obtain, after purification by column chromatography (Hex / EtOAc = 2/3), of the target compound (115 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.97 (d, 1H, J = 15.9 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 7.8 Hz), 6.42 (d, 1H, J = 15.9 Hz). 3.21 (t, 2H, J = 7.2 Hz), 1.73 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propylthio-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-ethynyl-phenyl) -methanesulfonamide, HCl salt (60.2 mg, 0.215 mmol) were reacted with NMM (0.15 ml), DMTMM (70.2 mg) and 3- (2-propylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (58.7 mg, 0.21 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (60 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (m, 1H), 6.17 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3, 26 (s, 3H), 3.23 (q, 2H, J = 7.5 Hz), 1.73 (m, 2H), 1.03 (t, 3H, J = 7.5 Hz).

Example 186: N- (4-methanesulfonylamino-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 reacted with NMM (0.15 ml), DMTMM (123 mg) and 3- (2- propylthio-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (114.4 mg, 0.393 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (57 mg, 30%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6 22 (m, 1H), 6.03 (m, 1H), 4.52 (d, 2H, J = 5.7 Hz), 3.23 (q, 2H, J = 6.9 Hz), 3 02 (s, 3H), 1.73 (m, 2H), 1.03 (t, 3H, J = 6.9 Hz).

Example 187: N- (4-methanesulfonylamino-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) was reacted with 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (50 mg, 0.17 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (39 mg, 47%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.61 (m, 2H), 7.42 (m, 1H), 7.20 (m, 2H), 6.89 (d, 1H, J = 7 5 Hz), 6.33 (d, 1H, J = 15.0 Hz), 6.17 (s broad, 1H), 5.90 (s broad, 1H), 4.80 (s broad. , 1H), 4.53 (d, 2H, J = 5.7 Hz), 3.50 (m, 2H), 3.03 (s, 3H), 2.32 (s, 3H), 1.49 (m, 4H), 1.40 (m, 2H), 0.96 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 485.

Example 188: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-butylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (60 mg, 0.21 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (60 mg, 57%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.60 (m, 2H), 7.23 (m, 2H), 6.89 (d, 1H, J = 7.8 Hz), 6.33 ( d, 1H, J = 15.3 Hz), 6.30 (s broad., 1H), 6.01 (s broad., 1H), 4.84 (c broad., 1H), 4.59 (d , 2H, J = 6.0 Hz), 3.49 (m, 2H), 3.05 (s, 3H), 2.25 (d, 3H, J = 2.1 Hz), 1.60 (m , 2H), 1.39 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 503.

Example 189: N- (3-fluoro-4-methanesulfonylamino-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 reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (82 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.85 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 15.3 Hz), 7.53 (d, 1H, J = 8.1 Hz), 7.43 (m, 1H), 7.39 (d, 1H, J = 9.9 Hz), 7.22 (m, 2H), 7.17 (s, 1H), 7.14 (m, 1H), 6.25 (d, 1H, J = 15.3 Hz), 6.18 (s, 1H), 6.08 (t, 1H), 4.58 ( d, 2H, J = 6.0 Hz), 3.29 (t, 2H, J = 8.7 Hz), 3.28 (s, 3H), 3.08 (t, 2H, J = 8.7 Hz).

Example 190: 3- [2- (3-diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

Step 1: Synthesis of 3- [2- (3-diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] acrylic acid ethyl ester

3- [2- (3-Diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] -acrylic acid ethyl ester was prepared according to the general procedure described in Example 145 (step 1).

2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (50 mg, 0.178 mmol) was reacted as described above with diethyl-prop-2-ynylamine-amine (2 equiv.) To give ethyl 3- [2- (3-diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] acrylic ester (30 mg, 47%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.14 (d, 1H, J = 16.2 Hz), 8.05 (d, 1H, J = 8.4 Hz), 7.63 (d, 1H, J = 8.4 Hz), 6.57 (d, 1H, J = 16.2 Hz), 4.30 (q, 2H, J = 7.2 Hz), 3.81 (s, 2H) 2.69 (q, 4H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz), 1.15 (t, 6H, J = 7.2 Hz).

Step 2: Synthesis of 3- [2- (3-diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

3- [2- (3-Diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide was prepared according to the general procedure described in Example 107 (step 2).

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) methanesulfonamide, HCl salt (31 mg, 0.11 mmol) was reacted with 3- [2- (3-diethylamino-prop-1-ynyl) ) -4-trifluoromethyl-phenyl] -acrylic acid (30 mg, 0.092 mmol) as described above, to obtain 3- [2- (3-diethylamino-prop-1-ynyl) -4-trifluoromethyl-phenyl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide (7 mg, 12%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.05 (d, 1H, J = 15.9 Hz), 8.81 (d, 1H, J = 8.1 Hz), 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 (s, 1H), 4.52 (d, 2H, J = 6.0 Hz), 3.77 (s, 2H), 3.47 (s, 1H), 3, 25 (s, 3H), 2.71 (q, 4H, J = 7.2 Hz), 1.13 (t, 6H, J = 7.2 Hz).

Example 191: 3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (40 mg, 0.15 mmol) was reacted with 3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (40 mg, 0.12 mmol), after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (32 mg, 51%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.04 (broad s, 1H), 8.63 (t, 1H), 7.78 (m, 2H), 7.63 (d, 1H , J = 15.9 Hz), 7.25 (m, 8H), 6.99 (d, 1H, J = 8.1 Hz), 6.65 (d, 1H, J = 15.9 Hz), 4.53 (d, 2H, J = 5.1 Hz), 4.35 (d, 2H, J = 6.3 Hz), 2.99 (s, 3H), 2.28 (s, 3H).

Example 192: 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, an HCl salt (65 mg, 0.24 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (55 mg, 0.20 mmol), obtaining, after purification by crystallization from methylene chloride, the target compound (43 mg, 44%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.18 (broad s, 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), 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 (s, 3H), 2.94 (m, 2H), 2, 22 (d, 3H, J = 2.7 Hz), 1.62 (m, 2H), 1.35 (m, 2H), 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-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (65 mg, 0.24 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (55 mg, 0.20 mmol), obtaining, after purification by crystallization from methylene chloride, the target compound (49 mg, 50%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (broad s, 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), 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 (s, 3H), 2.93 (m, 2H), 1, 60 (m, 2H), 1.42 (d, 3H, J = 7.5 Hz), 1.33 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 488.

Example 194: 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (66 mg, 0.24 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) acrylic acid (55 mg, 0.20 mmol), obtaining the target compound (69 mg, 73%) after purification by column chromatography (Hex / EtOAc = 1/2).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s broad, 1H), 5.92 (t, 1H), 4.55 (d, 2H, J = 5.4 Hz), 3.03 (s, 3H), 2.99 ( m, 2H), 2.33 (s, 3H), 1.70 (m, 2H), 1.41 (m, 2H), 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-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (27 mg, 0.10 mmol) was reacted with 3- (2-benzylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (30 mg, 0.093 mmol), obtaining the target compound (39 mg, 78%) after purification by column chromatography (Hex / EtOAc = 2/3).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.30 (broad s, 1H), 8.35 (d, 1H, J = 7.8 Hz), 7.64 (m, 2H), 7.27 (m, 8H), 7.01 (t, 1H), 6.89 (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 (s, 3H), 1.48 (d, 3H, J = 6.9 Hz).

ESI [M + H] ⁺ : 537.

Example 196: 3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (28 mg, 0.10 mmol) was reacted with 3- (2-benzylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (30 mg, 0.093 mmol), obtaining the target compound (44 mg, 87%) after purification by column chromatography (Hex / EtOAc = 2/3).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (broad s, 1H), 8.75 (t, 1H), 7.81 (m, 2H), 7.65 (d, 1H , J = 15.3 Hz), 7.27 (m, 7H), 6.99 (d, 1H, J = 7.2 Hz), 6.66 (d, 1H, J = 15.3 Hz), 4.53 (d, 2H, J = 6.0 Hz), 4.48 (s, 1H), 4.39 (d, 2H, J = 5.7 Hz), 3.04 (s, 3H).

ESI [M + H] ⁺ : 547.

Example 197: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl) pyridin-3-yl-acrylamide

Stage 1: 3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid

To a suspension of 3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (366 mg, 1.22 mmol) in THF (3 ml) was added 1N. LiOH solution (3.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H ₂ O and then washed with EtOAc, acidified with 1N HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. MgSO ₄ , and concentrated in vacuo to give 3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (340 mg, 97%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 3.00 (t, 2H, J = 7.8 Hz), 1.73 (m, 2H) 1.39 (m, 4H); 0.91 (t, 3H, J = 7.2 Hz).

Stage 2: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl) -pyridin-3-yl-acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (74 mg, 0.27 mmol) was reacted with 3- (2-pentyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (77 mg, 0.27 mmol), obtained after purification by column chromatography (Hex / EtOAc = 1/1) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl) -pyridin-3-yl-acrylamide (57 mg, 42%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.93 (m, 2H), 7.52 (d, 1H, J = 8.1 Hz), 7.30 (s broad, 1H), 7, 17 (m, 1H), 6.39 (d, 1H, J = 15.3 Hz), 6.42 (s broad., 1H), 6.09 (s broad., 1H), 4.54 (d , 2H, J = 6.0 Hz), 3.49 (s, 1H), 3.27 (s, 3H), 2.98 (m, 2H), 1.72 (m, 2H), 1.37 (m, 4H); 0.89 (m, 3H).

ESI [M + H] ⁺ : 512.

Example 198: N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (70 mg, 0.26 mmol) was reacted with 3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (74 mg, 0.26 mmol), after purification by column chromatography (Hex / EtOAc = 3/2) N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl ) -pyridin-3-yl-acrylamide (57 mg, 46%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s broad, 1H), 5.94 (s broad, 1H), 4.55 (d, 2H, J = 5.7 Hz), 3.03 (s, 3H), 2.98 (s, 3H), 2.32 (s, 3H), 1.72 (m, 2H ), 1.37 (m, 4H), 0.89 (m, 3H).

ESI [M + H] ⁺ : 484.

Example 199: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl) -pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (49 mg, 0.18 mmol) was reacted with 3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (52 mg, 0.18 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (58 mg, 63%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.94 (m, 2H), 7.41 (m, 1H), 6.99 (m, 2H), 6.40 (d, 1H, J = 15 , 0 Hz), 6.09 (s broad, 1H), 6.06 (s broad, 1H), 4.56 (d, 2H, J = 6.0 Hz), 3.22 (s, 3H ), 2.96 (m, 2H), 1.72 (m, 2H), 1.37 (m, 4H), 0.89 (m, 3H).

ESI [M + H] ⁺ : 506.

Example 200: Synthesis of N- (4-methanesulfonylamino-3,5-difluoro-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (55 mg, 0.19 mmol) was reacted with 3- (2-piperid-1-yl-6-trifluoromethyl-pyridin- 3-yl) -acrylic acid (50 mg, 0.16 mmol) to give 3-N- (4-methanesulfonylamino-3,5-difluoro-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl -pyridin-3-yl) -acrylamide (35 mg, 41%).

¹ H NMR (300 MHz, DMSO): δ 9.50 (s, 1H, broad), 8.82 (t, 1H, J = 6.0 Hz), 7.01 (d, 1H, J = 7 8 Hz), 7.45 (d, 1H, J = 15.9 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.13 (s, 1H), 7.12 ( d, 1H, J = 8.7 Hz), 6.75 (d, 1H, J = 15.9 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.19 (s, 4H), 3.04 (s, 3H), 1.63 (s, 6H).

Example 201: N- (4-methanesulfonylamino-3,5-difluoro-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, the HCl salt (53 mg, 0.19 mmol) was reacted with 3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridine- 3-yl] -acrylic acid (50 mg, 0.16 mmol) to give N- (4-methanesulfonylamino-3,5-difluoro-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridine -3-yl] acrylamide (31 mg, 37%).

¹ H NMR (300 MHz, DMSO): δ 9.50 (s, 1H, broad), 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 -7.09 (m, 2H), 6.84 (d, 1H, J = 15.6 Hz), 4.39 (d, 2H, J = 5.7 Hz), 3.04 (s, 3H) .

Example 202: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-butylamino-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (47 mg, 0.17 mmol) was reacted with 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (50 mg, 0.17 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (52 mg, 59%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.84 (m, 1H), 7.51 (d, 1H, J = 7.8 Hz), 6.79 (m, 1H), 6.47 ( c broad, 3H), 6.30 (d, 1H, J = 15.6 Hz), 4.05 (d, 2H, J = 2.1 Hz), 3.50 (m, 2H), 3, 32 (s, 3H), 1.65 (m, 2H), 1.26 (m, 2H), 0.95 (m, 3H).

