BR112017011312B1 - COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND - Google Patents

COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND Download PDF

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BR112017011312B1
BR112017011312B1 BR112017011312-0A BR112017011312A BR112017011312B1 BR 112017011312 B1 BR112017011312 B1 BR 112017011312B1 BR 112017011312 A BR112017011312 A BR 112017011312A BR 112017011312 B1 BR112017011312 B1 BR 112017011312B1
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propan
methylsulfonyl
chloro
thiophene
benzo
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BR112017011312-0A
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BR112017011312A2 (en
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Chan Hee Park
Sang Hwi Lee
Junhwan Im
Soon Ok Lee
JongMin Kim
Kwang Seok Ko
Byungho KIM
Minjung KONG
Mi Sun Kim
Hyung Jo Moon
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C&C Research Laboratories
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Priority claimed from PCT/KR2015/012920 external-priority patent/WO2016089060A2/en
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COMPOSTO, COMPOSIÇÃO FARMACÊUTICA E USO DO COMPOSTO. Um derivado heterocíclico representado pela fórmula (I), ou um sal farmaceuticamente aceitável ou um estereoisômero do mesmo, que apresenta um efeito inibitório sobre a ativação da proteína STAT3 e é útil para a prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3.COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND. A heterocyclic derivative represented by formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, which exhibits an inhibitory effect on STAT3 protein activation and is useful for the prevention or treatment of diseases associated with STAT3 protein activation.

Description

CAMPO DA INVENÇÃOFIELD OF THE INVENTION

[001]A presente invenção se refere a novos compostos heterocíclicos, usos dos mesmos para a prevenção ou tratamento de doenças associadas com a ativação de proteínas STAT, particularmente, proteína STAT3 e às composições farmacêuticas compreendendo os mesmos.[001] The present invention relates to new heterocyclic compounds, their uses for the prevention or treatment of diseases associated with the activation of STAT proteins, particularly STAT3 protein, and to pharmaceutical compositions comprising the same.

FUNDAMENTOS DA INVENÇÃOFUNDAMENTALS OF THE INVENTION

[002]Transdutor e ativador de sinal das proteínas de transcrição (STAT) são fatores de transcrição que transduzem sinais a partir de várias citocinas extracelulares e fatores de crescimento a um núcleo. Sete (7) subtipos de proteínas STAT (isto é, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b e STAT6) são correntemente conhecidos e, em geral, consistem de cerca de 750 a 850 aminoácidos. Além disso, cada subtipo de proteínas STAT contém vários domínios conservados que desempenham um papel importante na exibição da função de proteínas STAT. Especificamente, cinco (5) domínios a partir do terminal N ao terminal C de proteínas STAT foram relatados incluindo domínio em espiral enrolado, domínio de ligação ao DNA, domínio ligador, domínio SH2 e domínio de transativação (TAD). Além disso, estruturas cristalinas de raios X de STAT1, STAT3, STAT4 e STAT5 foram relatadas, desde 1998 (Becker S et al., Nature, 1998, 394; Vinkemeier U et al., Science, 1998, 279; Chen X et al., Cell, 1998, 93; D. Neculai et al., J. Biol. Chem., 2005, 280). Em geral, receptores ao quais citocinas e fatores de crescimento se ligam são categorizados em Classe I e Classe II. IL-2, IL-3, IL-5, IL-6, IL-12, G-CSF, GM-CSF, LIF, trombopoietina, etc., se ligam aos receptores Classe I, enquanto INF-α, INF-Y, IL-10, etc., se ligam aos receptores Classe II (Schindler C et al., Annu. Rev. Biochem., 1995, 64; Novick D et al., Cell, 1994, 77; Ho AS et al., Proc. Natl. Acad. Sci., 1993, 90). Dentre eles, os receptores de citocina envolvidos na ativação de proteínas STAT podem ser classificados, dependendo de suas formas estruturais de domínios extracelulares em uma família gp-130, uma família IL-2, uma família do fator de crescimento, uma família interferon e uma família do receptor de tirosina cinase. Citocinas da família interleucina-6 são citocinas multifuncionais representativas que medeiam várias atividades fisiológicas. Quando a citocina interleucina-6 se liga ao receptor de IL-6 que está presente sobre a superfície de membrana celular, ela atrai o receptor de gp-130 para formar um complexo do receptor de IL-6-gp-130. Ao mesmo tempo, JAK cinases (JAK1, JAK2, JAK3 e Tyk2) no citoplasma são recrutadas a uma região citoplasmática de gp130 para que sejam fosforiladas e ativadas. Subsequentemente, proteínas STAT citoplasmáticas latentes são atraída a um receptor, fosforiladas por JAK cinases e ativadas. A tirosina-705 adjacente ao domínio SH2 localizado no terminal C de proteínas STAT é fosforilada e a tirosina-705 ativada de cada monômero da proteína STAT se liga ao domínio SH2 de um outro monômero em uma maneira recíproca, desse modo, formando um homo- ou heterodímero. Os dímeros são translocalizados em um núcleo e se ligam a um promotor de ligação ao DNA específico para promover a transcrição. Através de seu processo de transcrição, várias proteínas (Myc, Ciclina D1/D2, Bcl-xL, Mcl, survivina, VEGF, HIF-1, imunossupressores, etc.) associadas com proliferação, sobrevivência, angiogênese e evasão imune celulares são produzidas (Stark et al., Annu. Rev. Biochem., 1997, 67; Levy et al., Nat. Rev. Mol. Cell Biol., 2002, 3).[002] Signal transducer and activator of transcription proteins (STAT) are transcription factors that transduce signals from various extracellular cytokines and growth factors to a nucleus. Seven (7) subtypes of STAT proteins (i.e., STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) are currently known and generally consist of about 750 to 850 amino acids. In addition, each STAT protein subtype contains several conserved domains that play an important role in the display of STAT protein function. Specifically, five (5) domains from the N-terminus to the C-terminus of STAT proteins have been reported including coiled-coil domain, DNA-binding domain, linker domain, SH2 domain and transactivation domain (TAD). Furthermore, X-ray crystal structures of STAT1, STAT3, STAT4 and STAT5 have been reported since 1998 (Becker S et al., Nature, 1998, 394; Vinkemeier U et al., Science, 1998, 279; Chen X et al. ., Cell, 1998, 93; D. Neculai et al., J. Biol. Chem., 2005, 280). In general, receptors to which cytokines and growth factors bind are categorized into Class I and Class II. IL-2, IL-3, IL-5, IL-6, IL-12, G-CSF, GM-CSF, LIF, thrombopoietin, etc., bind to Class I receptors, while INF-α, INF-Y , IL-10, etc., bind to Class II receptors ( Schindler C et al., Annu. Rev. Biochem., 1995, 64; Novick D et al., Cell, 1994, 77; Ho AS et al., Proc. Natl. Acad. Sci., 1993, 90). Among them, the cytokine receptors involved in the activation of STAT proteins can be classified, depending on their structural forms of extracellular domains into a gp-130 family, an IL-2 family, a growth factor family, an interferon family and a receptor tyrosine kinase family. Cytokines of the interleukin-6 family are representative multifunctional cytokines that mediate various physiological activities. When the cytokine interleukin-6 binds to the IL-6 receptor that is present on the cell membrane surface, it attracts the gp-130 receptor to form an IL-6-gp-130 receptor complex. At the same time, JAK kinases (JAK1, JAK2, JAK3 and Tyk2) in the cytoplasm are recruited to a cytoplasmic region of gp130 to be phosphorylated and activated. Subsequently, latent cytoplasmic STAT proteins are attracted to a receptor, phosphorylated by JAK kinases and activated. Tyrosine-705 adjacent to the SH2 domain located at the C-terminus of STAT proteins is phosphorylated, and the activated tyrosine-705 of each STAT protein monomer binds to the SH2 domain of another monomer in a reciprocal manner, thereby forming a homo- or heterodimer. The dimers are translocated into a nucleus and bind to a specific DNA-binding promoter to promote transcription. Through its transcription process, several proteins (Myc, Cyclin D1/D2, Bcl-xL, Mcl, survivin, VEGF, HIF-1, immunosuppressants, etc.) associated with cell proliferation, survival, angiogenesis, and immune evasion are produced ( Stark et al., Annu Rev. Biochem., 1997, 67; Levy et al., Nat. Rev. Mol. Cell Biol., 2002, 3).

[003]Em particular, a proteína STAT3 é conhecida por desempenhar um papel crucial na resposta inflamatória aguda e na via de transdução de sinal de IL-6 e EGF (Akira et al., Cell, 1994, 76; Zhong et al., Science, 1994, 264). De acordo com o relato clínico recente, a proteína STAT3 é constantemente ativada em pacientes com cânceres sólidos que ocorrem na próstata, estômago, mama, pulmão, pâncreas, rim, útero, ovário, cabeça e pescoço, etc., e também em pacientes com câncer sanguíneo, tal como leucemia aguda e crônica, mieloma múltiplo, etc. Além disso, foi relatado que a taxa de sobrevivência de um grupo de pacientes com STAT3 ativada é consideravelmente menor do que aquela de um grupo de pacientes com STAT3 inativada (Masuda et al., Cancer Res., 2002, 62; Benekli et al., Blood, 2002, 99; Yuichi et al., Int. J. Oncology, 2007, 30). Por enquanto, STAT3 foi identificada como um fator essencial para o crescimento e manutenção de células tronco embrionárias murinas em um estudo utilizando um modelo de camundongo nocaute de STAT3. Além disso, um estudo com um modelo de camundongo deficiente de STAT3 específico do tecido revela que STAT3 desempenha um papel importante no crescimento celular, apoptose e motilidade celular em uma maneira específica do tecido (Akira et al., Oncogene 2000, 19). Além disso, visto que a apoptose induzida pela STAT3 antissentido foi observada em várias linhagens celulares de câncer, STAT3 é considerada como um novo alvo anticâncer promissor. STAT3 também é considerada como um alvo potencial no tratamento de pacientes com diabetes, doenças imunorrelacionadas, hepatite C, degeneração macular, infecção por papilomavírus humano, linfoma não-Hodgkin, tuberculose, etc. Por enquanto, células Th17 recém identificadas foram relatadas através de alguns artigos recentes associados com várias doenças autoimunes (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Exp., 2015, 11). Com base nestes relatos, um controle da diferenciação e função de células Th17 é considerado como um alvo satisfatório no tratamento de doenças relacionadas. Em particular, visto que as transduções de sinal de IL-6 e IL-23 dependentes de STAT3 são conhecidas como fatores importantes na diferenciação de células Th17 (Xuexian O. Yang et al., J. Biol. Chem., 2007, 282; Harris T J et al., J. Immunol., 2007, 179), espera-se que uma inibição da função de STAT3 seja eficaz no tratamento de doenças associadas com células Th17, tais como lúpus eritematoso sistêmico, uveíte, artrite reumatoide, doença da tireoide autoimune, doença inflamatória intestinal, psoríase e artrite psoriática (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Exp., 2015, 11).[003] In particular, the STAT3 protein is known to play a crucial role in the acute inflammatory response and in the IL-6 and EGF signal transduction pathway (Akira et al., Cell, 1994, 76; Zhong et al., Science, 1994, 264). According to the recent clinical report, STAT3 protein is constantly activated in patients with solid cancers occurring in prostate, stomach, breast, lung, pancreas, kidney, uterus, ovary, head and neck, etc., and also in patients with blood cancer such as acute and chronic leukemia, multiple myeloma, etc. Furthermore, it has been reported that the survival rate of a group of patients with activated STAT3 is considerably lower than that of a group of patients with inactivated STAT3 (Masuda et al., Cancer Res., 2002, 62; Benekli et al. , Blood, 2002, 99; Yuichi et al., Int. J. Oncology, 2007, 30). So far, STAT3 has been identified as an essential factor for the growth and maintenance of murine embryonic stem cells in a study using a STAT3 knockout mouse model. Furthermore, a study with a tissue-specific STAT3-deficient mouse model reveals that STAT3 plays an important role in cell growth, apoptosis, and cell motility in a tissue-specific manner (Akira et al., Oncogene 2000, 19). Furthermore, since antisense STAT3-induced apoptosis has been observed in several cancer cell lines, STAT3 is considered as a promising new anticancer target. STAT3 is also considered as a potential target in the treatment of patients with diabetes, immune-related diseases, hepatitis C, macular degeneration, human papillomavirus infection, non-Hodgkin's lymphoma, tuberculosis, etc. So far, newly identified Th17 cells have been reported through some recent papers associated with various autoimmune diseases (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Exp., 2015, 11). Based on these reports, a control of Th17 cell differentiation and function is considered as a satisfactory target in the treatment of related diseases. In particular, since STAT3-dependent IL-6 and IL-23 signal transductions are known to be important factors in Th17 cell differentiation ( Xuexian O. Yang et al., J. Biol. Chem., 2007, 282; Harris T J et al., J. Immunol., 2007, 179), an inhibition of STAT3 function is expected to be effective in the treatment of diseases associated with Th17 cells, such as systemic lupus erythematosus, uveitis, rheumatoid arthritis, autoimmune thyroid, inflammatory bowel disease, psoriasis, and psoriatic arthritis (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Exp., 2015, 11).