ESI [M + H] ⁺ : 507.

Example 203: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (107.2 mg, 0.393 mmol) were reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (99 mg, 58% )

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 4.48 (d, 2H, J = 6.0 Hz), 3.27 (t, 2H, J = 7.2 Hz) 3.17 (s, 3H); 3.06 (t, 2H, J = 7.2 Hz).

ESI [M + H] ⁺ : 540.

Example 204: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (100 mg, 0.37 mmol) was reacted with 3- [2- (2-methoxyethylamino) -6-trifluoromethyl- pyridin-3-yl] -acrylic acid (102 mg, 0.35 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (107 mg, 60%).

¹ H NMR (300 MHz, DMSO-d ₆ ): 9.52 (broad s, 1H), δ 8.76 (t, 1H), 7.81 (d, 1H, J = 7.8 Hz), 7.59 (d, 1H, J = 15.3 Hz), 7.11 (m, 3H), 6.99 (d, 1H, J = 7.8 Hz), 6.64 (d, 1H, J = 15.3 Hz), 4.41 (d, 2H, J = 6.0 Hz), 3.50 (m, 4H), 3.25 (s, 3H), 3.03 (s, 3H).

ESI [M + H] ⁺ : 509.

Example 205: 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (100 mg, 0.37 mmol) was reacted with 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (96 mg, 0.35 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (125 mg, 73%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (broad s, 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 (d, 1H, J = 15.6 Hz), 4.43 (d, 2H, J = 5.7 Hz), 3.05 (s, 3H), 2.94 (m, 2H), 1, 62 (m, 2H), 1.35 (m, 2H), 0.90 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 492.

Example 206: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, an HCl salt (167 mg, 0.60 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (30 mg, 0.50 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (211 mg, 87%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (broad s, 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 (d, 1H, J = 15.6 Hz), 4.53 (s, 1H), 4.41 (d, 2H, J = 6.0 Hz), 3.07 (s, 3H), 2.93 (m, 2H), 1.66 (m, 2H); 0.94 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 484.

Example 207: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (100 mg, 0.37 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (90 mg, 0.35 mmol), obtaining the target compound (134 mg, 80%) after purification by column chromatography (Hex / EtOAc = 1/2).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (broad s, 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 (d, 1H, J = 15.6 Hz), 4.43 (d, 2H, J = 5.7 Hz), 3.05 (s, 3H), 2.92 (m, 2H), 1, 67 (m, 2H), 0.93 (t, 3H, J = 6.9 Hz).

ESI [M + H] ⁺ : 478.

Example 208: N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (102 mg, 0.37 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (90 mg, 0.35 mmol), obtaining the target compound (120 mg, 75%) after purification by column chromatography (Hex / EtOAc = 1/2).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.03 (broad s, 1H), 8.77 (t, 1H), 8.15 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 8.4 Hz), 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 (s, 3H), 2.92 (m, 2H), 2.30 (s, 3H), 1.67 (m, 2H); 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-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (105 mg, 0.39 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (90 mg, 0.35 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (151 mg, 91%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.56 (broad s, 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 (s, 3H), 2.91 (m, 2H), 1, 67 (m, 2H), 1.41 (d, 3H, J = 6.9 Hz), 0.92 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 474.

Example 210: (R) -3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (92 mg, 0.34 mmol) was reacted with 3- (2-sec-butylamino-6-trifluoromethyl- pyridin-3-yl) -acrylic acid (82 mg, 0.28 mmol), obtaining, after purification by crystallization from Hex / EtOAc mixture, the target compound (133 mg, 95%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.56 (broad s, 1H), 8.64 (d, 1H, J = 8.4 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.58 (d, 1H, J = 15.6 Hz), 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), 5.03 (t, 1H), 4.06 (m, 1H), 3, 00 (s, 3H), 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-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (105 mg, 0.39 mmol) was reacted with 3- [2- (2-methyl-butyl) - 6-trifluoromethyl-pyridin-3-yl] -acrylic acid (101 mg, 0.35 mmol), obtaining, after purification by crystallization from ether, the target compound (73 mg, 42%).

¹ H NMR (300 MHz, DMSO-d ₆ ): 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 (s, 3H), 3.00 (m, 1H), 2.70 (m, 1H), 1.92 (m, 1H), 1.41 (d, 3H, J = 6 9 Hz), 1.30 (m, 2H), 0.84 (m, 6H).

ESI [M + H] ⁺ : 502.

Example 212: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (105 mg, 0.39 mmol) was reacted with 3- [2- (2-methoxyethylamino) - 6-trifluoromethyl-pyridin-3-yl] -acrylic acid (102 mg, 0.35 mmol), obtaining, after purification by crystallization from ether, the target compound (114 mg, 65%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (broad s, 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), 6.99 (d, 1H, J = 7.8 Hz), 6, 64 (d, 1H, J = 15.3 Hz), 5.04 (t, 1H, J = 6.9 Hz), 3048 (s, 4H), 3.25 (s, 3H), 3.01 ( s, 3H), 1.41 (d, 3H, J = 6.9 Hz).

Example 213: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-butylamino) -6-trifluoromethyl-pyridin-3-yl-acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (103 mg, 0.38 mmol) was reacted with 3- (2-butylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (110 mg, 0.38 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (120 mg, 63%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 9.23 (s broad, 1H), 8.24 (s broad, 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 (m, 2H), 2.99 (s, 3H), 1.60 (m, 2H), 1.50 (d, 3H, J = 7.2 Hz), 0.94 (m, 3H).

ESI [M + H] ⁺ : 503.

Example 214: N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, HCl salt (52 mg, 0.19 mmol) was reacted with 3- (2-pentyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (55 mg, 0.19 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (65 mg, 68%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (s, broad, 1H), 6.01 (s, broad, 1H), 4.61 (d, 2H, J = 6.0 Hz ), 3.05 (s, 3H), 2.97 (m, 2H), 2.25 (s, 3H), 1.71 (m, 2H), 1.34 (m, 2H), 0.89 (m, 3H).

ESI [M + H] ⁺ : 502.

Example 215: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-pentyl-6-trifluoromethyl) pyridin-3-yl-acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (54 mg, 0.20 mmol) was reacted with 3- (2-pentyl-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (57 mg, 0.20 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (35 mg, 35%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.90 (m, 2H), 7.53 (m, 2H), 6.45 (broad s, 1H), 6.37 (d, 1H, J = 15.6 Hz), 5.85 (d, 1H, J = 7.8 Hz), 5.22 (m, 1H), 3.04 (s, 3H), 2.96 (m, 2H), 1.70 (m, 2H), 1.58 (s, 3H), 1.36 (m, 4H), 0.88 (m, 3H).

ESI [M + H] ⁺ : 502.

Example 216: N- (4-methanesulfonylamino-3-methyl-benzyl) -3- [2- (propan-1-sulfonyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide

N- (4-Methanesulfonylamino-3-methyl-benzyl) -3- (2-propylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide (34.9 mg, 0.0715 mmol) for 3 hours at room at temperature, they were reacted with m-CPBA (60%, 43.7 mg) to obtain the desired compound (31 mg, 83%) after purification by column chromatography (Hex / EtOAc = 1/4).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.24 (d, 1H, J = 14.1 Hz), 8.20 (d, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 8.1 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.15 (m, 2H), 6.55 (d, 1H, J = 15.9 Hz) 6.50 (t, 1H), 6.38 (s, 1H), 4.45 (d, 2H, J = 6.0 Hz), 3.62 (m, 2H), 3.00 (s, 3H), 2.68 (s, 3H), 1.94 (m, 2H), 1.11 (t, 3H, J = 7.5 Hz).

Example 217: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (109 mg, 0.40 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (82 mg, 0.30 mmol), obtaining, after purification by crystallization from ether, the target compound (109 mg, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (broad s, 1H), 8.76 (t, 1H, J = 6.0 Hz), 7.80 (d, 1H, J = 7.5 Hz), 7.64 (d, 1H, J = 15.6 Hz), 7.13 (d, 2H, J = 8.7 Hz), 6.96 (d, 1H, J = 7 8 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.62 (d, 1H, J = 15.6 Hz), 4.41 (d, 2H, J = 6.0 Hz), 4.22 (m, 1H), 3.05 (s, 3H), 1.18 (d, 6H, J = 6.3 Hz).

ESI [M + H] ⁺ : 493.

Example 218: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (107 mg, 0.40 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (82 mg, 0.30 mmol), obtaining, after purification by crystallization from ether, the target compound (137 mg, 93%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.54 (broad s, 1H), 8.65 (d, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.57 (d, 1H, J = 15.3 Hz), 7.25 (m, 3H), 6.96 (d, 1H, J = 7.5 Hz), 6, 80 (d, 1H, J = 7.5 Hz), 6.60 (d, 1H, J = 15.3 Hz), 5.03 (t, 1H, J = 7.5 Hz), 4.20 ( m, 1H), 3.01 (s, 3H), 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-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (110 mg, 0.40 mmol) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (82 mg, 0.30 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (92 mg, 65%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.00 (broad s, 1H), 8.64 (t, 1H), 7.76 (d, 1H, J = 7.2 Hz), 7.62 (d, 1H, J = 15.3 Hz), 7.18 (m, 3H), 6.95 (d, 1H, J = 7.5 Hz), 6.80 (d, 1H, J = 7.2 Hz), 6.61 (d, 1H, J = 15.3 Hz), 4.45 (d, 2H, J = 5.4 Hz), 4.20 (m, 1H), 2, 95 (s, 3H), 2.29 (s, 3H), 1.18 (d, 6H, J = 5.7 Hz).

ESI [M + H] ⁺ : 471.

Example 220: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-isopropylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (55 mg, 0.20 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (88 mg, 90%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.25 (broad s, 1H), 8.64 (t, 1H), 7.75 (d, 1H, J = 7.5 Hz), 7.62 (d, 1H, J = 15.3 Hz), 7.14 (m, 2H), 6.95 (d, 1H, J = 6.6 Hz), 6.80 (d, 1H, J = 7.5 Hz), 6.62 (d, 1H, J = 15.3 Hz), 4.41 (d, 2H, J = 5.4 Hz), 4.21 (m, 1H), 2, 99 (s, 3H), 2.21 (s, 3H), 1.18 (d, 6H, J = 6.3 Hz).

ESI [M + H] ⁺ : 489.

Example 221: N- (3-Ethinyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (106 mg, 0.39 mmol) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (70 mg, 0.26 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (86 mg, 66%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (broad s, 1H), 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), 4.52 (s, 1H), 4.39 (d, 2H, J = 5.7 Hz), 3, 30 (m, 2H), 3.07 (s, 3H), 1.58 (m, 2H), 0.87 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 499.

Example 222: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (92 mg, 0.34 mmol) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70 mg, 0.26 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (74 mg, 58%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.49 (broad s, 1H), 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), 6, 64 (d, 1H, J = 15.3 Hz), 4.41 (d, 2H, J = 6.0 Hz), 3.30 (m, 2H), 3.04 (s, 3H), 1, 58 (m, 2H); 0.88 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 493.

Example 223: N- (3-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (70 mg, 0.26 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (98 mg, 77%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.27 (broad s, 1H), 8.64 (t, 1H), 7.75 (d, 1H, J = 7.2 Hz), 7.58 (d, 1H, J = 15.6 Hz), 7.15 (m, 3H), 6.95 (d, 1H, J = 7.8 Hz), 6.63 (d, 1H, J = 15.6 Hz), 4.40 (d, 2H, J = 5.4 Hz), 3.27 (m, 2H), 2.97 (s, 3H), 2.21 (s, 3H), 1.57 (m, 2H); 0.87 (t, 3H, J = 7.2 Hz).

Example 224: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (91 mg, 0.34 mmol) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (70 mg, 0.26 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (106 mg, 83%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s broad, 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), 6.95 (d, 1H, J = 8.1 Hz), 6, 63 (d, 1H, J = 15.6 Hz), 5.03 (t, 1H, J = 7.2 Hz), 3.27 (m, 2H), 3.00 (s, 3H), 1, 56 (m, 2H), 1.40 (d, 3H, J = 6.6 Hz), 0.86 (t, 3H, J = 7.5 Hz).

Example 225: N- (4-methanesulfonylamino-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) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70 mg, 0.26 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (85 mg, 69%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.12 (broad s, 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), 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 (s, 3H), 2.29 (s, 3H), 1.57 (m, 2H); 0.87 (t, 3H, J = 7.2 Hz).

Example 226: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (30 mg, 0.11 mmol) was reacted with 3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (20 mg, 0.73 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (30 mg, 84%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (broad s, 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 (d, 1H, J = 15.6 Hz), 4.43 (d, 2H, J = 5.4 Hz), 3.05 (s, 3H), 2.83 (d, 2H, J = 6 , 9 Hz), 2.01 (m, 1H), 0.88 (t, 3H, J = 6.6 Hz).

Example 227: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

Stage 1: synthesis of 2,6-difluoro-4-iodoaniline

N-iodosuccinimide was added dropwise to a solution of 2,6-difluoroaniline (5.0 g, 38.7 mmol) and p-toluenesulfonic acid (1.45 g, 7.62 mmol) in DMF (70 ml) at 5 ° C. (9.6 g, 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 with 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 to give 2,6-difluoro-4-iodoaniline (9.12 g, 92.4%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.16 (d, 1H, J = 1.8 Hz), 7.14 (d, 1H, J = 1.8 Hz), 3.76 (s broad ., 2H).

Stage 2: synthesis of 1- (4-amino-3,5-difluoro-phenyl) ethanone

Suspension of 2,6-difluoro-4-iodoaniline (1 g, 3.92 mmol) and Pd (OAc) ₂ (0.025 eq.), DPPP (0.05 eq.) In [bmim] [BF3] (6 ml) stirred for 10 minutes After degassing the mixture three times, butyl vinyl ether (5 equivalents) and Et ₃ N (1.2 equivalents) were sequentially introduced. The mixture was stirred for 15 hours at 115 ° C. The mixture was cooled to room temperature and then 1N was added. HCl. After stirring the mixture for 0.5 hours, CH ₂ Cl _{2 was} added. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography to give 1- (4-amino-3,5-difluoro-phenyl) ethanone (300 mg, 45%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.15 (d, 1H, J = 1.2 Hz), 7.13 (d, 1H, J = 1.2 Hz), 3.76 (s, 2H, broad.).

Stage 3: synthesis of N- (4-acetyl-2,6-difluoro-phenyl) methanesulfonamide

To a solution of 1- (4-amino-3,5-difluoro-phenyl) ethanone (2.35 g, 13.73 mmol) and Et ₃ N (2 ml) in CH ₂ Cl ₂ (10 ml) at 0 ° C was added dropwise MsCl (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 and concentrated under reduced pressure. The crude product was used directly in the next reaction. The crude residue was dissolved in THF (8 ml), then 1N was added to the solution. NaOH (4 ml) and CH ₃ OH (4 ml). After stirring for 5 hours at room temperature, the mixture was diluted with EtOAc and 1N. 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 give N- (4-acetyl-2,6-difluoro-phenyl) methanesulfonamide (1.85 g, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.60 (d, 1H, J = 3.3 Hz), 7.56 (d, 1H, J = 3.3 Hz), 6.43 (s, 1H), 3.89 (s, 3H), 3.58 (s, 3H).

Step 4: Synthesis of N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylamino) ethyl] phenyl} methanesulfonamide

To a solution of N- (4-acetyl-2,6-difluoro-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 brine was added. After extracting the mixture three times using EtOAc, the mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography to give N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylimino) ethyl] phenyl} methanesulfonamide (2.2 g, 85%). To a solution of N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylimino) ethyl] phenyl} methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 ml) at -48 ° C, NaBH ₄ (944 mg, 24.9 mmol) dissolved in THF (2 ml) was added portionwise. The mixture was stirred for 10 hours at a temperature of from -48 ° C to about room temperature, and then CH ₃ OH was added dropwise to stop gas formation. The mixture was concentrated under reduced pressure and then purified by chromatography to give N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylamino) ethyl] phenyl} methanesulfonamide (1.89 g, fifty%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.04 (d, 1H, J = 2.4 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.59 (s, 1H), 4.54-4.49 (m, 1H), 3.53 (d, 1H, J = 3.6 Hz), 3.20 (s, 3H), 1.50 (d, 3H, 6 6 Hz); 1.23 (s, 9H).

Step 5: Synthesis of (R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt

To a solution of N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylamino) ethyl] phenyl} methanesulfonamide (789 mg, 2.22 mmol) in CH ₃ OH (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 CH ₂ Cl ₂ and Et ₂ O to give (R) -N- [4- (1-aminoethyl) -2,6-difluorophenyl] methanesulfonamide, HCl salt (611 g, 96%) .

¹ H NMR (300 MHz, DMSO): δ 8.73 (s, 3H, broad), 7.48 (d, 1H, J = 2.7 Hz), 7.43 (d, 1H, J = 2 , 7 Hz), 4.43 (q, 1H, J = 3.6 Hz), 3.53 (d, 1H, J = 3.6 Hz), 3.07 (s, 3H), 1.51 ( d, 3H, 6.9 Hz).

Step 6: Synthesis of (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (70 mg, 0.24 mmol) was reacted with 3- (2-isopropylamino-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (67 mg, 0.24 mmol), obtaining, after purification by crystallization from ether, the target compound (108 mg, 89%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.49 (broad s, 1H), 8.68 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.5 Hz), 7.57 (d, 1H, J = 15.3 Hz), 7.17 (d, 2H, J = 9.0 Hz), 6.96 (d, 1H, J = 7 8 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.62 (d, 1H, J = 15.3 Hz), 5.03 (m, 1H), 4.22 ( m, 1H), 3.04 (s, 3H), 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-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (70 mg, 0.24 mmol) was reacted with 3- (2-butyl-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (67 mg, 0.24 mmol), obtaining, after purification by crystallization from ether, the target compound (115 mg, 95%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s broad, 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), 7.67 (d, 1H, J = 15.6 Hz), 7.17 (d, 2H, J = 8 4 Hz), 6.75 (d, 1H, J = 15.6 Hz), 5.04 (m, 1H), 3.03 (s, 3H), 2.93 (m, 2H), 1, 61 (m, 2H), 1.41 (d, 3H, J = 6.9 Hz), 1.36 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 506.

Example 229: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (60 mg, 0.21 mmol) was reacted with 3- (2-propylamino-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (56 mg, 0.20 mmol), obtaining, after purification by crystallization from ether, the target compound (95 mg, 95%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (broad s, 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), 6.96 (d, 1H, J = 7.5 Hz), 6, 63 (d, 1H, J = 15.3 Hz), 5.03 (m, 1H), 3.28 (m, 2H), 3.04 (s, 3H), 1.56 (m, 2H), 1.40 (d, 3H, J = 6.5 Hz), 0.87 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 507.

Example 230: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (62 mg, 0.22 mmol) was reacted with 3- (2-propyl-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (56 mg, 0.22 mmol), obtaining, after purification by crystallization from ether, the target compound (81 mg, 73%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s broad, 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), 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 (s, 3H), 2.91 (m, 2H), 1, 65 (m, 2H), 1.41 (d, 3H, J = 6.9 Hz), 0.92 (t, 3H, J = 7.2 Hz).

ESI [M + H] ⁺ : 492.

Example 231: N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-6-ethynyl-2-fluoro-phenyl) methanesulfonamide, an HCl salt (75 mg, 0.27 mmol) was reacted with 3- (2-isopropyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (70 mg, 0.27 mmol), obtaining, after purification by recrystallization (Hex / EtOAc) N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6 trifluoromethyl-pyridin-3-yl) -acrylamide (54 mg, 42%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, 1H, J = 15.6 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 8.4 Hz), 7.31 (s, 1H), 7.19 (m, 1H), 6.41 (s, 1H), 6.35 (d, 1H, J = 15.6 Hz), 6.02 (s broad, 1H), 4.55 (d, 2H, J = 5.7 Hz), 3.49 (s, 1H), 3.48 (m, 1H), 3, 27 (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H).

ESI [M + H] ⁺ : 484.

Example 232: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (74 mg, 0.27 mmol) was reacted with 3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70 mg, 0.27 mmol), obtaining, after purification by recrystallization (Hex / EtOAc), the target compound (46 mg, 36%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.60 (s, 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 (s, 3H), 1.24 (s, 3H), 1.21 (s, 3H).

Example 233: N- (4-methanesulfonylamino-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) was reacted with 3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (74 mg, 0.27 mmol), obtaining, after purification by recrystallization (Hex / EtOAc), the target compound (61 mg, 50%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.03 (d, 1H, J = 15.6 Hz), 7.83 (d, 1H, J = 8.1 Hz), 7.45 (m, 2H), 7.22 (s, 1H), 7.19 (s, 1H), 6.34 (d, 1H, J = 15.3 Hz), 6.19 (s, 1H), 5.98 ( s, 1H), 4.54 (d, 2H, J = 6.0 Hz), 3.47 (m, 1H), 3.03 (s, 3H), 2.32 (s, 3H), 1, 31 (s, 3H); 1.29 (s, 3H).

Example 234: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (73 mg, 0.27 mmol) was reacted with 3- (2-isopropyl-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (70 mg, 0.27 mmol), obtaining, after purification by recrystallization (Hex / EtOAc), the target compound (69 mg, 54%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 6.34 (d, 1H, J = 15.9 Hz), 5.87 (s broad, 1H), 5, 21 (s broad, 1H), 3.90 (d, 1H, J = 5.1 Hz), 3.44 (m, 1H), 3.04 (s, 3H), 1.54 (s, 3H ), 1.29 (s, 3H), 1.27 (s, 3H).

ESI [M + H] ⁺ : 474.

Example 235: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-sec-butyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (89 mg, 0.33 mmol) was reacted with 3- (2-sec-butyl-6-trifluoromethyl-pyridin-3- il) -acrylic acid (89 mg, 0.33 mmol), obtaining, after purification by recrystallization (Hex / EtOAc = 2: 3), the target compound (33 mg, 20%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6.35 (d, 1H, J = 15.3 Hz), 6.03 (s broad, 2H), 4.57 (d, 2H, J = 6.0 Hz), 3.22 (s, 3H), 1.88 (m, 2H), 1.66 (m, 1H), 1.27 ( d, 2H, J = 6.6 Hz), 0.82 (t, 3H, J = 7.5 Hz).

Example 236: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (61.8 mg, 0.215 mmol) was reacted with NMM (0.10 ml), DMTMM (93 mg) and 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (67 mg, 0.208 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (98.3 mg, 85%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6.95 (d, 1H, J = 8.1 Hz), 6.48 (s, 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 (s, 3H), 3.07 (t, 2H, J = 8.4 Hz).

Example 237: (R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (61.4 mg, 0.228 mmol) was reacted with NMM (0.10 ml), DMTMM (97 mg) and 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (72 mg, 0.224 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (80.8 mg, 67%).

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 6.22 (d, 1H, J = 15.3 Hz), 5.83 (d, 1H, J = 7.5 Hz) 5.20 (m, 1H J = 6.9 Hz), 3.25 (t, 2H, J = 7.8 Hz), 3.07 (t, 2H, J = 7.8 Hz), 3, 02 (s, 3H).

ESI [M + H] ⁺ : 554.

Example 238: (R) -3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N - [(1R) - (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (80 mg, 0.28 mmol) was reacted with 3- (2-butylamino-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (96 mg, 0.33 mmol), obtaining, after purification by crystallization from ether, the target compound (140 mg, 96%).

¹ H NMR (300 MHz, DMSO): δ 9.49 (s, 1H), 8.68 (d, 1H, J = 7.2 Hz), 7.77 (d, 1H, J = 7.2 Hz ), 7.54 (d, 1H, J = 15.3 Hz), 7.19-7.12 (m, 3H), 6.95 (d, 1H, J = 7.8 Hz), 6.63 (d, 1H, J = 15.6 Hz), 5.05-5.01 (m, 1H), 3.34-3.26 (m, 2H), 3.05 (s, 3H), 1, 55-1.45 (m, 2H), 1.40 (d, 3H, J = 5.7 Hz), 0.88 (t, 3H, J = 7.5 Hz).

ESI [M + H] ⁺ : 521.

Example 239: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (80 mg, 0.28 mmol) was reacted with 3- (2-piperide-1- il-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (100 mg, 0.33 mmol), obtaining, after purification by crystallization from ether, the target compound (140 mg, 95%).