[004]Recentemente, os anticorpos IL-6 e IL-23 estão sob estudos clínicos no tratamento de artrite e psoríase associadas com células Th17 e exibem uma eficácia clínica (Nishimoto N. et al., Artrite Rheum., 2004, 50; Gerald G. et al., N. Engl. J. Med., 2007, 356). Isto também confirma que a inibição da transdução de sinal de STAT3 é um método terapêutico eficaz para tais doenças.[004] Recently, IL-6 and IL-23 antibodies are under clinical studies in the treatment of arthritis and psoriasis associated with Th17 cells and exhibit clinical efficacy (Nishimoto N. et al., Artrite Rheum., 2004, 50; Gerald G. et al., N. Engl. J. Med., 2007, 356). This also confirms that inhibition of STAT3 signal transduction is an effective therapeutic method for such diseases.

[005]Ao contrário, embora apresentando vias de resposta intracelular de citocinas e fatores de crescimento idênticos àqueles de STAT3, STAT1 aumenta a inflamação e imunidades congênitas e adquiridas para inibir a proliferação de células de câncer ou causar respostas pró-apoptóticas, diferente de STAT3 (Valeria Poli et al., Review, Landes Bioscience, 2009).[005] On the contrary, although presenting intracellular response pathways of cytokines and growth factors identical to those of STAT3, STAT1 increases inflammation and congenital and acquired immunity to inhibit the proliferation of cancer cells or cause pro-apoptotic responses, unlike STAT3 (Valeria Poli et al., Review, Landes Bioscience, 2009).

[006]De modo a desenvolver inibidores de STAT3, os seguintes métodos podem ser considerados: i) inibição da fosforilação da proteína STAT3 por IL-6/gp- 130/JAK cinase, ii) inibição da dimerização de proteínas STAT3 ativadas e iii) inibição da ligação do dímero de STAT3 ao DNA nuclear. Inibidores de STAT3 moleculares pequenos estão, correntemente, sob desenvolvimento. Especificamente, OPB-31121 e OPB-51602 estão sob estudos clínicos em pacientes com cânceres sólidos ou cânceres sanguíneos pela Otsuka Pharmaceutical Co., Ltd. Além disso, S3I-201 (Siddiquee et al., Proc. Natl. Acad. Sci., 2007, 104), S3I-M2001 (Siddiquee et al., Chem. Biol., 2007, 2), LLL-12 (Lin et al., Neoplasia, 2010, 12), Stattic (Schust et al., Chem. Biol. 2006, 13), STA-21 (Song et al., Proc. Natl. Acad. Sci., 2005, 102), SF-1-066 (Zhang et al., Biochem. Pharm., 2010, 79) e STX-0119 (Matsuno et al., ACS Med. Chem. Lett., 2010, 1), etc. foram relatados eficazes em um experimento de inibição de crescimento de células de câncer e no modelo animal (modelo de xenoenxerto in vivo). Além disso, embora os compostos de peptídeos que imitam a sequência de aminoácidos de pY-705 (STAT3) adjacente ao sítio de ligação ao domínio SH2 ou a sequência de aminoácidos do receptor de gp-130 em que JAK cinases se ligam tenham sido estudados (Coleman et al., J. Med. Chem.,2005, 48), o desenvolvimento dos compostos de peptídeos não foram bem sucedidos, devido aos problemas, tais como solubilidade e permeabilidade em membrana.[006] In order to develop STAT3 inhibitors, the following methods can be considered: i) inhibition of STAT3 protein phosphorylation by IL-6/gp-130/JAK kinase, ii) inhibition of activated STAT3 protein dimerization, and iii) inhibition of STAT3 dimer binding to nuclear DNA. Small molecular STAT3 inhibitors are currently under development. Specifically, OPB-31121 and OPB-51602 are under clinical studies in patients with solid cancers or blood cancers by Otsuka Pharmaceutical Co., Ltd. In addition, S3I-201 (Siddiquee et al., Proc. Natl. Acad. Sci., 2007, 104), S3I-M2001 (Siddiquee et al., Chem. Biol., 2007, 2), LLL-12 (Lin et al., Neoplasia, 2010, 12), Stattic (Schust et al., Chem. Biol. 2006, 13), STA-21 (Song et al., Proc. Natl. Acad. Sci., 2005, 102), SF-1-066 (Zhang et al., Biochem. Pharm., 2010, 79) and STX-0119 (Matsuno et al., ACS Med. Chem. Lett., 2010, 1), etc. have been reported effective in a cancer cell growth inhibition experiment and in the animal model (in vivo xenograft model). Furthermore, although peptide compounds that mimic the pY-705 (STAT3) amino acid sequence adjacent to the SH2 domain binding site or the gp-130 receptor amino acid sequence to which JAK kinases bind have been studied ( Coleman et al., J. Med. Chem., 2005, 48), the development of peptide compounds were not successful, due to problems such as solubility and membrane permeability.

SUMÁRIO DA INVENÇÃOSUMMARY OF THE INVENTION

[007]Consequentemente, é um objetivo da presente invenção fornecer novos derivados heterocíclicos para a inibição da ativação da proteína STAT3.[007] Consequently, it is an object of the present invention to provide new heterocyclic derivatives for the inhibition of STAT3 protein activation.

[008]É um outro objetivo da presente invenção fornecer usos dos derivados heterocíclicos para a prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3.[008] It is another object of the present invention to provide uses of heterocyclic derivatives for the prevention or treatment of diseases associated with the activation of the STAT3 protein.

[009]De acordo com um aspecto da presente invenção, é fornecido um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) e um sal farmaceuticamente aceitável e um estereoisômero do mesmo: em que um entre X1, X2, X3 e X4 é -C(-Rx)=, e os outros são, independentemente, - C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH= ou -N=; Rx é Xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)- ou -N(-Rs’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6, alquilcarbonila C1-6- alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou heterociclila de 5 a 10 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio, alquila C1-6, carbamoil-alquila C1-6, alquilamino C1-6-alquila C1-6 ou dialquilamino C1-6-alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, independentemente, hidrogênio, halogênio, nitro, amino, alcóxi C1-6, haloalcóxi C1-6, ou alquilsulfonila C1-6; A e B são, independentemente, um carbociclo C3-10 monocíclico ou bicíclico, saturado ou insaturado ou heterociclo de 5 a 12 membros; Rc é =O, =NH, =N(-alquila C1-6) ou =N(-OH); RN é hidrogênio ou alquila C1-6, ou RN é ligado a RA para formar uma cadeia; LB é -[C(-RL)(-RL’)]m-, -[C(-RL)(-RL’)]n-O-, -O-, -NH-, -N(alquila C1-6)-, -S(=O)2-, -C(=O)-, ou -C(=CH2)-, em que m é um número inteiro de 0 a 3, n é um número inteiro de 1 a 3, RL e RL’ são, independentemente, hidrogênio, hidróxi, halogênio ou alquila C1-6, ou RL e RL’ são ligados para formar uma cadeia; RA é hidrogênio, halogênio, ciano, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alquilcarbonila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, alquilamino C16, dialquilamino C1-6, alquiltio C1-6, alquilaminocarbonila C1-6, dialquilaminocarbonila C1-6, alquinila C2-8, alcóxi-carbonilamino C1-6-alcóxi C1-6, aminoalcóxi C1-6 ou heterociclila de 3 a 6 membros, ou RA é ligado a RN para formar uma cadeia; RB é hidrogênio, halogênio, hidróxi, ciano, nitro, amino, oxo, aminossulfonila, sulfonilamido, alquilamino C1-6, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, cicloalquilóxi C3-8, alquenila C2-8, alquenilóxi C28, alquinila C2-8, alquinilóxi C2-8, alquilamino C1-6-alcóxi C1-6, dialquilamino C1-6-alcóxi C1-6, alcóxi-carbonila C1-6, carbamoil, carbamoila-alcóxi C1-6, alquiltio C1-6, alquilsulfinila C1-6, alquilsulfonila C1-6, heterociclila de 5 a 10 membros, heterociclila de 5 a 10 membros-alquila C1-6, heterociclila de 5 a 10 membros-alcóxi C1-6 ou heterociclila de 5 a 10 membros-óxi; p é um número inteiro de 0 a 4, e, quando p é 2 ou maior, porções de RA são as mesmas ou diferentes; q é um número inteiro de 0 a 4, e, quando q é 2 ou maior, porções de RB são as mesmas ou diferentes; e cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo ou contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, - S(=O)- e -S(=O)2- na cadeia, e não substituída ou substituída com pelo menos um selecionado a partir do grupo que consiste de halogênio, alquila C1-6 e alcóxi C1-6; e cada um entre o dito heterociclo e porções de heterociclila contém, independentemente, pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, -S(=O)- e -S(=O)2-.[009] According to one aspect of the present invention, there is provided a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) and a pharmaceutically acceptable salt and a stereoisomer thereof: wherein one of X1, X2, X3 and X4 is -C(-Rx)=, and the others independently are -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH= or -N=; Rx is Xs is =O or =NH; Ls is -C(-Rs')(-Rs'')- or -N(-Rs')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, C1-6 aminoalkyl, or 5- to 10-membered heterocyclyl , or Rs is joined to Rs' to form a chain; Rs' and Rs'' are independently hydrogen, halogen, C1-6 alkyl, carbamoyl-C1-6 alkyl, C1-6 alkylamino-C1-6 alkyl or diC1-6 alkylamino-C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is, independently, hydrogen, halogen, nitro, amino, C1-6 alkoxy, C1-6 haloalkoxy, or C1-6 alkylsulfonyl; A and B are, independently, a C3-10 monocyclic or bicyclic, saturated or unsaturated carbocycle or 5- to 12-membered heterocycle; Rc is =O, =NH, =N(-C1-6 alkyl) or =N(-OH); RN is hydrogen or C1-6 alkyl, or RN is linked to RA to form a chain; LB is -[C(-RL)(-RL')]m-, -[C(-RL)(-RL')]nO-, -O-, -NH-, -N(C1-6 alkyl) -, -S(=O)2-, -C(=O)-, or -C(=CH2)-, where m is an integer from 0 to 3, n is an integer from 1 to 3, RL and RL' are independently hydrogen, hydroxy, halogen or C1-6 alkyl, or RL and RL' are linked to form a chain; RA is hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C16 alkylamino, C1-6 dialkylamino , C1-6 alkylthio, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C2-8 alkynyl, C1-6 alkoxycarbonylamino-C1-6 alkoxy, C1-6 aminoalkoxy or 3- to 6-membered heterocyclyl, or RA is attached to RN to form a chain; RB is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6 alkylamino, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C3-8 cycloalkyloxy, C2-8 alkenyl, C28 alkenyloxy, C2-8 alkynyl, C2-8 alkynyloxy, C1-6 alkylamino-C1-6 alkoxy, C1-6 dialkylamino-C1-6 alkoxy, alkoxy- C1-6 carbonyl, carbamoyl, carbamoyl-C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C1-6 alkyl, 5 to 10 membered-C 1-6 alkoxy or 5 to 10 membered heterocyclyl-oxy; p is an integer from 0 to 4, and when p is 2 or greater, RA portions are the same or different; q is an integer from 0 to 4, and when q is 2 or greater, portions of RB are the same or different; and each of said chains is independently a saturated or unsaturated C2-10 hydrocarbon chain not containing or containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, - S-, -S(=O)- and -S(=O)2- in the chain, and unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1-6 alkoxy ; and each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-.

[010]De acordo com um outro aspecto da presente invenção, é fornecido um uso de um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima, e um sal farmaceuticamente aceitável e um estereoisômero do mesmo para a fabricação de um medicamento para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3.[010] According to another aspect of the present invention, there is provided a use of a compound selected from the group consisting of a heterocyclic derivative represented by the above formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof for the manufacture of a medicament for preventing or treating diseases associated with STAT3 protein activation.

[011]De acordo com um outro aspecto da presente invenção, é fornecida uma composição farmacêutica para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3, compreendendo um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima, e um sal farmaceuticamente aceitável e um estereoisômero do mesmo como ingredientes ativos.[011] According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating diseases associated with STAT3 protein activation, comprising a compound selected from the group consisting of a heterocyclic derivative represented by the formula ( I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof as active ingredients.