¹ H NMR (300 MHz, DMSO): δ 9.95 (s, 1H), 8.68 (d, 1H, J = 7.5 Hz), 7.99 (d, 1H, J = 7.5 Hz ), 7.42 (d, 1H, J = 7.2 Hz), 7.41 (d, 1H, J = 15.0 Hz), 7.25-7.15 (m, 3H), 6.74 (d, 1H, J = 15.6 Hz), 5.06-5.02 (m, 1H), 3.32 (s, 4H, broad), 3.05 (s, 3H), 1.61 (s, 5H, broad), 1.40 (t, 3H, J = 5.1 Hz).

ESI [M + H] ⁺ : 533.

Example 240: (S) -3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N - [(1S) - (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide

(S) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (40 mg, 0.14 mmol) was reacted with 3- (2-butylamino-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (48 mg, 0.16 mmol), obtaining, after purification by crystallization from ether, the target compound (57 mg, 80%).

¹ H NMR (300 MHz, DMSO): δ 9.49 (s, 1H), 8.68 (d, 1H, J = 7.5 Hz), 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), 5.05-5.00 (m, 1H), 3.34-3.29 (m, 2H), 3.05 (s, 3H), 1, 58-1.48 (m, 2H), 1.40 (d, 3H, J = 6.9 Hz), 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-methanesulfonylamino-3-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-methyl-phenyl) methanesulfonamide, HCl salt (98 mg, 0.359 mmol) were reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (25 mg, 15%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.03 (d, 1H, J = 15 Hz), 7.84 (d, 1H, J = 7.8 Hz), 7.45 (m, 2H) , 7.22 (s, 1H), 6.99 (s broad, 1H), 6.33 (d, 1H, J = 15.3 Hz), 6.20 (s, 1H), 4.54 ( d, 2H, J = 5.7 Hz), 3.21 (m, 1H), 3.03 (s, 3H), 2.32 (s, 3H), 1.85 (m, 1H), 1, 66 (m, 1H), 1.26 (d, 3H, J = 6.6 Hz), 0.81 (t, 3H, J = 7.2 Hz).

Example 242: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (77 mg, 0.27 mmol) was reacted with NMM (0.10 ml), DMTMM (90 mg) and 3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70 mg, 0.27 mmol), obtained after purification by column chromatography (Hex / EtOAc = 1/1) target compound (75 mg, 57%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.99 (d, 1H, J = 15.6 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 8.1 Hz), 7.02 (s, 1H), 6.99 (s, 1H), 6.35 (d, 1H, J = 15.3 Hz), 6.12 (s, 1H), 5.95 (d, 1H, J = 7.2 Hz), 5.19 (m, 1H), 3.44 (m, 1H), 3.22 (s, 3H), 1.53 ( d, 3H, J = 6.6 Hz), 1.30 (s, 3H), 1.28 (s, 3H).

Example 243: (R) -3- (2-sec-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (69 mg, 0.256 mmol) was reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (40 mg, 32%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.00 (d, 1H, J = 15.3 Hz), 7.84 (d, 1H, J = 8.1 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 8.1 Hz), 7.19 (s, 1H), 7.16 (s, 1H), 6.46 (s, 1H), 6.32 (d, 1H, J = 15.3 Hz), 5.85 (d, 1H, NH), 5.22 (m, 1H), 3.19 (m, 1H), 3, 03 (s, 3H), 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-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (22 mg, 0.215 mmol) was reacted with NMM (0.10 ml), DMTMM (43 mg) and 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (21 mg, 0.081 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (22 mg, 55%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.02 (d, 1H), 7.92 (d, 1H, J = 15.3 Hz), 7.62 (m, 3H), 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 ( s, 3H), 1.56 (m, 2H), 1.49 (d, 3H, J = 6.5 Hz), 0.87 (t, 3H, J = 7.2 Hz).

Example 245: (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (138 mg, 0.48 mmol) was reacted 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), obtained after purification by column chromatography (Hex / EtOAc = 1/1 ) target compound (178 mg, 74%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.94 (d, 1H, J = 4.2 Hz), 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 (s, 1H), 6.45 (d, 1H, J = 15.3 Hz) 6.35 (d, 1H, J = 7.5 Hz), 5.13 (m, 1H), 3.19 (s, 3H), 2.83 (d, 2H, J = 7.2 Hz) 2.12 (m, 1H), 1.46 (d, 3H, J = 6.9 Hz), 0.90 (d, 6H).

ESI [M-H] -: 504.

Example 246: N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-ethylamino) -6-trifluoromethyl-pyridin-3-yl-acrylamide

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (145 mg, 0.54 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridine- 3-yl) -acrylic acid (140 mg, 0.54 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (113 mg, 41%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (m, 3H), 7.18 (s, 1H), 7.14 (m, 1H), 6.90 (d, 1H, J = 7 , 2 Hz), 6.48 (s, 1H), 6.33 (d, 1H, J = 15.0 Hz), 5.82 (s broad, 1H), 5.21 (m, 1H), 4.78 (s broad, 1H), 3.53 (m, 2H), 3.03 (s, 3H), 1.56 (d, 3H, J = 5.5 Hz), 1.25 (t , 3H, J = 7.5 Hz).

ESI [MH] -: 473.

Example 247: N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-ethylamino-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (4-Aminomethyl-3-methyl-phenyl) methanesulfonamide, HCl salt (78 mg, 0.284 mmol) was reacted with 2-ethylamino-6-trifluoromethyl-pyridin-3-yl-acrylic acid (74 mg, 0.284 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2: 3), the target compound (83 mg, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.66 (d, 1H, J = 14.7 Hz), 7.57 (m, 1H), 7.19 (m, 2H), 6.90 ( m, 1H), 6.35 (d, 1H, J = 15.3 Hz), 6.30 (s, 1H), 5.96 (s, 1H), 4.86 (s, 1H), 4, 53 (d, 2H, J = 5.4 Hz), 3.54 (m, 2H), 3.02 (s, 3H), 2.31 (s, 3H), 1.26 (t, 3H, J = 6.6 Hz).

ESI [M-H] -: 455.

Example 248: N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,5-difluoro-phenyl) methanesulfonamide, HCl salt (33 mg, 0.12 mmol) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (38 mg, 0.14 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (35 mg, 59%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.84 (broad s, 1H), 8.69 (t, 1H, J = 5.7 Hz), 7.77 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 15.6 Hz), 7.25 (m, 2H), 7.14 (m, 1H), 6.96 (d, 1H, J = 7.5 Hz), 6.62 (d, 1H, J = 15.6 Hz), 4.39 (d, 2H, J = 5.4 Hz), 3.28 (m, 2H), 3, 07 (s, 3H), 1.57 (m, 2H), 0.87 (t, 3H, J = 7.2 Hz).

ESI [MH] -: 491.

Example 249: 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (301 mg, 1.07 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (200 mg, 0.76 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (110 mg, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 8.75 (t, 1H, J = 6.0 Hz), 7.80 (d, 1H, J = 7 5 Hz), 7.59 (d, 1H, J = 15.6 Hz), 7.30 (s, 1H), 7.29 (d, 1H, J = 9.0 Hz), 7.13 ( t, 1H, J = 5.1 Hz), 6.96 (d, 1H, J = 7.8 Hz), 6.63 (d, 1H, J = 15.3 Hz), 4.51 (s, 1H), 4.39 (d, 2H, J = 6.0 Hz), 3.41-3.37 (m, 2H), 3.06 (s, 3H), 1.14 (t, 3H, J = 6.9 Hz).

ESI [MH] -: 483.

Example 250: 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-vinyl-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-vinyl-phenyl) methanesulfonamide, an HCl salt (258 mg, 0.92 mmol) were reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (200 mg, 0.76 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (270 mg, 60%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.32 (s, 1H), 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 (s, 1H), 7.18-7.04 (m, 2H), 6.96 (d, 1H , J = 7.8 Hz), 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 Hz), 3.50-3.40 (m, 2H), 3.00 (s, 3H), 1.13 (t , 3H, J = 6.9 Hz).

ESI [MH] -: 485.

Example 251: N- (2-chloro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

A mixture of N- (4-aminomethyl-3-chloro-phenyl) methanesulfonamide, an HCl salt and N- (4-aminomethyl-phenyl) methanesulfonamide, an HCl salt (80 mg) was reacted with 3- (2-propyl-6 -trifluoromethyl-pyridin-3-yl) -acrylic acid (76 mg, 0.28 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (77 mg, 57%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.98 (broad s, 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), 7.70 (d, 1H, J = 15.9 Hz), 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), 3.02 (s, 3H), 2.91 (m, 2H), 1.66 (m, 2H), 0.93 (t, 3H, J = 7.5 Hz).

ESI [MH] -: 474.

Example 252: N- (4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

A mixture of N- (4-aminomethyl-3-chloro-phenyl) methanesulfonamide, an HCl salt and N- (4-aminomethyl-phenyl) methanesulfonamide, an HCl salt (80 mg) was reacted with 3- (2-propyl-6 -trifluoromethyl-pyridin-3-yl) -acrylic acid (76 mg, 0.28 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (50 mg, 39%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.69 (broad s, 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 (d, 1H, J = 15.9 Hz), 4.37 (d, 2H, J = 5.7 Hz), 3.00 (m, 5H), 1.66 (m, 2H), 0.93 (t, 3H, J = 7.5 Hz).

ESI [M-H] -: 440.

Example 253: N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2-chloro-phenyl) -methanesulfonamide, HCl salt (58 mg, 0.22 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (60 mg, 0.22 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (65 mg, 62%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.98 (m, 1H), 7.89 (m, 1H), 7.46 (m, 4H), 6.38 (d, 1H, J = 15 , 3 Hz), 6.02 (s broad, 1H), 4.59 (dd, 2H, J = 7.8 Hz, 6.0 Hz), 3.49 (s, 3H), 1.76 ( m, 2H), 1.26 (m, 2H), 1.01 (m, 3H).

Example 254: N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl) pyridin-3-yl-acrylamide

N- (3-Chloro-4-aminomethyl-phenyl) methanesulfonamide, HCl salt (61 mg, 0.22 mmol) was reacted with 3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (60 mg, 0.22 mmol), obtaining the target compound (73 mg, 68%) after purification by column chromatography (Hex / EtOAc = 1: 1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.59 (m, 3H), 7.31 (m, 2H), 6.90 (m, 1H), 6.84 (s broad, 1H), 6.36 (d, 1H, J = 15.0 Hz), 6.13 (s broad, 1H), 4.55 (dd, 2H, J = 14.1Hz, 6.3 Hz), 3.48 (s, 3H), 1.65 (m, 4H), 0.97 (t, 3H, J = 7.2 Hz).

Example 255: N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl) -pyridin-3-yl-acrylamide

N- (4-Aminomethyl-2,5-difluoro-phenyl) methanesulfonamide, HCl salt (61 mg, 0.22 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (58 mg, 0.22 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (20 mg, 18%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.91 (m, 1H), 8.22 (m, 1H), 7.67 (d, 1H, J = 15.3 Hz), 7.57 ( d, 1H, J = 7.5 Hz), 6.87 (m, 2H), 6.36 (d, 1H, J = 15.0 Hz), 6.25 (s broad, 1H), 5, 01 (s broad, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.06 (s, 3H), 3.04 (m, 2H), 1.25 (m, 3H )

ESI [MH] -: 477.

Example 256: 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-phenyl) methanesulfonamide, HCl salt (117 mg, 0.46 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (100 mg, 0.38 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (118 mg, 56%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (s, 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), 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 (s, 3H), 1.14 (t, 3H, J = 6.9 Hz).

ESI [MH] -: 459.

Example 257: N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, HCl salt (125 mg, 0.46 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (100 mg, 0.38 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (110 mg, 60%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.50 (s, 1H), 8.76 (t, 1H, J = 6.0 Hz), 7.80 (d, 1H, J = 7 8 Hz), 7.59 (d, 1H, J = 15.3 Hz), 7.13 (s, 1H), 7.13 (d, 1H, J = 8.4 Hz), 6.96 ( d, 1H, J = 7.5 Hz), 6.64 (d, 1H, J = 15.6 Hz), 4.41 (d, 2H, J = 6.0 Hz), 3.42-3, 35 (m, 2H), 3.04 (s, 3H), 1.14 (t, 3H, J = 6.9 Hz).

ESI [MH] -: 477.