[012]Ainda de acordo com um outro aspecto da presente invenção, é fornecido um método para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3 em um mamífero, que compreende administrar um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima, e um sal farmaceuticamente aceitável e um estereoisômero do mesmo ao mamífero.[012] According to yet another aspect of the present invention, a method is provided for preventing or treating diseases associated with the activation of the STAT3 protein in a mammal, which comprises administering a compound selected from the group consisting of a derivative heterocyclic represented by the above formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof to the mammal.

[013]O derivado heterocíclico representado pela fórmula (I) acima, ou um sal farmaceuticamente aceitável ou um estereoisômero do mesmo, apresenta um efeito inibitório excelente sobre a ativação da proteína STAT3 e, assim, pode ser usado para a prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3.[013] The heterocyclic derivative represented by the above formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, has an excellent inhibitory effect on STAT3 protein activation and thus can be used for the prevention or treatment of diseases associated with STAT3 protein activation.

DESCRIÇÃO DETALHADA DA INVENÇÃODETAILED DESCRIPTION OF THE INVENTION

[014]A presente invenção será ainda descrita em detalhes neste relatório abaixo.[014] The present invention will be further described in detail in this report below.

[015]No relatório descritivo da presente invenção, o termo “halogênio” se refere a flúor, cloro, bromo ou iodo, a menos que de outro modo especificado.[015] In the descriptive report of the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.

[016]O termo “alquila” se refere a uma porção de hidrocarboneto linear ou ramificada, a menos que de outro modo especificado.[016] The term "alkyl" refers to a linear or branched hydrocarbon moiety, unless otherwise specified.

[017]Os termos “haloalquila”, “haloalcóxi”, “halofenila”, etc., respectivamente, se referem a alquila, alcóxi, e fenila substituído com pelo menos um halogênio.[017] The terms "haloalkyl", "haloalkoxy", "halophenyl", etc., respectively, refer to alkyl, alkoxy, and phenyl substituted with at least one halogen.

[018]O termo “carbociclo” se refere a um anel de hidrocarboneto aromático ou não aromático, que pode ser saturado ou insaturado, e um radical monocíclico ou policíclico. O termo “carbociclila” se refere a um radical de “carbociclo” e é usado como um termo inclusivo de “cicloalquila” e “arila”. O termo “cicloalquila” se refere a um radical de hidrocarboneto saturado, que pode ser monocíclico ou policíclico. O termo “arila” se refere a um anel de hidrocarboneto aromático, que pode ser monocíclico ou policíclico.[018] The term "carbocycle" refers to an aromatic or non-aromatic hydrocarbon ring, which may be saturated or unsaturated, and a monocyclic or polycyclic radical. The term "carbocyclyl" refers to a radical of "carbocycle" and is used as an inclusive term of "cycloalkyl" and "aryl". The term "cycloalkyl" refers to a saturated hydrocarbon radical, which may be monocyclic or polycyclic. The term "aryl" refers to an aromatic hydrocarbon ring, which may be monocyclic or polycyclic.

[019]Os termos “carbociclo”, “carbociclila”, “cicloalquila” e “arila” podem se referir, por exemplo, a um monociclo ou policiclo que apresenta 3 a 20 átomos de carbono, e será indicado como “carbociclo C3-20”, “carbociclila C3-20”, “cicloalquila C320” e “arila C3-20”, respectivamente.[019] The terms "carbocycle", "carbocyclyl", "cycloalkyl" and "aryl" may refer, for example, to a monocycle or polycycle that has 3 to 20 carbon atoms, and will be indicated as "C3-20 carbocycle ”, “C3-20 carbocyclyl”, “C320 cycloalkyl” and “C3-20 aryl”, respectively.

[020]O termo “heterociclo” se refere a um anel aromático ou não aromático que apresenta pelo menos um heteroátomo, que pode ser saturado ou insaturado, e um monociclo ou policiclo. O termo “heterociclila” se refere a um radical de “heterociclo”, que é usado como um termo inclusivo de “heterocicloalquila” e “heteroarila”. O termo “heterocicloalquila” se refere a um radical de anel saturado que apresenta pelo menos um heteroátomo, que pode ser monocíclico ou policíclico. O termo “heteroarila” se refere a um radical de anel aromático que apresenta pelo menos um heteroátomo, que pode ser monocíclico ou policíclico.[020] The term "heterocycle" refers to an aromatic or non-aromatic ring that has at least one heteroatom, which can be saturated or unsaturated, and a monocycle or polycycle. The term "heterocyclyl" refers to a radical of "heterocycle", which is used as an inclusive term of "heterocycloalkyl" and "heteroaryl". The term "heterocycloalkyl" refers to a saturated ring radical having at least one heteroatom, which may be monocyclic or polycyclic. The term "heteroaryl" refers to an aromatic ring radical having at least one heteroatom, which may be monocyclic or polycyclic.

[021]O termo “heteroátomo” pode ser selecionado a partir de N, O e S.[021] The term “heteroatom” can be selected from N, O and S.

[022]Os termos “heterociclo”, “heterociclila”, “heterocicloalquila” e “heteroarila” podem se referir, por exemplo, a um mono- ou policiclo que apresenta 3 a 20 heteroátomos e/ou átomos de carbono, e será indicado como “heterociclo de 3 a 20 membros”, “heterociclila de 3 a 20 membros”, “heterocicloalquila de 3 a 20 membros” e “heteroarila de 3 a 20 membros”.[022] The terms "heterocycle", "heterocyclyl", "heterocycloalkyl" and "heteroaryl" may refer, for example, to a mono- or polycycle that has 3 to 20 heteroatoms and/or carbon atoms, and will be indicated as "3 to 20 membered heterocycle", "3 to 20 membered heterocyclyl", "3 to 20 membered heterocycloalkyl" and "3 to 20 membered heteroaryl".

[023]O termo “cadeia” se refere a uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo quaisquer heteroátomos na cadeia, por exemplo, etileno, propileno, butileno e -CH2-CH=CH-; ou uma cadeia de hidrocarboneto C2-10 saturada ou insaturada contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, -S(=O)- e -S(=O)2- na cadeia, por exemplo, -CH2-O-CH2-, -CH2-O-CH2-O-CH2-, -CH2-CH=CH-NH- e - CH2-CH2-S(=O)2-CH2-O-, a menos que de outro modo especificado. A cadeia pode ser substituída com pelo menos um selecionado a partir do grupo que consiste de halogênio, alquila C1-6 e alcóxi C1-6.[023] The term "chain" refers to a saturated or unsaturated C2-10 hydrocarbon chain not containing any heteroatoms in the chain, for example, ethylene, propylene, butylene and -CH2-CH=CH-; or a saturated or unsaturated C2-10 hydrocarbon chain containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S (=O)2- on the chain, for example, -CH2-O-CH2-, -CH2-O-CH2-O-CH2-, -CH2-CH=CH-NH- and -CH2-CH2-S(= O)2-CH2-O-, unless otherwise specified. The chain may be substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1-6 alkoxy.

[024]De acordo com um aspecto da presente invenção, é fornecido um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) e um sal farmaceuticamente aceitável e um estereoisômero do mesmo: em que um entre x1, x2, x3 e x4 é -C(-Rx)=, e os outros são, independentemente, - C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH= ou -N=; Rx é xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)- ou -N(-Rs’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6, alquilcarbonila C1-6- alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou heterociclila de 5 a 10 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio, alquila C1-6, carbamoil-alquila C1-6, alquilamino C1-6-alquila C1-6 ou dialquilamino C1-6-alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, independentemente, hidrogênio, halogênio, nitro, amino, alcóxi C1-6, haloalcóxi C1-6 ou alquilsulfonila C1-6; A e B são, independentemente, um carbociclo C3-10 monocíclico ou bicíclico, saturado ou insaturado ou heterociclo de 5 a 12 membros; Rc é =O, =NH, =N(-alquila C1-6) ou =N(-OH); RN é hidrogênio ou alquila C1-6, ou RN é ligado a RA para formar uma cadeia; LB é -[C(-RL)(-RL’)]m-, -[C(-RL)(-RL’)]n-O-, -O-, -NH-, -N(alquila C1-6)-, -S(=O)2-, -C(=O)-, ou -C(=CH2)-, em que m é um número inteiro de 0 a 3, n é um número inteiro de 1 a 3, RL e RL’ são, independentemente, hidrogênio, hidróxi, halogênio ou alquila C1-6 ou RL e RL’ são ligados para formar uma cadeia; RA é hidrogênio, halogênio, ciano, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alquilcarbonila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, alquilamino C16, dialquilamino C1-6, alquiltio C1-6, alquilaminocarbonila C1-6, dialquilaminocarbonila C1-6, alquinila C2-8, alcóxi-carbonilamino C1-6-alcóxi C1-6, aminoalcóxi C1-6 ou heterociclila de 3 a 6 membros, ou RA é ligado a RN para formar uma cadeia; RB é hidrogênio, halogênio, hidróxi, ciano, nitro, amino, oxo, aminossulfonila, sulfonilamido, alquilamino C1-6, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, cicloalquilóxi C3-8, alquenila C2-8, alquenilóxi C28, alquinila C2-8, alquinilóxi C2-8, alquilamino C1-6-alcóxi C1-6, dialquilamino C1-6-alcóxi C1-6, alcóxi-carbonila C1-6, carbamoila, carbamoila-alcóxi C1-6, alquiltio C1-6, alquilsulfinila C1-6, alquilsulfonila C1-6, heterociclila de 5 a 10 membros, heterociclila de 5 a 10 membros-alquila C1-6, heterociclila de 5 a 10 membros-alcóxi C1-6 ou heterociclila de 5 a 10 membros-óxi; p é um número inteiro de 0 a 4, e, quando p é 2 ou maior, porções RA são as mesmas ou diferentes; q é um número inteiro de 0 a 4, e, quando q é 2 ou maior, porções RB são as mesmas ou diferentes; e cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo ou contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, - S(=O)- e -S(=O)2- na cadeia, e não substituída ou substituída com pelo menos um selecionado a partir do grupo que consiste de halogênio, alquila C1-6 e alcóxi C1-6; e cada um entre o dito heterociclo e porções de heterociclila contém, independentemente, pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, -S(=O)- e -S(=O)2-.[024] According to one aspect of the present invention, there is provided a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) and a pharmaceutically acceptable salt and a stereoisomer thereof: wherein one of x1, x2, x3 and x4 is -C(-Rx)=, and the others are, independently, -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH= or -N=; Rx is xs is =O or =NH; Ls is -C(-Rs')(-Rs'')- or -N(-Rs')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, C1-6 aminoalkyl, or 5- to 10-membered heterocyclyl , or Rs is joined to Rs' to form a chain; Rs' and Rs'' are independently hydrogen, halogen, C1-6 alkyl, carbamoyl-C1-6 alkyl, C1-6 alkylamino-C1-6 alkyl or diC1-6 alkylamino-C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is independently hydrogen, halogen, nitro, amino, C1-6 alkoxy, C1-6 haloalkoxy, or C1-6 alkylsulfonyl; A and B are, independently, a C3-10 monocyclic or bicyclic, saturated or unsaturated carbocycle or 5- to 12-membered heterocycle; Rc is =O, =NH, =N(-C1-6 alkyl) or =N(-OH); RN is hydrogen or C1-6 alkyl, or RN is linked to RA to form a chain; LB is -[C(-RL)(-RL')]m-, -[C(-RL)(-RL')]nO-, -O-, -NH-, -N(C1-6 alkyl) -, -S(=O)2-, -C(=O)-, or -C(=CH2)-, where m is an integer from 0 to 3, n is an integer from 1 to 3, RL and RL' are independently hydrogen, hydroxy, halogen or C1-6 alkyl or RL and RL' are linked to form a chain; RA is hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C16 alkylamino, C1-6 dialkylamino , C1-6 alkylthio, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C2-8 alkynyl, C1-6 alkoxycarbonylamino-C1-6 alkoxy, C1-6 aminoalkoxy or 3- to 6-membered heterocyclyl, or RA is attached to RN to form a chain; RB is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6 alkylamino, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C3-8 cycloalkyloxy, C2-8 alkenyl, C28 alkenyloxy, C2-8 alkynyl, C2-8 alkynyloxy, C1-6 alkylamino-C1-6 alkoxy, C1-6 dialkylamino-C1-6 alkoxy, alkoxy- C1-6 carbonyl, carbamoyl, carbamoyl-C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C1-6 alkyl, 5 to 10 membered-C 1-6 alkoxy or 5 to 10 membered heterocyclyl-oxy; p is an integer from 0 to 4, and when p is 2 or greater, RA portions are the same or different; q is an integer from 0 to 4, and when q is 2 or greater, RB portions are the same or different; and each of said chains is independently a saturated or unsaturated C2-10 hydrocarbon chain not containing or containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, - S-, -S(=O)- and -S(=O)2- in the chain, and unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1-6 alkoxy ; and each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-.