Example 258: 3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide

N- (4-Aminomethyl-2-fluoro-6-methyl-phenyl) methanesulfonamide, HCl salt (124 mg, 0.46 mmol) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (100 mg, 0.38 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (230 mg, 62%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.26 (s, 1H), 8.64 (t, 1H, J = 6.0 Hz), 7.75 (d, 1H, J = 7 5 Hz), 7.57 (d, 1H, J = 15.6 Hz), 7.22-7.17 (m, 1H), 6.96 (d, 1H, J = 7.8 Hz), 6.63 (d, 1H, J = 15.6 Hz), 4.41 (d, 2H, J = 5.4 Hz), 3.42-3.37 (m, 2H), 2.98 (s , 3H), 2.21 (s, 3H), 1.14 (t, 3H, J = 6.9 Hz).

ESI [MH] -: 473.

Example 259: N- (3-cyano-5-fluoro-4-methanesulfonylamino-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) was reacted with 3- (2-ethylamino-6-trifluoromethyl-pyridin-3- il) -acrylic acid (100 mg, 0.38 mmol), obtaining, after purification by recrystallization from diethyl ether, the target compound (113 mg, 54%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.07 (s, 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), 6.64 (d, 1H, J = 15.6 Hz), 4.45 (d, 2H, J = 5.7 Hz), 3.42-3.38 (m, 2H), 3.11 (s , 3H), 1.14 (t, 3H, J = 6.9 Hz).

Example 260: 3- (2-Butylamino-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide

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 and 1 M LiAlH _{4 was} added dropwise into THF (3.3 ml, 3.3 mmol). The resulting mixture was stirred for 1 hour at -78 ° C and then slowly heated to -20 ° C for 2 hours, then quenched by adding 10% sodium potassium tartrate, then EtOAc. After vigorous stirring for 30 minutes at room temperature, the two phases were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain an aldehyde.

A solution of carbon tetrabromide (4.35 g, 13.1 mmol) in methylene chloride in a nitrogen atmosphere at 0 ° C was treated with triphenylphosphine (6.87 g, 26.2 mmol) and stirred for 1 h at 0 ° C. The mixture was treated with the aldehyde obtained above, stirred for 1 h at 0 ° C and then quenched with water. The separated organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was treated with hexane and the supernatant was collected. 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 to give the desired compound (1.60 g, 61%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.51 (d, 1H, J = 7.8 Hz), 7.09 (s, 1H), 6.89 (d, 1H, J = 7, 8 Hz), 4.40 (s. Broad, 1H), 3.45 (m, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H , J = 7.2 Hz).

Stage 2: (2-Butylamino-6-trifluoromethyl-pyridin-3-yl) -propanoic acid methyl ester

A solution of butyl- [3- (2,2-dibromvinyl) -6-trifluoromethyl-pyridin-2-yl] -amine (1.02 g, 2.54 mmol) in THF under nitrogen atmosphere at -78 ° C was slowly treated 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 methyl chloroformate (0.235 ml, 3.05 mmol) at -78 ° C and heated to 0 ° C for 1 h. The mixture was diluted 1: 1 with a mixture of saturated NaHCO ₃ and a solution of NH ₄ Cl, and the aqueous layer was extracted with 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 title compound (78 mg, 10%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.85 (d, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 7.8 Hz), 3.78 (m, 2H), 3.64 (s, 3H), 1.48 (m, 2H), 1.26 (m, 2H), 0.82 (t, 3H, J = 7.5 Hz).

Stage 3: (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -propinic acid

To a suspension of methyl ester of (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -propanoic 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 with 1 N. HCl to pH 1 ~ 2. The solution was extracted three times with methylene chloride and then dried over anhydrous. Na ₂ SO ₄ , and concentrated in vacuo to give the desired compound (50 mg, 65%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.17 (d, 1H, J = 7.8 Hz), 7.80 (d, 1H, J = 7.8 Hz), 3.71 ( m, 5H), 1.47 (m, 2H), 1.26 (m, 2H), 0.81 (t, 3H, J = 7.2 Hz).

Stage 4: 3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide

N- (4-Aminomethyl-2-ethynyl-6-fluoro-phenyl) -methanesulfonamide, HCl salt (80 mg, 0.29 mmol) was reacted with (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -propinic acid (70 mg, 0.24 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (84 mg, 57%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (m, 2H), 8.38 (d, 1H, J = 7.8 Hz), 7.92 (d, 1H, J = 7 , 8 Hz), 7.27 (m, 2H), 4.53 (s, 1H), 4.36 (d, 2H, J = 5.7 Hz), 3.77 (m, 2H), 3, 07 (s, 3H), 1.51 (m, 2H), 1.28 (m, 2H), 0.82 (t, 3H, J = 7.2 Hz).

Example 261: 3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide

N- (4-Aminomethyl-2,6-difluoro-phenyl) methanesulfonamide, an HCl salt (82 mg, 0.30 mol) was reacted with (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propinic acid (68 mg, 0.25 mmol) obtained as described in steps 1-3 of Example 260, to obtain the desired compound (74 mg, 50%) after purification by crystallization from a Hex / EtOAc mixture.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.55 (t, 1H, J = 5.7 Hz), 9.50 (s broad, 1H), 8.25 (d, 1H, J = 8.1 Hz), 7.83 (d, 1H, J = 8.1 Hz), 7.13 (d, 2H, J = 8.4 Hz), 4.40 (d, 2H, J = 6 , 0 Hz), 3.03 (m, 5H), 1.70 (m, 2H), 1.36 (m, 2H), 0.91 (t, 3H, J = 7.2 Hz).

Example 262: [1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide of 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (86 mg, 0.30 mol) was reacted with (2-butyl-6-trifluoromethyl- pyridin-3-yl) -propinic acid (68 mg, 0.25 mmol), obtaining, after purification by crystallization from a Hex / EtOAc mixture, the target compound (76 mg, 50%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.24 (d, 1H), 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), 1.70 (m, 2H), 1, 38 (m, 5H), 0.92 (t, 3H, J = 7.2 Hz).

ESI [M-H] -: 502.

Example 263: 3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 2-chloro-4-methanesulfonylamino-benzylamide

A mixture of N- (4-aminomethyl-3-chloro-phenyl) methanesulfonamide, an HCl salt and N- (4-aminomethyl-phenyl) methanesulfonamide, an HCl salt (80 mg) was reacted with (2-butyl-6-trifluoromethyl -pyridin-3-yl) -propinic acid (76 mg, 0.28 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (80 mg, 55%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.99 (s. Broad., 1H), 9.44 (s. Broad., 1H), 8.23 (d, 1H, J = 7, 8 Hz), 7.82 (d, 1H, J = 8.1 Hz), 7.27 (m, 3H), 4.41 (d, 2H, J = 6.0 Hz), 3.03 (m 5H), 1.69 (m, 2H), 1.36 (m, 2H), 0.91 (t, 3H, J = 7.2 Hz).

Example 264: N- (4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- [4- (1-Aminomethyl) phenyl] methanesulfonamide, HCl salt (111 mg, 0.47 mmol) were reacted 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), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (144 mg).

¹ H NMR (300 MHz, CDCl ₃ ): 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), 6.71 (s, 1H), 6.22 (d, 1H, J = 15.3 Hz), 5.99 (m, 1H), 4.54 (d, 2H, J = 5.7 Hz), 3.28 (m, 2H), 3.10 (m, 2H), 3.08 (m, 3H).

Example 265: 3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-benzyl) acrylamide

N- [4- (1-Aminomethyl) phenyl] methanesulfonamide, HCl salt (117 mg, 0.496 mmol) were reacted with NMM (350 μl), DMTMM (165 mg) and 3- (2-isobutyl-6- trifluoromethyl-pyridin-3-yl) -acrylic acid (116 mg, 0.498 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/2), the target compound (92 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.93 (d, 1H, J = 15.6 Hz), 7.90 (d, 1H, J = 9.3 Hz), 7.46 (d, 1H, J = 8.1 Hz), 7.31 (s, 1H), 7.23 (m, 4H), 6.48 (m, 1H), 6.44 (d, 1H, J = 15.3 Hz), 4.51 (d, 2H, J = 6.0 Hz), 2.97 (s, 3H), 2.83 (d, J = 6.9 Hz), 2.15 (m, 1H) 0.90 (d, 6H).

Example 266: 3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 4-methanesulfonylamino-benzylamide

A mixture of N- (4-aminomethyl-3-chloro-phenyl) methanesulfonamide, an HCl salt and N- (4-aminomethyl-phenyl) methanesulfonamide, an HCl salt (80 mg) was reacted with (2-butyl-6-trifluoromethyl -pyridin-3-yl) -propanoic acid (76 mg, 0.28 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (45 mg, 33%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.72 (s. Broad., 1H), 9.45 (s. Broad., 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), 1.70 (m, 2H), 1.36 (m, 2H), 0.91 (t , 3H, J = 7.2 Hz).

ESI [M-H] -: 452.

Example 267: N- (4-ethenesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- [4- (1-Aminomethyl) phenyl] ethenesulfonamide, HCl salt (97.8 mg, 0.392 mmol) were reacted with NMM (0.2 ml), DMTMM (121 mg) and 3- (2- isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (97.9 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (62 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.86 (s, 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), 6.15 (d, 1H, J = 16.5 Hz), 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 [MH] -: 467.

Example 268: N- (4-ethenesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- [4- (1-Aminomethyl) phenyl] ethenesulfonamide, HCl salt (95.5 mg, 0.384 mmol) were reacted with NMM (0.2 ml), DMTMM (116 mg) and 3- (2- phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (99.9 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (17 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.83 (s, 1H), 7.80 (d, 1H, J = 15.3 Hz), 7.48 (d, 1H, J = 8.1 Hz), 7.22 (m, 6H), 6.47 (d, 1H, J = 9.9 Hz), 6.30 (d, 1H, J = 15.3 Hz), 6.20 (d, 1H, J = 16.5 Hz), 5.89 (d, 1H, J = 9.6 Hz), 4.47 (d, 2H, J = 5.7 Hz), 3.32 (m, 2H) 3.04 (m, 2H).

Example 269: N- (4-ethenesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide

N- [4- (1-aminomethyl) phenyl] ethenesulfonamide, HCl salt (96.6 mg, 0.388 mmol) were reacted with NMM (0.2 ml), DMTMM (124.8 mg) and 3- ( 2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (107.2 mg), after obtaining the target compound (19 mg) after purification by column chromatography (Hex / EtOAc = 1/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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), 6.96 (s, 1H), 6.40 (d, 1H, J = 15.6 Hz), 6.27 (d, 1H, J = 16.5 Hz), 6.20 (m, 1H), 5.96 (d, 1H, J = 9.6 Hz), 4.53 (d, 2H, J = 5.7 Hz), 2.86 (d, 1H, J = 7.2 Hz), 2.15 (m, 1H), 0.92 (d, 6H, J = 6.6 Hz) .

Example 270: 3- (2-Isopropylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-trifluoromethanesulfonylamino-benzyl) acrylamide

N- [4- (1-Aminomethyl) phenyl] trifluoromethanesulfonamide, HCl salt (78.4 mg) were reacted with NMM (0.2 ml), DMTMM (119.8 mg) and 3- (2-isopropylamino -6-trifluoromethyl-pyridin-3-yl) -acrylic acid (70.8 mg), after obtaining the target compound (20 mg) after purification by column chromatography (Hex / EtOAc = 1/1).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.08 (s, 1H), 7.61 (m, 3H), 7.28 (m, 1H), 7.10 (d, 1H, J = 8 , 1 Hz), 6.87 (m, 1H), 6.65 (d, 1H, J = 8.4 Hz), 6.32 (d, 1H, J = 16.5 Hz), 4.72 ( m, 1H), 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-methanesulfonylamino-benzylamide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid

¹ H NMR (300 MHz, CDCl ₃ ): 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 (s, 1H), 5.76 (s, 1H), 5.63 ( t, 1H, J = 7.5 Hz), 4.34 (d, 2H, J = 6.0 Hz), 3.33 (s, 2H), 3.01 (s, 3H), 2.74 ( m, 2H), 2.29 (m, H), 1.74 (m, 2H), 1.10 (t, 1H, J = 7.5 Hz), 0.94 (t, 3H, J = 7 5 Hz).