[025]Em uma forma de realização preferida do composto da fórmula (I), um entre X2 e X3 é -C(-Rx)= e o outro é -C(-Rx’)= ou -N=; X1 e X4 são, independentemente, -C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH=; Rx e Rx’ são os mesmos definidos acima na fórmula (I); e Rc, RN, A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I).[025] In a preferred embodiment of the compound of formula (I), one of X2 and X3 is -C(-Rx)= and the other is -C(-Rx')= or -N=; X1 and X4 are independently -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH=; Rx and Rx' are the same as defined above in formula (I); and Rc, RN, A, B, LB, RA, RB, p and q are the same defined above in formula (I).

[026]Em uma forma de realização preferida do composto da fórmula (I), um entre X2 e X3 é -C(-Rx)= e o outro é -C(-Rx’)= ou -N=; X1 e X4 são, independentemente, -C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH=; Rx é Xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)- ou -N(-Rs’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6 ou heterociclila de 5 a 6 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio ou alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, independentemente, hidrogênio ou halogênio; cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-7 saturada ou insaturada não contendo ou contendo pelo menos um heteroátomo selecionado a partir do grupo que consiste de O, N e S; e Rc, RN, A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I).[026] In a preferred embodiment of the compound of formula (I), one of X2 and X3 is -C(-Rx)= and the other is -C(-Rx')= or -N=; X1 and X4 are independently -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH=; Rx is Xs is =O or =NH; Ls is -C(-Rs')(-Rs'')- or -N(-Rs')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, or 5- to 6-membered heterocyclyl, or Rs is joined to Rs' to form a chain; Rs' and Rs'' are independently hydrogen, halogen or C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is independently hydrogen or halogen; each of said chains is independently a saturated or unsaturated C2-7 hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of O, N and S; and Rc, RN, A, B, LB, RA, RB, p and q are the same defined above in formula (I).

[027]Em uma forma de realização preferida do composto da fórmula (I), um entre X2 e X3 é -C(-Rx)= e o outro é -C(-Rx’)= ou -N=; X1 e X4 são, independentemente, -C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH=; Rx é Xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)- ou -N(-Rs’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6 ou heterociclila de 5 a 6 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio ou alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, independentemente, hidrogênio ou halogênio; cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-7 saturada ou insaturada não contendo ou contendo pelo menos um heteroátomo selecionado a partir do grupo que consiste de O, N e S; Rc e RN são os mesmos definidos acima na fórmula (I); A é benzeno ou um heteroarila de 5 a 10 membros contendo 1 a 3 átomos de nitrogênio; B é um carbociclo C6-10 monocíclico ou bicíclico, saturado ou insaturado ou heterociclo de 5 a 10 membros; LB é -[C(-RL)(-RL’)]m-, -O-, -NH- ou -N(alquila C1-6)-, em que m é 0 ou 1, RL e RL’ são, independentemente, hidrogênio, hidróxi, halogênio ou alquila C1-6 ou RL e RL’ são ligados para formar alquileno C2-5; RA é halogênio, alcóxi-carbonilamino C1-6-alcóxi C1-6, aminoalcóxi C1-6 ou heterociclila de 3 a 6 membros; RB é halogênio, alquila C1-6, alcóxi C1-6, haloalquilóxi C1-6, alquenilóxi C2-6, alquinilóxi C2-6, alcóxi-carbonila C1-6, carbociclila C3-10-óxi ou heterociclila de 3 a 10 membros-alcóxi C1-3; e cada uma entre as ditas porções heteroarila, heterociclo e heterociclila contém, independentemente, 1 a 3 heteroátomos selecionados a partir do grupo que consiste de O, N e S.[027] In a preferred embodiment of the compound of formula (I), one of X2 and X3 is -C(-Rx)= and the other is -C(-Rx')= or -N=; X1 and X4 are independently -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH=; Rx is Xs is =O or =NH; Ls is -C(-Rs')(-Rs'')- or -N(-Rs')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, or 5- to 6-membered heterocyclyl, or Rs is joined to Rs' to form a chain; Rs' and Rs'' are independently hydrogen, halogen or C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is independently hydrogen or halogen; each of said chains is independently a saturated or unsaturated C2-7 hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of O, N and S; Rc and RN are the same as defined above in formula (I); A is benzene or a 5- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; B is a C6-10 monocyclic or bicyclic, saturated or unsaturated carbocycle or 5- to 10-membered heterocycle; LB is -[C(-RL)(-RL')]m-, -O-, -NH- or -N(C1-6 alkyl)-, where m is 0 or 1, RL and RL' are, independently, hydrogen, hydroxy, halogen or C1-6 alkyl or RL and RL' are bonded to form C2-5 alkylene; RA is halogen, C1-6alkoxycarbonylamino-C1-6alkoxy, C1-6aminoalkoxy, or 3- to 6-membered heterocyclyl; RB is halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxycarbonyl, C3-10 carbocyclyl-oxy, or 3- to 10-membered heterocyclyl- C1-3 alkoxy; and each of said heteroaryl, heterocycle and heterocyclyl moieties independently contains 1 to 3 heteroatoms selected from the group consisting of O, N and S.

[028]Em uma forma de realização preferida do composto da fórmula (I), X1 e X4 são -CH=; X2 é -C(-Rx)=; X3 é -N= ou -C(-Rx’)-; Y é -C=; Z é -S-; Rx é Ls é -C(-CH3)(-CH3)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6alquila C1-6, alquilcarbonila C1- 6alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou um heterociclila de 5 a 10 membros contendo 1 a 3 heteroátomos selecionados a partir do grupo que consiste de O, N e S; Rx’ é hidrogênio, halogênio, nitro, amino, alcóxi C1-6, haloalcóxi C1-6 ou alquilsulfonila C1-6; Rc é =O; RN é hidrogênio; e A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I).[028] In a preferred embodiment of the compound of formula (I), X1 and X4 are -CH=; X2 is -C(-Rx)=; X3 is -N= or -C(-Rx')-; Y is -C=; Z is -S-; Rx is Ls is -C(-CH3)(-CH3)-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C1-6 alkylcarbonylC1-6 alkyl, C2-7 alkenyl, amino, aminoC1-6 alkyl, or a 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, N and S; Rx' is hydrogen, halogen, nitro, amino, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 alkylsulfonyl; Rc is =O; RN is hydrogen; and A, B, LB, RA, RB, p and q are the same defined above in formula (I).

[029]Em uma forma de realização preferida do composto da fórmula (I), X1, X3 e X4 são -CH=; X2 é -C(-Rx)=; Y é -C=; Z é -S-; Rx é Ls é -C(-Rs’)(-Rs’’)-; Xs é =O ou =NH; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6, alquilcarbonila C1-6- alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou um heterociclila de 5 a 10 membros contendo 1 a 3 heteroátomos selecionados a partir do grupo que consiste de O, N e S; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio, alquila C1-6, carbamoilalquila C1-6, alquilamino C1-6-alquila C1-6 ou dialquilamino C1-6-alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, em que a cadeia é uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo ou contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste de -O-, -NH-, -N=, -S-, - S(=O)- e -S(=O)2- na cadeia, e não substituída ou substituída com pelo menos um selecionado a partir do grupo que consiste de halogênio, alquila C1-6 e alcóxi C1-6; Rc é =O; RN é hidrogênio; e A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I).[029] In a preferred embodiment of the compound of formula (I), X1, X3 and X4 are -CH=; X2 is -C(-Rx)=; Y is -C=; Z is -S-; Rx is Ls is -C(-Rs')(-Rs'')-; Xs is =O or =NH; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, aminoC1-6 alkyl or a 5 to 10 heterocyclyl members containing 1 to 3 heteroatoms selected from the group consisting of O, N and S; Rs' and Rs'' are independently hydrogen, halogen, C1-6 alkyl, carbamoylC1-6 alkyl, C1-6 alkylamino-C1-6 alkyl, or diC1-6 alkylamino-C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, wherein the chain is a saturated or unsaturated C2-10 hydrocarbon chain containing no or containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N= , -S-, -S(=O)- and -S(=O)2- in the chain, and unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1 alkoxy -6; Rc is =O; RN is hydrogen; and A, B, LB, RA, RB, p and q are the same defined above in formula (I).

[030]Em uma forma de realização preferida do composto da fórmula (I), X1, X3 e X4 são -CH=; X2 é -C(-Rx)=; Y é -C=; Z é -S-; Rx é o mesmo definido acima na fórmula (I); Rc é =O; RN é hidrogênio; e A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I). Em uma forma de realização preferida do composto da fórmula (I), X1, X2 e X4 são -CH=; X3 é -C(-Rx)=; Y é -C=; Z é -S- ou -NH-; Rx é Xs é =O; Ls é -C(-CH3)(-CH3)-; Rs é metila; Rc é =O; RN é hidrogênio; e A, B, LB, RA, RB, p e q são os mesmos definidos acima na fórmula (I).[030] In a preferred embodiment of the compound of formula (I), X1, X3 and X4 are -CH=; X2 is -C(-Rx)=; Y is -C=; Z is -S-; Rx is the same as defined above in formula (I); Rc is =O; RN is hydrogen; and A, B, LB, RA, RB, p and q are the same defined above in formula (I). In a preferred embodiment of the compound of formula (I), X1, X2 and X4 are -CH=; X3 is -C(-Rx)=; Y is -C=; Z is -S- or -NH-; Rx is Xs is =O; Ls is -C(-CH3)(-CH3)-; Rs is methyl; Rc is =O; RN is hydrogen; and A, B, LB, RA, RB, p and q are the same defined above in formula (I).

[031]Em uma forma de realização preferida do composto da fórmula (I), se A é heterociclo de 5 membros, m é um número inteiro de 1 a 3. O heterociclo de 5 membros é, preferivelmente, um anel aromático de 5 membros não substituído ou substituído com pelo menos um selecionado a partir do grupo que consiste de halogênio, alquila C1-10 e haloalquila C1-10. O heterociclo de 5 membros contém pelo menos um heteroátomo selecionado a partir do grupo que consiste de N, S e O.[031] In a preferred embodiment of the compound of formula (I), if A is a 5-membered heterocycle, m is an integer from 1 to 3. The 5-membered heterocycle is preferably a 5-membered aromatic ring unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-10 alkyl and C1-10 haloalkyl. The 5-membered heterocycle contains at least one heteroatom selected from the group consisting of N, S and O.

[032]Exemplos preferidos do composto, de acordo com a presente invenção, são listados abaixo, e um sal farmaceuticamente aceitável e um estereoisômero do mesmo também são incluídos no escopo da presente invenção: 1) N-(3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 2) N-(3-cloro-5-(2-(3-propóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 3) N-(3-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 4) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroetóxi)-5- (trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida; 5) N-(3-cloro-5-(2-(3-(1,1,2,2-tetrafluoroetóxi)-5-(trifluorometóxi)fenil)propan- 2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 6) N-(3-metóxi-5-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 7) N-(3-cloro-5-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 8) N-(3-cloro-5-(2-(3-(2-morfolinoetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 9) N-(3-bromo-5-(2-(3-isopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 10) N-(3-(2-(3-(but-2-in-1-ilóxi)-5-(trifluorometóxi)fenil)propan-2-il)-5- clorofenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 11) N-(3-cloro-5-(2-(3-isobutóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 12) N-(3-cloro-5-(2-(3-(2,2,2-trifluoroetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 13) N-(3-cloro-5-(2-(3-(2,2-difluoroetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 14) N-(3-(2-(3-(alilóxi)-5-(trifluorometóxi)fenil)propan-2-il)-5-clorofenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 15) N-(3-cloro-5-(2-(3-ciclopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 16) N-(3-cloro-5-(2-(3-isopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 17) N-(3-cloro-5-(2-(4-metoxifenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 18) N-(3-cloro-5-(2-(4-fluorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 19) N-(3-cloro-5-(2-(4-fluorofenil)propan-2-il)fenil)-6-fluoro-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 20) N-(3-bromo-5-(2-(4-fluorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 21) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 22) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 23) 6-cloro-N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 24) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxamida; 25) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- (fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 26) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2- il)tieno[2,3-c]piridino-2-carboxamida; 27) N-(3-cloro-5-(2-(5-clorotiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 28) N-(3-cloro-5-(2-(5-isopropiltiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 29) N-(3-cloro-5-(2-(5-metoxitiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 30) N-(3-cloro-5-(2-(2-metoxitiofen-3-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 31) N-(3-cloro-5-(2-(1-metil-1H-pirrol-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 32) N-(3-cloro-5-(2-(4-metiltiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 33) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(1- (metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxamida; 34) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(4-(metilsulfonil)tetra- hidro-2H-piran-4-il)benzo[b]tiofeno-2-carboxamida; 35) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-6-(2-(metilsulfonil)propan-2- il)-1H-indol-2-carboxamida; 36) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-((S- metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxamida; 37) N-(3-cloro-5-(4-(trifluorometóxi)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 38) N-(3-cloro-5-(4-(trifluorometil)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 39) N-(3-bromo-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 40) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-(2-(metilsulfonil)propan-2-il)-1H-indol- 2-carboxamida; 41) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-((metilsulfonil)metil)benzo[b]tiofeno-2- carboxamida; 42) N-(3-cloro-5-(4-clorofenóxi)fenil)-5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxamida; 43) N-(3-cloro-5-(4-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 44) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-fluoro-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 45) 6-cloro-N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 46) N-(3-(4-clorofenóxi)-5-metoxifenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 47) N-(3-cloro-5-(3-cloro-5-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 48) N-(3-cloro-5-(3-(trifluorometóxi)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 49) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 50) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2-il)tieno[2,3- c]piridino-2-carboxamida; 51) N-(3-cloro-5-(3-cloro-4-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 52) N-(3-cloro-5-(3,4-difluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 53) N-(3-cloro-5-(3-fluoro-5-metoxifenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 54) N-(3-cloro-5-(4-cloro-3-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 55) N-(3-cloro-5-(2-(3-cloro-5-metoxifenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 56) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(4-(metilsulfonil)tetra-hidro-2H-piran-4- il)benzo[b]tiofeno-2-carboxamida; 57) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-((2-metoxietil)sulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 58) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 59) N-(3-(azetidin-1-il)-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 60) N-(3-cloro-5-((6-cloropiridin-3-il)óxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 61) N-(3-cloro-5-((5-cloropiridin-2-il)óxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 62) N-(2-cloro-6-(3,5-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 63) N-(6-cloro-4-(4-clorofenóxi)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 64) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 65) N-(2-cloro-6-((6-cloropiridin-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 66) N-(4-cloro-6-(4-clorofenóxi)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 67) N-(2-cloro-6-(4-(trifluorometil)fenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 68) N-(2-cloro-6-(4-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 69) N-(2-bromo-6-(4-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 70) N-(2-cloro-6-(3-cloro-5-metoxifenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 71) N-(2-cloro-6-(3-cloro-4-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 72) N-(2-cloro-6-(4-cloro-3-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 73) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(1,1-dioxidotetra-hidrotiofen-2- il)benzo[b]tiofeno-2-carboxamida; 74) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(1,1-dioxidotetra-hidro-2H- tiopiran-2-il)benzo[b]tiofeno-2-carboxamida; 75) N-(2-cloro-6-(4-clorofenóxi)pirimidin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 76) N-(6-cloro-2-(4-clorofenóxi)pirimidin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 77) N-(2-(4-clorofenóxi)-6-fluoropiridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 78) N-(2-(biciclo[2,2,1]hept-5-en-2-ilóxi)-6-cloropiridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 79) N-(2-cloro-6-(3,4-difluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 80) N-(2-cloro-6-(3-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 81) N-(2-cloro-6-(3-(trifluorometóxi)fenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 82) N-(2-cloro-6-(3,4-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 83) N-(2-cloro-6-(4-cloro-2-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 84) N-(2-cloro-6-(4-(trifluorometóxi)fenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 85) N-(2-cloro-6-((5-cloropiridin-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 86) N-(2-cloro-6-((4-clorobenzil)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 87) N-(3-cloro-5-(2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2-il)fenil)- 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 88) N-(1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 89) N-(3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 90) N-(2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-4-il)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 91) N-(4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-2-il)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 92) N-(3-cloro-5-((2,2,6,6-tetrametilpiperidin-4-il)óxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 93) (2-(3-(4-clorofenóxi)-5-(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxamido)fenóxi)etil)carbamato de terc-butila; 94) N-(3-(2-aminoetóxi)-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 95) N-(5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-il)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 96) (8-cloro-6-(4-clorofenóxi)-2,3-di-hidro-4H-benzo[b][1,4]oxazin-4-il)(5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofen-2-il)metanona; 97) N-(3-cloro-5-(1-(4-clorofenil)ciclopropil)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 98) N-(3-cloro-5-((2,4-difluorofenil)(metil)amino)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 99) N-(3-cloro-5-((4-clorofenil)(metil)amino)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 100) N-(2-cloro-6-((4-clorofenil)(metil)amino)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 101) N-(2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 102) N-(2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 103) 2,2,2-trifluoroacetato de N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboximidamida; 104) N-(2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 105) N-(2-(4-(terc-butil)piperidin-1-il)-6-cloropiridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 106) N-(2-cloro-6-(octa-hidro-2H-pirido[1,2-a]pirazin-2-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 107) N-(2-cloro-6-(7-etil-2,7-diazaespiro[4,4]nonan-2-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 108) N-(2-cloro-6-(octa-hidroisoquinolin-2(1H)-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 109) N-(2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 110) N-(2-cloro-6-((1-metil-1H-pirazol-5-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 111) N-(2-cloro-6-((1,3,5-trimetil-1H-pirazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 112) N-(2-cloro-6-((1-metil-1H-pirazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 113) N-(2-cloro-6-((3,5-dimetilisoxazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 114) N-(2-cloro-6-((5-metiltiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 115) N-(2-cloro-6-((2-metiltiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 116) N-(2-cloro-6-((4,5-dimetilisoxazol-3-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 117) N-(2-cloro-6-((5-(trifluorometil)tiofen-3-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 118) 3-((6-cloro-4-(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxamido)piridin-2-il)óxi)isoxazol-5-carboxilato de metila; 119) N-(2-cloro-6-((4-metiltiazol-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 120) N-(2-cloro-6-((5-metiltiofen-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; e 121) N-(2-cloro-6-((2-clorotiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida.[032] Preferred examples of the compound according to the present invention are listed below, and a pharmaceutically acceptable salt and a stereoisomer thereof are also included within the scope of the present invention: 1) N-(3-chloro-5-( 2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 2) N-(3-chloro-5-(2-(3-propoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 3) N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 4) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 5) N-(3-chloro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 6) N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 7) N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 8) N-(3-chloro-5-(2-(3-(2-morpholinoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 9) N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 10) N-(3-(2-(3-(but-2-yn-1-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(2-( methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 11) N-(3-chloro-5-(2-(3-isobutoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 12) N-(3-chloro-5-(2-(3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl) )propan-2-yl)benzo[b]thiophene-2-carboxamide; 13) N-(3-chloro-5-(2-(3-(2,2-difluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan -2-yl)benzo[b]thiophene-2-carboxamide; 14) N-(3-(2-(3-(allyloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 15) N-(3-chloro-5-(2-(3-cyclopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 16) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2 -carboxamide; 17) N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 18) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 19) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 20) N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 21) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 22) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 23) 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 24) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 25) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 26) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c] pyridine-2-carboxamide; 27) N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 28) N-(3-chloro-5-(2-(5-isopropylthiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 29) N-(3-chloro-5-(2-(5-methoxythiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 30) N-(3-chloro-5-(2-(2-methoxythiophen-3-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 31) N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 32) N-(3-chloro-5-(2-(4-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 33) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxamide; 34) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[ b]thiophene-2-carboxamide; 35) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxamide ; 36) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxamide; 37) N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 38) N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 39) N-(3-bromo-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 40) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxamide; 41) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 42) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 43) N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 44) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 45) 6-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 46) N-(3-(4-chlorophenoxy)-5-methoxyphenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 47) N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 48) N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 49) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 50) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine-2-carboxamide; 51) N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 52) N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 53) N-(3-chloro-5-(3-fluoro-5-methoxyphenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 54) N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 55) N-(3-chloro-5-(2-(3-chloro-5-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 56) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxamide; 57) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 58) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 59) N-(3-(azetidin-1-yl)-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 60) N-(3-chloro-5-((6-chloropyridin-3-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 61) N-(3-chloro-5-((5-chloropyridin-2-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 62) N-(2-chloro-6-(3,5-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 63) N-(6-chloro-4-(4-chlorophenoxy)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 64) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 65) N-(2-chloro-6-((6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 66) N-(4-chloro-6-(4-chlorophenoxy)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 67) N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 68) N-(2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 69) N-(2-bromo-6-(4-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 70) N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 71) N-(2-chloro-6-(3-chloro-4-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 72) N-(2-chloro-6-(4-chloro-3-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 73) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxamide; 74) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene-2- carboxamide; 75) N-(2-chloro-6-(4-chlorophenoxy)pyrimidin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 76) N-(6-chloro-2-(4-chlorophenoxy)pyrimidin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 77) N-(2-(4-chlorophenoxy)-6-fluoropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 78) N-(2-(bicyclo[2,2,1]hept-5-en-2-yloxy)-6-chloropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 79) N-(2-chloro-6-(3,4-difluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 80) N-(2-chloro-6-(3-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 81) N-(2-chloro-6-(3-(trifluoromethoxy)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 82) N-(2-chloro-6-(3,4-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 83) N-(2-chloro-6-(4-chloro-2-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 84) N-(2-chloro-6-(4-(trifluoromethoxy)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 85) N-(2-chloro-6-((5-chloropyridin-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 86) N-(2-chloro-6-((4-chlorobenzyl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 87) N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 88) N-(1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 89) N-(3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 90) N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 91) N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 92) N-(3-chloro-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 93) tert-butyl (2-(3-(4-chlorophenoxy)-5-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)phenoxy)ethyl)carbamate ; 94) N-(3-(2-aminoethoxy)-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 95) N-(5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-yl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 96) (8-chloro-6-(4-chlorophenoxy)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-(methylsulfonyl)propan -2-yl)benzo[b]thiophen-2-yl)methanone; 97) N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 98) N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 99) N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 100) N-(2-chloro-6-((4-chlorophenyl)(methyl)amino)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2 -carboxamide; 101) N-(2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 102) N-(2-chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 103) N-(3-Chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboximidamide 2,2,2-trifluoroacetate ; 104) N-(2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2- yl)benzo[b]thiophene-2-carboxamide; 105) N-(2-(4-(tert-butyl)piperidin-1-yl)-6-chloropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 106) N-(2-chloro-6-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 107) N-(2-chloro-6-(7-ethyl-2,7-diazaspiro[4,4]nonan-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 108) N-(2-chloro-6-(octahydroisoquinolin-2(1H)-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 109) N-(2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 110) N-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide; 111) N-(2-chloro-6-((1,3,5-trimethyl-1H-pyrazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2- yl)benzo[b]thiophene-2-carboxamide; 112) N-(2-chloro-6-((1-methyl-1H-pyrazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide; 113) N-(2-chloro-6-((3,5-dimethylisoxazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 114) N-(2-chloro-6-((5-methylthiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 115) N-(2-chloro-6-((2-methylthiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 116) N-(2-chloro-6-((4,5-dimethylisoxazol-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 117) N-(2-chloro-6-((5-(trifluoromethyl)thiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b ]thiophene-2-carboxamide; 118) 3-((6-chloro-4-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)pyridin-2-yl)oxy)isoxazole-5-carboxylate of methyl; 119) N-(2-chloro-6-((4-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 120) N-(2-chloro-6-((5-methylthiophen-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; and 121) N-(2-chloro-6-((2-chlorothiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide.

[033]Os nomes listados acima dos compostos são descritos, de acordo com o método de nomenclatura fornecido pelo software ChemBioDraw Ultra (Versão 13.0.0.3015) da PerkinElmer.[033] The names listed above for the compounds are described, according to the naming method provided by the ChemBioDraw Ultra software (Version 13.0.0.3015) by PerkinElmer.

[034]A presente invenção fornece um sal farmaceuticamente aceitável de um derivado heterocíclico representado pela fórmula (I) acima. O sal farmaceuticamente aceitável deve apresentar baixa toxicidade aos seres humanos e não deve apresentar qualquer impacto negativo sobre as atividades biológicas e propriedades fisicoquímicas dos compostos precursores. Exemplos do sal farmaceuticamente aceitável podem incluir um sal de adição de ácido entre um ácido livre farmaceuticamente utilizável e um composto básico representado pela fórmula (I), um sal de metal alcalino (sal de sódio, etc.) e um sal de metal alcalino terroso (sal de potássio, etc.), um sal de adição de base orgânica entre uma base orgânica e ácido carboxílico representado pela fórmula (I), sal de adição de aminoácido, etc.[034] The present invention provides a pharmaceutically acceptable salt of a heterocyclic derivative represented by the above formula (I). The pharmaceutically acceptable salt must have low toxicity to humans and must not have any negative impact on the biological activities and physicochemical properties of the precursor compounds. Examples of the pharmaceutically acceptable salt may include an acid addition salt between a pharmaceutically usable free acid and a basic compound represented by the formula (I), an alkali metal salt (sodium salt, etc.) and an alkaline earth metal salt (potassium salt, etc.), an organic base addition salt between an organic base and carboxylic acid represented by the formula (I), amino acid addition salt, etc.