Example 272: 1- (3-chloro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid

Stage 1: 3-propionyl-2-propyl-6-trifluoromethyl-pyridine

2-Pentanone (1 ml, 9.4 mmol) was dissolved in 15 ml of dry toluene in a two-necked 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, after which butyryl chloride (0.49 ml, 4.7 mmol) was added to as one part with stirring. The flask was then removed from the ice bath and left for 1 minute, and a 1 M HCl solution was added with stirring. The mixture of the solution was extracted with EtOAc. The organic mixture was then washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. To a solution of the obtained crude residue in toluene (20 ml) was added 4-amino-1,1,1-trifluoro-3-buten-2-one (0.72 g, 4.7 mmol) and trifluoroacetic acid (0.42 ml) 5.64 mmol) and the mixture was stirred under reflux for 24 hours. The reaction mixture was washed with a 20% aqueous solution of Na ₂ CO ₃ and dried using Na ₂ SO ₄ . After removing the solvent, the residue was subjected to silica gel column chromatography to obtain the target compound (0.62 g, 51%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.91 (d, 1H, J = 8.1 Hz), 7.57 (d, 1H, J = 7.8 Hz), 2.90 (m, 4H), 1.76 (m, 4H), 1.00 (m, 4H).

Stage 2: 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid

A solution of 3-propionyl-2-propyl-6-trifluoromethyl-pyridine (0.62 g, 2.39 mmol) and cyanomethylphosphonic acid diethyl ester (1.1 eq., 2.7 g) in DMF was placed in a one-neck round-bottom flask on 50 ml, then NaH (144 mg, 3.59 mmol) was added portionwise and the mixture was stirred for 18 hours at room temperature. The reaction was quenched with 10 ml of ice water. The reaction mixture was extracted with ethyl acetate and then washed with 1 N. HCl solution, and the combined organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting liquid was hydrolyzed with a 20% KOH solution under reflux overnight. After this, the mixture was washed with EtOAc, the aqueous phase was acidified with HCl and extracted with 50 ml EtOAc three times. The combined organic layer was concentrated under reduced pressure to give a crude residue (0.349 g, 49%). The crude residue was used in the next step without further purification.

Stage 3: 1- (3-chloro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid

N- (3-Chloro-4-aminomethyl-phenyl) methanesulfonamide, HCl salt (69 mg, 0.23 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex -2-enoic acid (59 mg, 0.23 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1), the target compound (69 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (d, 1H, J = 8.4 Hz), 7.45 (m, 2H), 7.10 (m, 1H), 6.73 ( s. broad., 1H), 5.82 (tf, 1H), 5.75 (s. broad., 1H), 4.33 (d, 2H, J = 6.3 Hz), 3.20 (m , 2H), 3.01 (s, 3H), 2.71 (m, 2H), 1.74 (m, 4H), 0.94 (m, 3H).

ESI [MH] -: 516.

Example 273: 3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3-fluoro-4-methanesulfonylamino-5-methyl-benzylamide

N- (4-Aminomethyl-2-chloro-6-methyl-phenyl) methanesulfonamide, HCl salt (60 mg, 0.30 mol) was reacted with (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propinic acid (50 mg, 0.18 mmol), obtaining, after purification by crystallization from Hex / EtOAc mixture, the target compound (48 mg, 55%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (t, 1H), 9.18 (s broad, 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 (m, 2H), 1.35 (m, 2H), 0.90 (t, 3H, J = 7.5 Hz).

Example 274: [1- (3-Fluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide of 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid

(R) -N- [4- (1-aminoethyl) -2-fluorophenyl] methanesulfonamide, HCl salt (91 mg, 0.34 mol) was reacted with (2-butyl-6-trifluoromethyl-pyridin-3- il) -propinic acid (92 mg, 0.34 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1/1), the target compound (68 mg, 43%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 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 (m, 2H), 1.55 (m, 3H), 1.40 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz).

Example 275: 1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -amide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-eno acid

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.46 (m, 3H), 7.14 (s, 1H), 6.97 (m, 1H), 6.42 (s, 1H), 5, 83 (s, 1H), 5.62 (t, 1H, J = 7.5 Hz), 4.32 (d, 2H, J = 6.0 Hz), 3.48 (s, 1H), 3, 26 (s, 3H), 2.75 (m, 2H), 2.29 (m, 2H), 1.75 (m, 4H), 1.10 (m, 3H), 0.94 (m, 3H )

Example 276: 1- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid

N- (4-Aminomethyl-5-ethynyl-2-fluoro-phenyl) -methanesulfonamide, HCl salt (113 mg, 0.41 mmol) was reacted with 3- (2-propyl-6-trifluoromethyl-pyridin-3- il) -hex-2-enoic acid (122 mg, 0.41 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 1: 1) 1- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid (139 mg, 65.3%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.44 (s, 2H), 7.15 (s, 1H), 6.98 (m, 1H), 6.41 (s, 1H), 5, 83 (m, 2H), 4.32 (d, 2H, J = 6.0 Hz), 3.49 (s, 1H), 3.27 (s, 3H), 2.71 (m, 2H), 1.74 (m, 4H), 1.26 (m, 2H), 0.95 (m, 6H).

ESI [MH] -: 524.

Example 277: [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -amide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2- enic acid

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.44 (m, 2H), 6.82 (s, 1H), 6.79 (s, 1H), 6.14 (s, 1H), 5, 62 (t, 1H, J = 7.2 Hz), 4.97 (m, 1H), 4.12 (m, 1H), 3.25 (m, 2H), 3.21 (s, 3H), 2.74 (m, 2H), 2.27 (m, 2H), 1.74 (m, 2H), 1.37 (d, 3H, J = 7.2 Hz), 1.10 (t, 3H , J = 7.8 Hz), 0.95 (t, 3H, J = 7.5 Hz).

ESI [MH] -: 532.

Example 278: [1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) ethyl] -amide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2- enic acid

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, HCl salt (150 mg, 0.52 mmol) was reacted with 3- (2-propyl-6- trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid (158 mg, 0.52 mmol), obtained after purification by column chromatography (Hex / EtOAc = 1: 1) 1- (3-ethynyl-5-fluoro -4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid (162 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.44 (s, 1H), 7.40 (s, 1H), 6.87 (d, 2H, J = 8.4 Hz), 6.76 ( d, 1H, J = 8.4 Hz), 6.06 (s, 1H), 5.80 (t, 1H, J = 7.2 Hz), 5.59 (s, 1H), 4.97 ( m, 1H), 3.21 (s, 3H), 3.15 (m, 2H), 2.71 (m, 2H), 1.75 (m, 4H), 1.37 (m, 3H), 0.94 (m, 6H).

ESI [MH] -: 532.

Example 279: 3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-trifluoromethanesulfonylamino-benzyl) acrylamide

N- [4- (1-aminomethyl) phenyl] trifluoromethanesulfonamide, HCl salt (75 mg) was reacted with NMM (0.2 ml), DMTMM (119 mg) and 3- (2-phenethyl-6-trifluoromethyl -pyridin-3-yl) -acrylic acid (78 mg), obtaining, after purification by column chromatography (Hex / EtOAc = 2/3), the target compound (8.5 mg).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.82 (m, 2H), 7.51 (m, 1H), 7.19 (m, 3H), 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-difluoro-4-methanesulfonylamino-phenyl) ethyl] -amide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -but-2- enic acid

(R) -N- [4- (1-aminoethyl) -2,6-difluoro-phenyl] methanesulfonamide, the HCl salt (70 mg, 0.25 mmol) was reacted with 3- (2-propyl-6- trifluoromethyl-pyridin-3-yl) -but-2-enoic acid (67 mg, 0.25 mmol), obtaining, after purification by column chromatography (Hex / EtOAc = 3: 2), the target compound (32 mg, 24%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.45 (broad s, 2H), 6.82 (m, 2H), 6.06 (s, 1H), 5.80 (t, 1H, J = 7.2 Hz), 5.57 (s, 1H), 4.97 (m, 1H), 3.22 (s, 3H), 2.50 (s, 3H), 1.76 (m, 2H ), 1.55 (m, 2H), 1.37 (d, 3H, J = 6.9 Hz), 0.93 (t, 3H, J = 7.8 Hz).

Example 281: N- (3-ethenyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide

N- [4- (1-Aminomethyl) -2-ethenyl-6-fluoro-phenyl] methanesulfonamide, HCl salt (70 mg, 0.25 mmol) were reacted with NMM (0.055 ml), DMTMM (83 mg, 0.30 mmol) and 3- (2-morpholin-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (76 mg, 0.25 mmol), obtained after purification by column chromatography (Hex / EtOAc = 1/1) target compound (95 mg, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ + CDCl ₃ ): δ 8.84 (s broad., 1H), 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 (s, 1H), 7.18 (d, 1H, J = 7.5 Hz ), 7.10 (dd, 1H, J = 17.1 and 10.8 Hz), 7.01 (d, 1H, J = 9.3 Hz), 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 ), 3.75 (m, 4H), 3.24 (m, 4H), 2.90 (s, 3H).

Experimental Example: Biological Activity Test

1. Inflow test ⁴⁵ Sa

1) Department of posterior radicular spinal ganglia (DRG) of newborn rats and their primary culture

Newborn (2-3 days or younger) SD rats were placed on ice for 5 minutes for anesthesia and disinfected with 70% ethanol. DRGs of all spinal cord sections were excised (Wood et al., 1988, J. Neurosci. 8, pp3208-3220) and placed in DME / F12 medium, to which 1.2 g / L sodium bicarbonate and 50 mg / L gentamicin were added. DRGs were incubated sequentially at 37 ° C for 30 minutes in 200 Units / ml collagenase and 2.5 mg / ml trypsin, separately. The ganglia were washed twice with DME / F12 medium supplemented with 10% horse serum, triturated with a Pasteur melted pipette, filtered through a Nitex 80 membrane to obtain a single cell suspension, and this suspension was washed again. It was centrifuged, then resuspended in cell culture medium with a certain level of cell density. As a medium for cell culture, DME / F12 medium supplemented with 10% horse serum was diluted with an identical medium conditioned with C6 glioma cells for 2 days on a fused monomolecular layer (1: 1), and NGF was added (Nerve Growth Factor) to final concentration of 200 ng / ml. After growing the cells for 2 days in a medium to which cytosine arabinoside (Ara-C, 100 μM) was added to destroy dividing non-neural cells, the medium was replaced with medium without Ara-C. Re-suspended cells were plated at a density of 1500-2000 neurons / well on Terasaki plates precoated with 10 μg / ml poly-D-ornithine.

2) Inflow experiments ⁴⁵ Sa

After primary cultivation for 2 days, DRG nerve cells were equilibrated by washing 4 times with buffered HEPES (10 mM, pH 7.4) containing no Ca ²⁺ , Mg ²⁺ HBSS (H-HBSS). The solution in each well was removed from each well. Medium containing the test compound plus capsaicin (final concentration 0.5 μM) and ⁴⁵ Ca (final concentration 10 μCi / ml) in H-HBSS was added to each well and incubated at room temperature for 10 minutes. Terasaki plates were washed five times with H-HBSS and dried at room temperature. 0.3% SDS (10 μl) was added to each well to elute ⁴⁵ Ca. After scintillation cocktail was added to each well, the amount of ⁴⁵ Ca entering the neuron was measured by counting the radioactivity. The antagonistic activity of the test compounds in relation to the vanilloid receptor was calculated as the percentage of inhibition of the maximum capsaicin response at a concentration of 0.5 μM.

Table 1

Calcium Flow Test Results

2. Analgesic activity test: convulsions test in a mouse model with phenyl-p-quinone induction

Male ICR mice (average body weight 25 g) for the experiment were kept under controlled lighting conditions (12 hours light / 12 hours darkness). Animals received an intraperitoneal injection of 0.3 ml of a chemical stimulant phenyl-p-quinone (dissolved in saline containing 5% ethanol at a dose of 4.5 mg / kg), and 6 minutes later, the number of contractions of the abdominal muscles in the subsequent period was calculated 6 minutes Animals (10 animals / group) received 0.2 ml of a solution of the test compounds in a carrier consisting of a mixture of ethanol / Tween 80 / saline (10/10/80), intraperitoneally 30 minutes before the phenyl-p-quinone injection. In the case of oral administration of 0.2 ml of a solution of the test compounds in a carrier consisting of a mixture of ethanol / Tween 80 / saline (5/5/90), was administered 54 minutes before injection 0.2 ml of 0.02% phenyl-p- quinone. A decrease in the number of convulsions in response to a drug containing the test compound relative to their number in the control group receiving saline was taken as an indicator of the analgesic effect. The analgesic effect was calculated by the% inhibition equation (% inhibition = (C-T) / C × 100), where C and T are the number of convulsions in the control and compound-treated groups, respectively. Most examples of the present invention having good in vitro activity have been tested at various 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 research

1) Metabolic stability test

The diluted sample (final concentration 5 μg / ml in a buffer of 0.1 M potassium phosphate, pH 7.4) was preincubated with co-factors (glucose-6-phosphate 3.3 mM, NADPH 1.3 mM, MgCl ₂ 0 , 16 mM, glucose-6-phosphate dehydrogenase at a final concentration of 0.4 U / ml), and the enzymatic reaction was initiated by the addition of human intestinal microsomes (1 mg / ml protein) or rat liver (0.5 mg / ml protein). The reaction was completed using 2X volume of cold acetonitrile after 1 minute (starting point) or 30 minutes (sample reaction) of incubation. For human intestinal microsomes, a reaction time of 2 hours was used. The reaction mixture was extracted in a shaken bath for 20 minutes, after which the resulting supernatant was separated by centrifugation. The peak region of the parent compound was analyzed in the supernatant using an HPLC-UV method, and the degree of metabolism is shown as a decrease in the peak region of the compound (%) from the starting point.