[035]Exemplos de uma forma adequada de sais, de acordo com a presente invenção, pode ser um sal com um ácido inorgânico ou ácido orgânico, em que o ácido inorgânico pode ser ácido clorídrico, ácido sulfúrico, ácido nítrico, ácido fosfórico, ácido perclórico, ácido brômico, etc., e o ácido orgânico pode ser ácido acético, ácido metanossulfônico, ácido etanossulfônico, ácido p-toluenossulfônico, ácido fumárico, ácido maleico, ácido malônico, ácido ftálico, ácido succínico, ácido láctico, ácido cítrico, ácido glicônico, ácido tartárico, ácido salicílico, ácido málico, ácido oxálico, ácido benzoico, ácido embônico, ácido aspártico, ácido glutâmico, etc. A base orgânica que pode ser usada para a preparação do sal de adição de base orgânica pode incluir tris(hidroximetil)metilamina, diciclo-hexilamina, etc. Os aminoácidos que podem ser usados para a preparação de base de adição de aminoácido podem incluir aminoácidos naturais, tais como alanina e glicina.[035] Examples of a suitable form of salts, according to the present invention, can be a salt with an inorganic acid or organic acid, where the inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acid perchloric acid, bromic acid, etc., and the organic acid can be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, acid gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. The organic base that can be used for preparing the organic base addition salt may include tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used for preparing the amino acid addition base can include natural amino acids such as alanine and glycine.

[036]Os sais podem ser preparados usando um método convencional. Por exemplo, os sais podem ser preparados por meio da dissolução do composto representado pela fórmula (I) em um solvente miscível em água, tal como metanol, etanol, acetona e 1,4-dioxano, adição de um ácido livre ou uma base livre e depois cristalização do produto resultante.[036] The salts can be prepared using a conventional method. For example, salts can be prepared by dissolving the compound represented by formula (I) in a water-miscible solvent such as methanol, ethanol, acetone and 1,4-dioxane, adding a free acid or a free base. and then crystallizing the resulting product.

[037]Adicionalmente, os compostos da presente invenção podem apresentar um centro carbono quiral e, assim, podem estar presentes na forma de um isômero R ou S, um composto racêmico, um enantiômero individual ou uma mistura, um diastereômero individual ou uma mistura, e todos estes estereoisômeros e uma mistura dos mesmos podem pertencer ao escopo da presente invenção.[037] Additionally, the compounds of the present invention may have a chiral carbon center and, thus, may be present in the form of an R or S isomer, a racemic compound, an individual enantiomer or a mixture, an individual diastereomer or a mixture, and all these stereoisomers and a mixture thereof may fall within the scope of the present invention.

[038]Adicionalmente, os compostos da presente invenção também podem incluir um hidrato ou solvato do derivado heterocíclico representado pela fórmula (I). O hidrato ou solvato pode ser preparado usando um método conhecido e é preferido que seja não tóxico e solúvel em água e, em particular, é, preferivelmente, água ou um hidrato ou solvato que apresenta 1 a 5 moléculas de solvente alcoólico (especialmente, etanol, etc.) ligadas ao mesmo.[038] Additionally, the compounds of the present invention may also include a hydrate or solvate of the heterocyclic derivative represented by formula (I). The hydrate or solvate can be prepared using a known method and it is preferred that it is non-toxic and soluble in water and, in particular, is preferably water or a hydrate or solvate that has 1 to 5 molecules of alcoholic solvent (especially ethanol , etc.) linked to it.

[039]A presente invenção também fornece um uso de um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima e de um sal farmaceuticamente aceitável e de um estereoisômero do mesmo para a fabricação de um medicamento para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3.[039] The present invention also provides a use of a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above and a pharmaceutically acceptable salt and a stereoisomer thereof for the manufacture of a medicine for prevention or treatment of diseases associated with STAT3 protein activation.

[040]Além disso, a presente invenção fornece um método para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3 em um mamífero, que compreende administrar um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima e um sal farmaceuticamente aceitável e um estereoisômero do mesmo ao mamífero.[040] In addition, the present invention provides a method for preventing or treating diseases associated with activation of the STAT3 protein in a mammal, which comprises administering a compound selected from the group consisting of a heterocyclic derivative represented by formula (I ) above and a pharmaceutically acceptable salt and a stereoisomer thereof to the mammal.

[041]Além disso, a presente invenção fornece uma composição farmacêutica para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3, compreendendo um composto selecionado a partir do grupo que consiste de um derivado heterocíclico representado pela fórmula (I) acima e um sal farmaceuticamente aceitável e um estereoisômero do mesmo como ingredientes ativos.[041] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases associated with the activation of the STAT3 protein, comprising a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above and a pharmaceutically acceptable salt and a stereoisomer thereof as active ingredients.

[042]Especificamente, as doenças associadas com a ativação da proteína STAT3 são selecionadas a partir do grupo que consiste de cânceres sólidos, cânceres hematológicos ou sanguíneos, cânceres radio- ou quimio-resistentes, cânceres metastáticos, doenças inflamatórias, doenças imunológicas, diabetes, degeneração macular, infecção por papilomavírus humano e tuberculose.[042] Specifically, diseases associated with STAT3 protein activation are selected from the group consisting of solid cancers, hematological or blood cancers, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological diseases, diabetes, macular degeneration, human papillomavirus infection and tuberculosis.

[043]Mais especificamente, as doenças associadas com a ativação da proteína STAT3 são selecionadas a partir do grupo que consiste de câncer de mama, câncer de pulmão, câncer de estômago, câncer de próstata, câncer uterino, câncer ovariano, câncer renal, câncer pancreático, câncer de fígado, câncer de cólon, câncer de pele, câncer de cabeça e pescoço, câncer da tireoide, osteossarcoma, leucemia aguda ou crônica, mieloma múltiplo, linfoma de células B ou T, linfoma não-Hodgkin, doenças autoimunes compreendendo artrite reumatoide, psoríase, hepatite, doença inflamatória intestinal, doença de Crohn, diabetes, degeneração macular, infecção por papilomavírus humano e tuberculose.[043]More specifically, diseases associated with STAT3 protein activation are selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, cancer pancreatic, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B or T cell lymphoma, non-Hodgkin lymphoma, autoimmune diseases including arthritis rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.

[044]Em particular, um derivado heterocíclico representado pela fórmula (I) acima, ou um sal farmaceuticamente aceitável ou um estereoisômero do mesmo apresenta um efeito inibitório excelente sobre a ativação da proteína STAT3 e, assim, a presente invenção também fornece uma composição para a inibição da proteína STAT3 compreendendo o mesmo como um ingrediente ativo.[044] In particular, a heterocyclic derivative represented by the above formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, has an excellent inhibitory effect on STAT3 protein activation, and thus, the present invention also provides a composition for the inhibition of STAT3 protein comprising the same as an active ingredient.

[045]A composição farmacêutica da presente invenção, além do derivado heterocíclico representado pela fórmula (I) acima, do sal farmaceuticamente aceitável do mesmo, ou do estereoisômero do mesmo, ainda pode incluir como ingredientes ativos, aditivos farmaceuticamente aceitáveis comuns e não tóxicos, por exemplo, um portador, um excipiente, um diluente, um adjuvante, etc., que serão formulados em uma preparação, de acordo com um método convencional.[045] The pharmaceutical composition of the present invention, in addition to the heterocyclic derivative represented by formula (I) above, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, may also include as active ingredients, common pharmaceutically acceptable and non-toxic additives, for example, a carrier, an excipient, a diluent, an adjuvant, etc., which will be formulated into a preparation, according to a conventional method.

[046]A composição farmacêutica da presente invenção pode ser formulada em várias formas de preparações para administração oral, tal como tabletes, pílulas, pós, cápsulas, xaropes ou emulsões, ou para administração parenteral, tal como injeções intramusculares, intravenosas ou subcutâneas, etc., e, preferivelmente, na forma de uma preparação para administração oral.[046] The pharmaceutical composition of the present invention can be formulated into various forms of preparations for oral administration, such as tablets, pills, powders, capsules, syrups or emulsions, or for parenteral administration, such as intramuscular, intravenous or subcutaneous injections, etc. ., and preferably in the form of a preparation for oral administration.

[047]Exemplos dos aditivos que podem ser usados na composição farmacêutica da presente invenção podem incluir adoçantes, aglutinantes, solventes, auxiliares de solubilização, agentes umectantes, emulsificantes, agentes isotônicos, absorventes, agentes desintegrantes, antioxidantes, preservantes, lubrificantes, enchedores, agentes flavorizantes, etc. Por exemplo, eles podem incluir, lactose, dextrose, sacarose, manitol, sorbitol, celulose, glicina, sílica, talco, ácido esteárico, estearina, estearato de magnésio, aluminossilicato de magnésio, amido, gelatina, goma tragacanto, ácido algínico, alginato de sódio, metilcelulose, carboximetilcelulose sódica, ágar, água, etanol, polietilenoglicol, polivinilpirrolidona, cloreto de sódio, cloreto de cálcio, essência de laranja, essência de morango, flavor de baunilha, etc.[047] Examples of additives that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solvents, solubilization aids, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrating agents, antioxidants, preservatives, lubricants, fillers, agents flavorings, etc. For example, they may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, alginate sodium, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[048]A composição farmacêutica da presente invenção pode ser formulada em uma preparação para administração oral por mio da adição de aditivos aos ingredientes ativos, em que os aditivos podem incluir celulose, silicato de cálcio, amido de milho, lactose, sacarose, dextrose, fosfato de cálcio, ácido esteárico, estearato de magnésio, estearato de cálcio, gelatina, talco, tensoativos, agentes de suspensão, emulsificantes, diluentes, etc.[048] The pharmaceutical composition of the present invention can be formulated into a preparation for oral administration by adding additives to the active ingredients, in which additives may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.

[049]A composição farmacêutica da presente invenção pode ser formulada em uma preparação para injeção por meio da adição de aditivos aos ingredientes ativos, por exemplo, água, uma solução salina, uma solução de glicose, um análogo de solução de glicose aquosa, álcool, glicol, éter, óleo, graxo ácido, éster de ácido graxo, glicerídeo, tensoativos, agentes de suspensão, emulsificantes, etc.[049] The pharmaceutical composition of the present invention can be formulated into a preparation for injection by adding additives to the active ingredients, for example, water, a saline solution, a glucose solution, an analogue of aqueous glucose solution, alcohol , glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactants, suspending agents, emulsifiers, etc.

[050]O composto da presente invenção pode ser administrado, preferivelmente, em uma quantidade que varia de 0,1 a 2.000 mg/dia com base em um adulto com 70 kg de peso corpóreo. O composto da presente invenção pode ser administrado uma vez ao dia ou algumas doses divididas. A dosagem do composto da presente invenção pode variar, dependendo das condições de saúde, idade, peso corpóreo, sexo do sujeito, via de administração, severidade da doença, etc., e o escopo da presente invenção não será limitado à dose sugerida acima.[050] The compound of the present invention can be administered, preferably, in an amount ranging from 0.1 to 2,000 mg/day based on an adult with 70 kg of body weight. The compound of the present invention can be administered once a day or a few divided doses. The dosage of the compound of the present invention may vary depending on the health conditions, age, body weight, sex of the subject, route of administration, severity of the disease, etc., and the scope of the present invention will not be limited to the above suggested dose.

EXEMPLOEXAMPLE

[051]Em seguida, a presente invenção será descrita, mais especificamente, pelos seguintes exemplos, mas estes são fornecidos apenas para propósitos de ilustração e a presente invenção não é limitada aos mesmos.[051] Next, the present invention will be described more specifically by the following examples, but these are provided for illustrative purposes only and the present invention is not limited thereto.

[052]A definição das abreviações usadas nos exemplos seguintes é a seguinte.Tabela 1 Intermediário 1) Síntese de ácido 6-fluoro-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxílico (a) Síntese de 1-(bromometil)-2,4-difluoro-5-metilbenzeno[052] The definition of the abbreviations used in the following examples is as follows. Table 1 Intermediate 1) Synthesis of 6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of 1-(bromomethyl)-2,4-difluoro- 5-methylbenzene

[053]Paraformaldeído (247,0 mg, 7,81 mmols) foi dissolvido em solução a 33 % de HBr em AcOH (4,0 mL) e 2,4-difluoro-1-metilbenzeno (1,0 g, 7,81 mmols) e ZnBr2 (880,0 mg, 3,91 mmols) foram adicionados. A mistura de reação foi agitada a 120 °C durante 4 horas, esfriada até a temperatura ambiente, NaHCO3 sat. foi adicionado e extraído com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 1- (bromometil)-2,4-difluoro-5-metilbenzeno (1,1 g, 64 %) como um líquido incolor. RMN de 1H (400 MHz, CDCl3): δ 7,20 (t, 1H, J = 8,4 Hz), 6,77 (t, 1H, J = 9,5 Hz), 4,46 (s, 2H), 2,24 (s, 3H) (b) Síntese de 1,5-difluoro-2-metil-4-((metilsulfonil)metil)benzeno[053]Paraformaldehyde (247.0 mg, 7.81 mmol) was dissolved in a 33% solution of HBr in AcOH (4.0 mL) and 2,4-difluoro-1-methylbenzene (1.0 g, 7. 81 mmol) and ZnBr2 (880.0 mg, 3.91 mmol) were added. The reaction mixture was stirred at 120°C for 4 hours, cooled to room temperature, sat. was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 1-(bromomethyl)-2,4-difluoro-5-methylbenzene (1.1 g, 64%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.20 (t, 1H, J = 8.4 Hz), 6.77 (t, 1H, J = 9.5 Hz), 4.46 (s, 2H ), 2,24 (s, 3H) (b) Synthesis of 1,5-difluoro-2-methyl-4-((methylsulfonyl)methyl)benzene

[054]1-(Bromometil)-2,4-difluoro-5-metilbenzeno (260,0 mg, 1,18 mmol) foi dissolvido em EtOH anidro (6,0 mL) e metanossulfinato de sódio (120,0 mg, 1,18 mmol) foi adicionado. A mistura de reação foi submetida ao refluxo durante 2 horas, esfriada até a temperatura ambiente e concentrada sob pressão reduzida. O resíduo foi recristalizado com Et2O para obter 1,5-difluoro-2-metil-4-((metilsulfonil)metil)benzeno (160,0 mg, 61 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 7,32 (t, 1H, J = 8,3 Hz), 6,86 (t, 1H, J = 9,5 Hz), 4,24 (s, 2H), 2,82 (s, 3H), 2,27 (s, 3H) (c) Síntese de 1,5-difluoro-2-metil-4-(2-(metilsulfonil)propan-2-il)benzeno[054]1-(Bromomethyl)-2,4-difluoro-5-methylbenzene (260.0 mg, 1.18 mmol) was dissolved in anhydrous EtOH (6.0 mL) and sodium methanesulfinate (120.0 mg, 1.18 mmol) was added. The reaction mixture was refluxed for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from Et2O to obtain 1,5-difluoro-2-methyl-4-((methylsulfonyl)methyl)benzene (160.0 mg, 61%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.32 (t, 1H, J = 8.3 Hz), 6.86 (t, 1H, J = 9.5 Hz), 4.24 (s, 2H ), 2.82 (s, 3H), 2.27 (s, 3H) (c) Synthesis of 1,5-difluoro-2-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene

[055]1,5-Difluoro-2-metil-4-((metilsulfonil)metil)benzeno (3,4 g, 15,40 mmols) foi dissolvido em DMF anidra (22,4 mL) e NaOt-Bu (3,7 g, 38,60 mmols) e CH3I (4,8 mL, 77,20 mmols) foram adicionados a 0 °C. A mistura de reação foi agitada a 0 °C, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex : EtOAc = 4:1) para obter 1,5-difluoro-2-metil-4-(2-(metilsulfonil)propan-2-il)benzeno (370,0 mg, 10 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 7,38 (t, 1H, J = 9,2 Hz), 6,75 (t, 1H, J = 9,2 Hz), 2,70 - 2,81 (m, 3H), 1,90 (s, 3H), 1,74 (d, 6H, J = 7,2 Hz) (d) Síntese de 1-(bromometil)-2,4-difluoro-5-(2-(metilsulfonil)propan-2- il)benzeno[055]1,5-Difluoro-2-methyl-4-((methylsulfonyl)methyl)benzene (3.4 g, 15.40 mmol) was dissolved in anhydrous DMF (22.4 mL) and NaOt-Bu (3 .7 g, 38.60 mmol) and CH3I (4.8 mL, 77.20 mmol) were added at 0 °C. The reaction mixture was stirred at 0°C, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 4:1) to obtain 1,5-difluoro-2-methyl-4-(2-(methylsulfonyl)propan-2-yl) benzene (370.0 mg, 10%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.38 (t, 1H, J = 9.2 Hz), 6.75 (t, 1H, J = 9.2 Hz), 2.70 - 2.81 (m, 3H), 1.90 (s, 3H), 1.74 (d, 6H, J = 7.2 Hz) (d) Synthesis of 1-(bromomethyl)-2,4-difluoro-5-( 2-(methylsulfonyl)propan-2-yl)benzene

[056]1,5-Difluoro-2-metil-4-(2-(metilsulfonil)propan-2-il)benzeno (370,0 mg, 1,49 mmol) foi dissolvido em 1,2-dicloroetano anidro (15,0 mL) e N- bromossuccinimida (265,0 mg, 1,49 mmol) e AIBN (25,0 mg, 0,15 mmol) foram adicionados. A mistura de reação foi submetida ao refluxo a 100 °C durante 15 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em sílica em coluna (n-Hex:EtOAc=4:1) para obter 1-(bromometil)-2,4-difluoro-5-(2- (metilsulfonil)propan-2-il)benzeno (367,0 mg, 66 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 7,60 (t, 1H, J = 8,5 Hz), 6,88 (dd, 1H, J = 12,4, 9,2 Hz), 4,28 (s, 2H), 2,74 (s, 3H), 1,93 (d, 6H, J = 2,6 Hz) (e) Síntese de 2,4-difluoro-5-(2-(metilsulfonil)propan-2-il)benzaldeído[056] 1,5-Difluoro-2-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene (370.0 mg, 1.49 mmol) was dissolved in anhydrous 1,2-dichloroethane (15 .0 mL) and N-bromosuccinimide (265.0 mg, 1.49 mmol) and AIBN (25.0 mg, 0.15 mmol) were added. The reaction mixture was refluxed at 100 °C for 15 hours, cooled to room temperature, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column chromatography (n-Hex:EtOAc=4:1) to obtain 1-(bromomethyl)-2,4-difluoro-5-(2-(methylsulfonyl)propan-2-yl)benzene (367.0 mg, 66%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.60 (t, 1H, J = 8.5 Hz), 6.88 (dd, 1H, J = 12.4, 9.2 Hz), 4.28 (s, 2H), 2.74 (s, 3H), 1.93 (d, 6H, J = 2.6 Hz) (e) Synthesis of 2,4-difluoro-5-(2-(methylsulfonyl)propan -2-yl)benzaldehyde

[057]1-(Bromometil)-2,4-difluoro-5-(2-(metilsulfonil)propan-2-il)benzeno (367,0 mg, 1,12 mmol) foi dissolvido em CH3CN anidro (11,0 mL) e N-óxido de 4- metilmorfolina (263,0 mg, 2,24 mmols) e peneiras moleculares (1,0 g) foram adicionados. A mistura de reação foi agitada na temperatura ambiente durante 90 minutos, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi recristalizado com CH2Cl2 e n-Hex para obter 2,4-difluoro-5-(2- (metilsulfonil)propan-2-il)benzaldeído (200,0 mg, 66 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 10,16 (s, 1H), 8,07 (t, 1H, J = 8,6 Hz), 7,56 (dd, 1H, J = 12,6, 10,6 Hz), 2,90 (s, 3H), 1,87 (d, 6H, J = 2,5 Hz) (f) Síntese de 6-fluoro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila[057] 1-(Bromomethyl)-2,4-difluoro-5-(2-(methylsulfonyl)propan-2-yl)benzene (367.0 mg, 1.12 mmol) was dissolved in anhydrous CH3CN (11.0 mL) and 4-methylmorpholine N-oxide (263.0 mg, 2.24 mmol) and molecular sieves (1.0 g) were added. The reaction mixture was stirred at room temperature for 90 minutes, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was recrystallized with CH2Cl2 and n-Hex to obtain 2,4-difluoro-5-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (200.0 mg, 66%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.16 (s, 1H), 8.07 (t, 1H, J = 8.6 Hz), 7.56 (dd, 1H, J = 12.6, 10.6 Hz), 2.90 (s, 3H), 1.87 (d, 6H, J = 2.5 Hz) (f) Synthesis of 6-fluoro-5-(2-(methylsulfonyl)propan-2 Methyl-yl)benzo[b]thiophene-2-carboxylate

[058]2,4-Difluoro-5-(2-(metilsulfonil)propan-2-il)benzaldeído (170,0 mg, 0,65 mmol) foi dissolvido em DMF anidra (11,0 mL) e 2-mercaptoacetato de metila (58,0 μL, 0,65 mmol) e K2CO3 (179,6 mg, 1,30 mmol) foram adicionados. A mistura de reação foi agitada a 80 °C durante 5 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex : EtOAc = 1:1) para obter 6-fluoro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (165,0 mg, 77 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 8,08 (d, 1H, J = 7,6 Hz), 8,03 (s, 1H), 7,60 (d, 1H, J = 12,8 Hz), 3,96 (s, 3H), 2,77 (s, 3H), 2,00 (d, 6H, J = 2,6 Hz) (g) Síntese de ácido 6-fluoro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxílico[058]2,4-Difluoro-5-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (170.0 mg, 0.65 mmol) was dissolved in anhydrous DMF (11.0 mL) and 2-mercaptoacetate of methyl (58.0 µL, 0.65 mmol) and K2CO3 (179.6 mg, 1.30 mmol) were added. The reaction mixture was stirred at 80°C for 5 hours, cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 1:1) to obtain 6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- Methyl 2-carboxylate (165.0 mg, 77%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, 1H, J = 7.6 Hz), 8.03 (s, 1H), 7.60 (d, 1H, J = 12.8 Hz ), 3.96 (s, 3H), 2.77 (s, 3H), 2.00 (d, 6H, J = 2.6 Hz) (g) Synthesis of 6-fluoro-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid

[059]6-Fluoro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (165,0 mg, 0,50 mmol) foi dissolvido em THF (3,4 mL) e H2O (1,6 mL) e LÍOKH2O (210,0 mg, 4,99 mmols) foi adicionado. A mistura de reação foi agitada na temperatura ambiente durante 1 hora, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi recristalizado com CH2Cl2 e n-Hex para obter ácido 6-fluoro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (150,0 mg, quant) como um sólido branco.LC/MS ESI (-): 315 (M-1) Intermediário 2) Síntese de ácido 5-((metilsulfonil)metil)benzo[b]tiofeno-2- carboxílico (a) Síntese de 5-metilbenzo[b]tiofeno-2-carboxilato de metila[059] Methyl 6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (165.0 mg, 0.50 mmol) was dissolved in THF (3. 4 mL) and H2O (1.6 mL) and LIOKH2O (210.0 mg, 4.99 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was recrystallized from CH2Cl2 and n-Hex to obtain 6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (150.0 mg, quant) as a white solid.LC/MS ESI (-): 315 (M-1) Intermediate 2) Synthesis of 5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of 5-methylbenzo[b methyl]thiophene-2-carboxylate

[060]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 2-fluoro-5-metilbenzaldeído (300,0 mg, 2,17 mmols) como um material de partida para obter 5-metilbenzo[b]tiofeno-2-carboxilato de metila (164,0 mg, 37 %).LC/MS (ESI+): 207 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,99 (s, 1H), 7,29 (d, 1H, J = 8,4 Hz), 7,67 (s, 1H), 7,30 (dd, 1H, J = 8,3, 1,3 Hz), 3,94 (s, 3H), 2,48 (s, 3H) (b) Síntese de 5-(bromometil)benzo[b]tiofeno-2-carboxilato de metila[060] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 2-fluoro-5-methylbenzaldehyde (300.0 mg, 2.17 mmol) as a starting material to obtain 5-methylbenzo[b Methyl]thiophene-2-carboxylate (164.0 mg, 37%). LC/MS (ESI+): 207 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H) , 7.29 (d, 1H, J = 8.4 Hz), 7.67 (s, 1H), 7.30 (dd, 1H, J = 8.3, 1.3 Hz), 3.94 ( s, 3H), 2.48 (s, 3H) (b) Synthesis of methyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[061]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 5-metilbenzo[b]tiofeno-2-carboxilato de metila (100,0 mg, 0,49 mmol) como um material de partida para obter 5-(bromometil)benzo[b]tiofeno-2-carboxilato de metila (46,5 mg, 34 %). RMN de 1H (400 MHz, CDCl3): δ 8,04 (s, 1H), 7,89 (s, 1H), 7,85 (d, 1H, J = 8,4 Hz), 7,50 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 3,95 (s, 3H) (c) Síntese de 5-((metilsulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila[061] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of methyl 5-methylbenzo[b]thiophene-2-carboxylate (100.0 mg, 0.49 mmol) as a starting material for obtain methyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (46.5 mg, 34%). 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.89 (s, 1H), 7.85 (d, 1H, J = 8.4 Hz), 7.50 (d , 1H, J = 8.5 Hz), 4.63 (s, 2H), 3.95 (s, 3H) (c) Synthesis of 5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate of methyl