The metabolic stability of the partially structured CF ₃ -pyridinyl compounds of 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 metabolic stability data obtained are presented in Table 2.

2) PK study

The pharmacokinetic properties of the compounds were analyzed in rats using the following experiment. Rats were kept without food during the night before administration and until approximately 4 hours after administration. Rats were given a single oral administration of the compound at the same dose. The volume of administration was 10 ml / kg. Blood samples were taken from the retro-orbital sinus at various points in time over the next 7 hours. Immediately after each collection, plasma was separated from blood cells by centrifugation and stored at -20 ° C until analysis. Plasma samples were analyzed using reverse phase high performance chromatography (HPLC).

As shown in Table 3, the PK profile of compounds with a partial structure of CF ₃ -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 CF _{3 with} pyridinyl, a significant increase in absorption and visible half-life was observed.

Industrial applicability

As explained above, the compound of the present invention can be used to prevent or treat pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, bladder hypersensitivity, including urinary incontinence, cystitis, gastric ulcer and duodenal ulcer 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 the skin, eye or mucous membrane, hearing loss, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, disorders associated with hair growth, such as effluvium, alopecia, rhinitis, pancreatitis.

More specifically, the compound of the present invention can be used to prevent or treat pain that is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, non-inflammatory skeletal muscle pain (including fibromyalgia, myofascial pain syndrome and lower back pain), migraines and other types of headache.

Claims (40)

1. The compound of formula (I), its isomer or pharmaceutically acceptable salt:

wherein
- X is CR ₁₁ = CR ₁₂ or C илиC; wherein R ₁₁ and R ₁₂ , if present, are independently hydrogen, halogen, or C1-C5 alkyl;
- Z is N;
- Y is CR ₆ ;
R ₁ is hydrogen or C1-C5 alkyl;
R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, cyano, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl;
R ₆ is hydrogen, halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C5 alkoxy (C1 -C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, N-aryl-N- (C1-C5) alkylamino, preferably N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, arylthio, preferably phenylthio, heteroaryl, preferably pyridinyl or thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl, or morpholinyl,
R ₈ and R ₉ independently represent hydrogen, halogen, C1-C10 alkyl, and
each alkyl, alkenyl and alkynyl, as well as part of a group, for example, in alkoxy, alkylcarbonyl, alkylamino, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or substituted by one or more substituents telyami selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,
each aryl or heteroaryl, as well as part of a group, for example, in arylamino, aryloxy, may be independently unsubstituted or substituted with one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halogen (C1-C5) alkyl
each cycloalkyl, also as part of a group, for example in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halogen C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and
each piperazinyl, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted with one or more unsubstituted or substituted with halogen C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;
R ₇ is halogen (C1-C5) alkyl;
and
R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl. 2. The compound according to claim 1, its isomer or pharmaceutically acceptable salt, in which
X is —CH = CH—, —C (CH ₃ ) = CH—, —CH = C (CH ₃ ) -, —C (CH ₃ ) = C (CH ₃ ) -, —C (C ₂ H ₅ ) = CH-, -CH = C (C ₂ H ₅ ) -, -CF = CH-, -CH = CF- or C≡C;
R1 is hydrogen, methyl or ethyl;
R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl;
R ₆ is fluoro, bromo, chloro, hydroxymethyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen (C1-C6) alkyl, halogen (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 cycloalkylamino, which may be unsubstituted or substituted by one or more methyl groups, C3-C6 cycloalkoxy, C3-C6 oxacycloalkoxy, piperidyl, pyrrolidinyl, g logenfenil, phenyl, phenoxy, phenylamino, halophenoxy, morpholinyl; C1-C2 alkoxy (C1-C3) alkyl, phenyl (C1-C3) alkyl, phenyl (C2-C3) alkenyl, C1-C3 alkoxyalkynyl, di (C1-C3) alkylaminoalkynyl, (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 ;
R ₇ is halogen (C1-C5) alkyl;
R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl; and R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl. 3. The compound according to claim 1, its isomer or pharmaceutically acceptable salt, in which
X is CR ₁₁ = CR ₁₂ , wherein R ₁₁ and R ₁₂ are independently hydrogen, halogen or C1-C3 alkyl;
R ₁ is hydrogen or C1-C3 alkyl;
R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, cyano, methyl, ethyl, ethenyl, ethynyl trifluoromethyl;
R ₆ is halogen, carboxy, C1-C5 alkyl, C1-C5 alkoxy, hydroxy (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halogen (C1-C5) alkyl, halogen (C1-C5) alkoxy , C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, 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 its substituents selected from halogen, C1-C5 alkyl, and halo (C1-C5) alkyl;
R ₈ and R ₉ independently represent hydrogen, halogen, C1-C5 alkyl;
R ₇ is halogen (C1-C4) alkyl;
and
R ₁₀ is C1-C3 alkyl or C2-C3 alkenyl. 4. The compound according to claims 1 to 3, its isomer or a pharmaceutically acceptable salt in which R ₇ is trifluoromethyl. 5. The compound of formula (III), its isomer or pharmaceutically acceptable salt:

,
(III)
wherein
R ₁ is hydrogen or C1-C5 alkyl;
R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, cyano, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl;
R ₆ is hydrogen, halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, C1-C5 alkoxy (C1 -C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, piperidyl, piperazinyl, C1-C5 alkoxy (C1-C5) alkylamino, C1-C10 alkylamino, di (C1-C10 alkyl) amino C3-C8 cycloalkyl, C3-C8 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, N-aryl-N- (C1-C5) alkylamino, preferably N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, arylthio, preferred but phenylthio, heteroaryl, preferably thienyl, heteroarylamino, aryloxy, preferably phenoxy, heteroaryloxy, preferably pyridinyloxy, pyrrolidinyl or morpholinyl;
R ₈ and R ₉ independently represent hydrogen, halogen, C1-C10 alkyl,
moreover
each alkyl, alkenyl and alkynyl, as well as part of a group, for example, in alkoxy, alkylcarbonyl, alkylamino, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or substituted by one or more substituents telyami selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,
each aryl or heteroaryl, as well as part of a group, for example, in arylamino, aryloxy, may be independently unsubstituted or substituted with one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halogen (C1-C5) alkyl
each cycloalkyl, also as part of a group, for example in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with one or more unsubstituted or substituted with halogen C1-C3 alkyl, hydroxymethyl, hydroxy, methoxy or amino, and
each piperazinyl, piperidyl, morpholinyl and pyrrolidinyl may be unsubstituted or substituted with one or more unsubstituted or substituted with halogen C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl;
R ₇ is halogen (C1-C5) alkyl;
R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and
R ₁₁ and R ₁₂ independently represent hydrogen, C1-C5 alkyl or halogen. 6. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt,
wherein
R ₁ is hydrogen, methyl or ethyl;
R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl;
R ₆ is fluoro, bromo, chloro, hydroxymethyl, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, 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 alkylpiperazinyl, piperidyl, pyrrolidinyl, halogenphenyl, phenyl or morpholinyl;
R ₇ is halogen (C1-C4) alkyl;
R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl;
R ₁₀ is C1-C5 alkyl, halogen (C1-C5) alkyl or C2-C5 alkenyl; and
R ₁₁ and R ₁₂ , if present, are independently hydrogen or methyl. 7. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt,
wherein
R ₁ , R ₂ and R ₅ are hydrogen;
R ₃ is hydrogen, fluoro, chloro, cyano, methyl, ethenyl, ethynyl or trifluoromethyl;
R ₄ is hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;
R ₆ is fluoro, bromo, chloro, methyl, hydroxymethyl, methoxy, trifluoromethyl, diethylamino, piperidyl, pyrrolidinyl, trifluorophenyl, phenyl or morpholinyl;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₁₁ and R _12, if present, are hydrogen;
R ₉ is hydrogen or trifluoromethyl; and
R ₁₀ is methyl. 8. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ , R ₂ and R ₅ are hydrogen;
R ₃ is hydrogen, fluoro, chloro, cyano, methyl, ethenyl, ethynyl or trifluoromethyl;
R ₄ is hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;
R ₆ is fluoro, bromo, chloro, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, trifluoromethyl, diethylamino, methoxymethylamino, methoxyethylamino, methoxypropylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobutylamino-cyclobenethylamino-cyclo-benzo , ethylamino, propylamino, butylamino, pentylamino, N, N-dimethylamino, N-methyl-N-ethylamino N, N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N, N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, phenoxy, halogenophenoxy, piperidyl, pyr olidinil, trifluorophenyl, phenyl, or morpholinyl;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₁₁ and R ₁₂ are hydrogen;
R ₉ is hydrogen or trifluoromethyl; and
R ₁₀ is methyl. 9. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl;
R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl, ethyl or trifluoromethyl;
R ₆ is fluoro, chloro, bromo, methyl, n-butyl, methoxy, n-butyloxy, isobutyloxy, sec-butyloxy, methoxyethoxy, methoxyethylamino, diethylamino, n-butylamino, cyclopentylamino, phenoxy, N-pyrrolidinyl, N-piperidinyl or N morpholinyl;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₁₁ and R ₁₂ are hydrogen;
R ₉ is hydrogen or trifluoromethyl; and
R ₁₀ is methyl. 10. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, ethenyl or ethynyl;
R ₄ is hydrogen or fluoro;
R ₅ is hydrogen;
R ₆ is fluoro, bromo, chloro, methyl, propyl, butyl, pentyl, hydroxymethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, trifluoromethyl, N, N-dimethylamino, N-methyl-N -ethylamino N, N-diethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, N, N-dipropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, methoxymethylamino, methoxyethylamino, methoxypropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, ethylamino, propylamino, butylamino, pentylamino, phenoxy, halogenophenoxy, N-piperidyl, N- irrolidinil, trifluorophenyl, phenyl, or N-morpholinyl;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₉ is hydrogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 11. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen;
R ₂ is hydrogen;
R ₃ is hydrogen, ethenyl or ethynyl;
R ₄ is hydrogen or fluoro;
R ₅ is hydrogen;
R ₆ is bromo, chloro, n-butyl, methoxy, isobutyloxy, sec-butyloxy, methoxyethoxy, diethylamino, N-pyrrolidinyl, N-piperidyl, N-morpholinyl, cyclopentylamino, n-butylamino, phenoxy, n-butyloxy, methoxyethylamino;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₉ is hydrogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 12. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, methyl, ethyl, cyano, ethenyl, ethynyl or trifluoromethyl;
R ₄ is hydrogen, fluoro, chloro or methyl;
R ₅ is hydrogen;
R ₆ is fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, ethoxymethyl, methoxypropyl, phenylethyl, phenylethenyl, ethynyl, methoxypropinyl, diethylaminopropinyl, phenyl, halogenophenyl, methoxyphenyl, thienyl, pyridinyl, halo , propoxy, butoxy, pentoxy, trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, methoxyethoxy, tetrahydropyranyloxy, phenoxy, halogenophenoxy, benzyloxy, pyridinyloxy, ethylthio, propylthio, butylthio, pentylthio, ethylamino, propylamino, butylaminoamino, toxethylamino, methoxypropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, 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, ethoxycarbonyl N-piperidyl, piperazinyl or N morpholinyl;
R ₇ is trifluoromethyl;
R ₈ is hydrogen;
R ₉ is hydrogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 13. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl; R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, ethenyl, ethynyl or trifluoromethyl;
R ₄ and R ₅ independently represent hydrogen, fluoro, chloro, cyano, methyl or ethyl;
R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, phenylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R ₇ is trifluoromethyl;
R ₈ represents hydrogen or chlorine;
R ₉ is hydrogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 14. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₄ is hydrogen, fluoro, chloro or methyl;
R ₃ is hydrogen, fluoro, methyl, cyano, ethenyl, ethynyl or trifluoromethyl;
R ₅ is hydrogen;
R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, fluorophenyl, thienyl, n-propoxy , isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3-methylbutoxy, 2,2,2-trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, phenylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxymethylamino, methoxyethylamino, ethoxyethylamino, cyclopentylamino, benzylamino, phenylamino, N-ethyl-N-f nilamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, methoxy, N-pyrrolidinyl, N-ethoxycarbonyl-piperidyl or N-piperidyl;
R ₇ is trifluoromethyl;
R ₈ represents hydrogen or chlorine;
R ₉ is hydrogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 15. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, methyl, cyano, ethenyl or ethynyl;
R ₄ is hydrogen, fluoro or methyl;
R ₅ is hydrogen;
R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R ₇ is trifluoromethyl;
R ₈ and R ₉ are hydrogen;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 16. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, chloro, methyl, cyano, ethenyl or ethynyl;
R ₄ is hydrogen;
R ₅ is fluoro, chloro or methyl;
R ₆ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, ethoxymethyl, 2-phenylethyl, phenylethenyl, phenyl, fluorophenyl, thienyl, n-propoxy , isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 3-methylbutoxy, 2,2,2-trifluoroethoxy, cyclopentoxy, cyclopropylmethoxy, phenoxy, ethylthio, propylthio, isopropylthio, ethylamino, n-propylamino isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxymethylamino, methoxyethylamino, ethoxyethylamino, cyclopentylamino, benzylamino, phenylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, N-methyl-N-propylamino, N-pyrrolidinyl, N-piperidyl or ethoxycarbonyl N-piperidyl;
R ₇ is halogen (C1-C3) alkyl;
R ₈ and R ₉ independently represent hydrogen, halogen or trifluoromethyl;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 17. The compound according to claim 5, its isomer or pharmaceutically acceptable salt, in which
R ₁ is hydrogen or methyl;
R ₂ is hydrogen;
R ₃ is hydrogen, fluoro, chloro, methyl, cyano, ethenyl or ethynyl;
R ₄ is hydrogen;
R ₅ is fluoro;
R ₆ is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-phenylethyl, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino , isopropylamino, n-butylamino, isobutylamino, sec-butylamino, methoxyethylamino, ethoxyethylamino, benzylamino, N-ethyl-N-phenylamino or N-methyl-N-phenylamino;
R ₇ is trifluoromethyl;
R ₈ represents hydrogen or chlorine;
R ₉ is hydrogen;
R ₁₀ is methyl; and
R ₁₁ and R ₁₂ are hydrogen. 18. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt, wherein the compound is represented by formula VI:

,
wherein
W is hydrogen or fluorine;
X is —CR ₁₁ = CR ₁₂ - or —C≡C—;
R ₁ selected from hydrogen and C1-C3 alkyl;
R ₆ is halogen, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C1-C10 alkylcarbonyl, 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 cycloalkylamino, C3-C8 cycloalkoxy, C3-C8 oxacycloalkyloxy, N-aryl-N- (C1-C5) alkylamino, preferably N-phenyl-N- (C1-C5) alkylamino, aryl, preferably phenyl, arylamino, preferably phenylamino, heteroaryl, preferably thienyl, hetero ylamino, aryloxy, preferably phenoxy, pyrrolidinyl or morpholinyl;
R ₁₁ and R ₁₂ , if present, are independently selected from hydrogen and propyl;
R ₇ is CF ₃ , CF ₂ Cl or CF ₂ CF ₃ ;
R ₈ and R _{9 are} independently selected from hydrogen, halogen, or CF ₃ ;
moreover
each alkyl, alkenyl and alkynyl, as well as part of a group, for example, in alkoxy, alkylcarbonyl, alkylamino, may be independently unsubstituted or substituted with 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 methyl groups, unsubstituted or substituted by halogen (C1-C5) alkylamino, phenyl, which may be unsubstituted or substituted by one or more substituents telyami selected from halogen, unsubstituted C1-C3 alkyl, or halo (C1-C3) alkyl, unsubstituted or substituted by halogen or di (C1-C5) alkylamino,
each aryl or heteroaryl, as well as part of a group, for example, in arylamino, aryloxy, may be independently unsubstituted or substituted with one or more substituents selected from halogen, unsubstituted C1-C5 alkyl, unsubstituted C1-C5 alkoxy or halogen (C1-C5) alkyl
each cycloalkyl, also as part of a group, for example in cycloalkoxy or cycloalkylamino, may be unsubstituted or substituted with 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 with one or more unsubstituted or substituted with halogen C1-C3 alkyl, hydroxy (C1-C3) alkyl, C1-C3 alkoxy, (C1-C3) alkoxycarbonyl or hydroxyl. 19. The compound of claim 18, an isomer thereof or a pharmaceutically acceptable salt thereof, in which R ₈ and R _{9 are} both hydrogen. 20. The compound of claim 18, an isomer thereof or a pharmaceutically acceptable salt thereof, in which X is —CH═CH—. 21. The compound of claim 18, an isomer thereof or a pharmaceutically acceptable salt thereof, in which X is —CH═CH— and W, R ₈ and R ₉ are hydrogen. 22. The compound according to p. 18, its isomer or pharmaceutically acceptable salt, in which
R _{6 is} selected from C2-C6 alkyl, di (C1-C6 alkyl) amino, 2,2,2-trifluoro (C1-C3) alkoxy, C1-C3 alkoxy (C1-C5) alkylamino, C1-C6 alkylamino, C3- C6 cycloalkylamino, phenyl, phenylamino, phenyl (C1-C3) alkylamino, phenyl (C1-C3) alkyl or N-phenyl-N- (C1-C5) alkylamino, wherein each phenyl may be substituted with one or more halogens; and
R ₇ is CF ₃ . 23. The compound according to p. 18, its isomer or pharmaceutically acceptable salt, in which
R _{6 is} selected from C2-C5 alkyl, C1-C4 alkylamino or methoxyethylamino;
R ₇ is CF ₃ ; and
R ₁₂ is hydrogen. 24. The compound according to item 22, its isomer or pharmaceutically acceptable salt, in which
R ₆ is —NH— (C1-C4) alkyl or a linear or branched C2-C5 alkyl; and
R ₇ is CF ₃ . 25. The compound of claim 18, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen or methyl. 26. The compound according to claim 1 or 5, its isomer or a pharmaceutically acceptable salt in which, if R ₁ is methyl or ethyl, then the atom to which R ₁ is attached is in the (R) configuration. 27. The compound according to claim 1 or 5, its isomer or pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of the following compounds:
3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-hydroxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropyloxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- [2- (tetrahydro-furan-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluorophenoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-vinyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2,2,2-trifluoro-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide,
3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methoxy-pyrrolidin-1-yl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-cyclopropylmethoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] -acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-ethoxycarbonyl-piperid-1-yl) -6-trifluoromethyl-pyridin-3-yl] -acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-methyl-butoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-vinyl-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-ethyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-styryl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (methyl-propyl-amino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (methyl-propyl-amino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (methyl-phenyl-amino) -6-trifluoromethyl-pyridin-3-yl] -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (methyl-phenyl-amino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
3- (2-ethylthio-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl] -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- [2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propylthio-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
(R) -3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- [2- (3-fluorophenyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- [2- (2-methoxyethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
(R) -3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
3- (2-sec-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
(R) -N- [l- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -3- (2-sec-butyl-6-trifluoromethyl-pyridin-3-yl) -N-1- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -3- (2-W-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluorop-4-methanesulfonylamino-phenyl) -ethyl] -acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N-1- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethenyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-Butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,
[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide of 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid,
N- (4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-ethenesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide Z-3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,
3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,
[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide (Z) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid,
[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) ethyl] -amide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid, and
N- (3-ethenyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide. 28. The compound according to item 27, its isomer or pharmaceutically acceptable salt, and the compound is selected from the group consisting of the following compounds:
3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-methoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-diethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-cyclopentylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butyl-5-chloro-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropyloxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutoxy-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- [2- (tetrahydro-furan-3-yloxy) -6-trifluoromethyl-pyridin-3-yl] -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (4-fluorophenoxy) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (4-methanesulfonylamino-3-vinyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-piperid-1-yl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-cyano-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methyl-butyl) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- [2- (methyl-phenyl-amino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isobutyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) acrylamide,
(R) -3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-benzylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- [2- (2-methoxy-ethylamino) -6-trifluoromethyl-pyridin-3-yl] acrylamide,
3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- (3,5-difluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -3- (2-sec-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-pentyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (4-methanesulfonylamino-3-methyl-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) -N- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3-fluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-isopropyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-phenethyl-6-trifluoromethyl-pyridin-3-yl) acrylamide,
(R) -3- (2-butylamino-6-trifluoromethyl-pyridin-3-yl) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -acrylamide,
(R) -3- (2-sec-butyl-6-trifluoromethyl-pyridin-3-yl) -N-1- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) ethyl] -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-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-methanesulfonylamino-phenyl) ethyl] acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N-1- (4-methanesulfonylamino-3-methyl-benzyl) acrylamide,
N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -N- (3-ethenyl-5-fluoro-4-methanesulfonylamino-benzyl) acrylamide,
N- (3-chloro-4-methanesulfonylamino-benzyl) -3- (2-propylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (2,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3,5-difluoro-4-methanesulfonylamino-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
N- (3-fluoro-4-methanesulfonylamino-5-methyl-benzyl) -3- (2-ethylamino-6-trifluoromethyl-pyridin-3-yl) -acrylamide,
[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide of 3- (2-butyl-6-trifluoromethyl-pyridin-3-yl) -propanoic acid, and
[1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide (E) -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -hex-2-enoic acid. 29. A pharmaceutical composition having antagonistic activity against a vanilloid receptor, comprising a compound according to claim 1 or 5, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. 30. A pharmaceutical composition for the prophylaxis or treatment of a condition associated with pathological arousal and / or aberrant expression of vanilloid receptors, said composition comprising the compound of claim 1 or 7, its isomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 31. The pharmaceutical composition according to clause 29 for treating a condition selected from the group consisting of pain, inflammatory joint disease, neuropathies, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, hypersensitivity of the bladder, including urinary incontinence, cystitis, stomach ulcers and duodenum, 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 the skin, eyes or mucous membranes, hearing loss, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, disorders, associated with hair growth, such as effluvium, alopecia, rhinitis and pancreatitis. 32. The pharmaceutical composition according to 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, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and lower 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 the compound according to claim 1 or 7, its isomer or pharmaceutically acceptable salt for the manufacture of a medicament for the prophylaxis or treatment of a condition that is associated with aberrant expression and / or aberrant activation of the vanilloid receptor. 35. The use of the compound according to claim 1 or 7, its isomer or pharmaceutically acceptable salt for the manufacture of a medicament for the prevention or treatment of a condition selected from the group consisting of pain, inflammatory joint disease, neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, hypersensitivity of the bladder, including urinary incontinence, cystitis, gastric and duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), urge to def gastroesophageal reflux disease (GERD), Crohn’s disease, asthma, chronic obstructive pulmonary disease, cough,
neuropathic / allergic / inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of the skin, eyes or mucous membranes, hearing loss, tinnitus, vestibular hypersensitivity, episodic dizziness, heart diseases such as myocardial ischemia, hair growth disorders, such as effluvium, alopecia, rhinitis and pancreatitis. 36. The use of a compound according to claim 35, wherein the condition is pain that is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, non-inflammatory musculoskeletal muscle pain (including fibromyalgia, myofascial pain syndrome and lower back pain), migraines and other types of headache. 37. A method of obtaining a compound represented by formula (III):

which comprises administering a compound represented by formula (IIIa):

in reaction with a compound represented by formula (IIIb):

in which
R ₁ R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are as defined in claim 5. 38. The method according to clause 37, in which the reaction is carried out in the presence of a combination agent 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-triazin-2-yl) -4-methylmorpholinium chloride}. 39. The compound of formula (IIId)

wherein
W is hydrogen or fluorine;
R ₁ is hydrogen or C1-C3 alkyl, preferably methyl; and
R ₁₀ is C1-C3 alkyl, C2-C3 alkenyl or halogen C1-C3 alkyl, preferably methyl;
with the proviso that if R ₁ is hydrogen and R ₁₀ is methyl, then W is fluoro. 40. The use of the compounds of formula (IIId) according to § 39 as an intermediate in the preparation of a VR1 receptor ligand.