[062]O procedimento de síntese do Intermediário 1-b foi repetido, exceto para o uso de 5-(bromometil)benzo[b]tiofeno-2-carboxilato de metila (45,0 mg, 0,16 mmol) como um material de partida para obter 5-((metilsulfonil)metil)benzo[b]tiofeno- 2-carboxilato de metila (45,0 mg, quant). LC/MS (ESI+): 285 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,07 (s, 1H), 7,91 - 7,93 (m, 2H), 7,51 (d, 1H, J = 8,4 Hz), 4,37 (s, 2H), 3,96 (s, 3H), 2,80 (s, 3H) (d) Síntese de ácido 5-((metilsulfonil)metil)benzo[b]tiofeno-2-carboxílico[062] The procedure for the synthesis of Intermediate 1-b was repeated, except for the use of methyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (45.0 mg, 0.16 mmol) as a material crude to obtain methyl 5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate (45.0 mg, quant). LC/MS (ESI+): 285 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.91 - 7.93 (m, 2H), 7.51 ( d, 1H, J = 8.4 Hz), 4.37 (s, 2H), 3.96 (s, 3H), 2.80 (s, 3H) (d) Synthesis of 5-((methylsulfonyl) acid methyl)benzo[b]thiophene-2-carboxylic acid

[063]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-((metilsulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila (45,0 mg, 0,16 mmol) como um material de partida para obter ácido 5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxílico (39,3 mg, 90 %). RMN de 1H (400 MHz, DMSO-d6): δ 13,50 (brs, 1H), 8,15 (s, 1H), 8,08 (d, 1H, J = 8,5 Hz), 8,03 (s, 1H), 7,53 (d, 1H, J = 8,5 Hz), 4,62 (s, 2H), 2,94 (s, 3H)Intermediário 3) Síntese de ácido 5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxílico (a) Síntese de 5-(((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila[063] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate (45.0 mg, 0.16 mmol) as a starting material to obtain 5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid (39.3 mg, 90%). 1H NMR (400 MHz, DMSO-d6): δ 13.50 (brs, 1H), 8.15 (s, 1H), 8.08 (d, 1H, J = 8.5 Hz), 8.03 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 4.62 (s, 2H), 2.94 (s, 3H) Intermediate 3) Acid Synthesis 5- ((( trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylate

[064]5-(Bromometil)benzo[b]tiofeno-2-carboxilato de metila (263,0 mg, 0,92 mmol) e triflinato de sódio (216,0 mg, 1,38 mmol) foram dissolvidos em propionitrila (4,6 mL). A mistura de reação foi submetida ao refluxo durante 16 horas e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 4:1) para obter 5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila (171,8 mg, 55 %) como um sólido branco.LC/MS (ESI+): 339 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,08 (s, 1H), 7,94 - 7,96 (m, 2H), 7,49 (dd, 1H, J = 8,5, 1,6 Hz), 4,61 (s, 2H), 3,97 (s, 3H) (b) Síntese de ácido 5-(((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2- carboxílicoMethyl [064]5-(bromomethyl)benzo[b]thiophene-2-carboxylate (263.0 mg, 0.92 mmol) and sodium triflinate (216.0 mg, 1.38 mmol) were dissolved in propionitrile ( 4.6 mL). The reaction mixture was refluxed for 16 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 4:1) to obtain methyl 5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylate (171 .8 mg, 55%) as a white solid. LC/MS (ESI+): 339 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.94 - 7 .96 (m, 2H), 7.49 (dd, 1H, J = 8.5, 1.6 Hz), 4.61 (s, 2H), 3.97 (s, 3H) (b) Synthesis of 5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid

[065]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila (210,0 mg, 0,62 mmol) como um material de partida para obter ácido 5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxílico (151,8 mg) sem purificação. RMN de 1H (400 MHz, DMSO-d6): δ 13,62 (brs, 1H), 8,20 (s, 1H), 8,15 (d, 1H, J = 8,5 Hz), 8,12 (s, 1H), 7,58 (dd, 1H, J = 8,5, 1,6 Hz), 5,41 (s, 2H) Intermediário 4) Síntese de ácido 5-(fluoro(metilsulfonil)metil)benzo[b]tiofeno- 2-carboxílico (a) Síntese de 2-metil-4-((metilsulfonil)metil)-1-nitrobenzeno[065] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylate (210.0 mg, 0. 62 mmol) as a starting material to obtain 5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid (151.8 mg) without purification. 1H NMR (400 MHz, DMSO-d6): δ 13.62 (brs, 1H), 8.20 (s, 1H), 8.15 (d, 1H, J = 8.5 Hz), 8.12 (s, 1H), 7.58 (dd, 1H, J = 8.5, 1.6 Hz), 5.41 (s, 2H) Intermediate 4) Synthesis of 5-(fluoro(methylsulfonyl)methyl)benzoic acid [b]thiophene-2-carboxylic acid (a) Synthesis of 2-methyl-4-((methylsulfonyl)methyl)-1-nitrobenzene

[066]O procedimento de síntese do Intermediário 1-b foi repetido, exceto para o uso de 4-(bromometil)-2-metil-1-nitrobenzeno (2,0 g, 8,69 mmols) como um material de partida para obter 2-metil-4-((metilsulfonil)metil)-1-nitrobenzeno (1,7 g, 86 %). RMN de 1H (400 MHz, CDCl3): δ 8,02 (d, 1H, J = 8,1 Hz), 7,40 - 7,42 (m, 2H), 4,29 (s, 2H), 2,86 (s, 3H), 2,64 (s, 3H) (b) Síntese de 4-(fluoro(metilsulfonil)metil)-2-metil-1-nitrobenzeno[066] The procedure for the synthesis of Intermediate 1-b was repeated, except for the use of 4-(bromomethyl)-2-methyl-1-nitrobenzene (2.0 g, 8.69 mmol) as a starting material for obtain 2-methyl-4-((methylsulfonyl)methyl)-1-nitrobenzene (1.7 g, 86%). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J = 8.1 Hz), 7.40 - 7.42 (m, 2H), 4.29 (s, 2H), 2 .86 (s, 3H), 2.64 (s, 3H) (b) Synthesis of 4-(fluoro(methylsulfonyl)methyl)-2-methyl-1-nitrobenzene

[067]2-Metil-4-((metilsulfonil)metil)-1-nitrobenzeno (760,0 mg, 3,32 mmols) e N-fluoro-N-(fenilsulfonil)benzeno sulfonamida (2,1 g, 6,64 mmols) foram dissolvidos em THF anidro (16,6 mL) e solução 1,6 M de n-BuLi em n-Hex (4,2 mL, 6,64 mmols) foi lentamente adicionada às gotas a -78 °C. A mistura de reação foi agitada durante 9 horas, H2O foi adicionada na temperatura ambiente e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:1) para obter 4-(fluoro(metilsulfonil)metil)-2- metil-1-nitrobenzeno (175,0 mg, 21 %) como um sólido marrom. RMN de 1H (400 MHz, CDCl3): δ 8,05 (d, 1H, J = 8,9 Hz), 7,94 (m, 1H), 7,54 (m, 1H), 6,09 (d, 1H, J = 46,8 Hz), 3,04 (d, 3H, J = 1,6 Hz), 2,65 (s, 3H) (c) Síntese de 2-(bromometil)-4-(fluoro(metilsulfonil)metil)-1-nitrobenzeno[067] 2-Methyl-4-((methylsulfonyl)methyl)-1-nitrobenzene (760.0 mg, 3.32 mmol) and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.1 g, 6. 64 mmol) was dissolved in anhydrous THF (16.6 mL) and 1.6 M solution of n-BuLi in n-Hex (4.2 mL, 6.64 mmol) was slowly added dropwise at -78 °C. The reaction mixture was stirred for 9 hours, H2O was added at room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:1) to obtain 4-(fluoro(methylsulfonyl)methyl)-2-methyl-1-nitrobenzene (175.0 mg, 21 %) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 1H, J = 8.9 Hz), 7.94 (m, 1H), 7.54 (m, 1H), 6.09 (d , 1H, J = 46.8 Hz), 3.04 (d, 3H, J = 1.6 Hz), 2.65 (s, 3H) (c) Synthesis of 2-(bromomethyl)-4-(fluoro (methylsulfonyl)methyl)-1-nitrobenzene

[068]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 4-(fluoro(metilsulfonil)metil)-2-metil-1-nitrobenzeno (168,0 mg, 0,68 mmol) como um material de partida para obter 2-(bromometil)-4- (fluoro(metilsulfonil)metil)-1-nitrobenzeno (129,5 mg). RMN de 1H (400 MHz, CDCl3): δ 8,05 (d, 1H, J = 8,9 Hz), 7,95 (m, 1H), 7,93 (m, 1H), 6,10 (d, 1H, J = 46,8 Hz), 4,84 (s, 2H), 2,65 (s, 3H) (d) Síntese de 5-(fluoro(metilsulfonil)metil)-2-nitrobenzaldeído[068] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 4-(fluoro(methylsulfonyl)methyl)-2-methyl-1-nitrobenzene (168.0 mg, 0.68 mmol) as a starting material to obtain 2-(bromomethyl)-4-(fluoro(methylsulfonyl)methyl)-1-nitrobenzene (129.5 mg). 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 1H, J = 8.9 Hz), 7.95 (m, 1H), 7.93 (m, 1H), 6.10 (d , 1H, J = 46.8 Hz), 4.84 (s, 2H), 2.65 (s, 3H) (d) Synthesis of 5-(fluoro(methylsulfonyl)methyl)-2-nitrobenzaldehyde

[069]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 2-(bromometil)-4-(fluoro(metilsulfonil)metil)-1-nitrobenzeno (127,0 mg) como um material de partida para obter 5-(fluoro(metilsulfonil)metil)-2- nitrobenzaldeído (13,5 mg, rendimento de 2 etapas: 8 %). RMN de 1H (400 MHz, CDCl3): δ 10,44 (s, 1H), 8,23 (d, 1H, J = 8,5 Hz), 8,13 (d, 1H, J = 1,9 Hz), 7,97 (dd, 1H, J = 8,5, 2,0 Hz), 6,21 (d, 1H, J = 47,0 Hz), 3,10 (d, 3H, J = 1,7 Hz) (e) Síntese de 5-(fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila[069] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 2-(bromomethyl)-4-(fluoro(methylsulfonyl)methyl)-1-nitrobenzene (127.0 mg) as a starting material to obtain 5-(fluoro(methylsulfonyl)methyl)-2-nitrobenzaldehyde (13.5 mg, 2-step yield: 8%). 1H NMR (400 MHz, CDCl3): δ 10.44 (s, 1H), 8.23 (d, 1H, J = 8.5 Hz), 8.13 (d, 1H, J = 1.9 Hz ), 7.97 (dd, 1H, J = 8.5, 2.0 Hz), 6.21 (d, 1H, J = 47.0 Hz), 3.10 (d, 3H, J = 1, 7 Hz) (e) Synthesis of methyl 5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate

[070]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 5-(fluoro(metilsulfonil)metil)-2-nitrobenzaldeído (10,0 mg, 0,04 mmol) como um material de partida para obter 5-(fluoro(metilsulfonil)metil)benzo[b]tiofeno-2- carboxilato de metila (11,0 mg, quant). LC/MS (ESI+): 303 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,11 (s, 1H), 8,08 (s, 1H), 7,98 (d, 1H, J = 8,6 Hz), 7,63 (dd, 1H, J = 8,5, 1,6 Hz), 6,17 (d, 1H, J = 46,2 Hz), 3,97 (s, 3H), 3,02 (d, 3H, J = 1,4 Hz) (f) Síntese de ácido 5-(fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxílico[070] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 5-(fluoro(methylsulfonyl)methyl)-2-nitrobenzaldehyde (10.0 mg, 0.04 mmol) as a starting material for obtain methyl 5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate (11.0 mg, quant). LC/MS (ESI+): 303 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.08 (s, 1H), 7.98 (d, 1H, J = 8.6 Hz), 7.63 (dd, 1H, J = 8.5, 1.6 Hz), 6.17 (d, 1H, J = 46.2 Hz), 3.97 (s, 3H), 3.02 (d, 3H, J = 1.4 Hz) (f) Synthesis of 5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid

[071]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxilato de metila (11,0 mg, 0,04 mmol) como um material de partida para obter ácido 5- (fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxílico (6,7 mg, 64 %). RMN de 1H (400 MHz, DMSO-d6): δ 8,23 (s, 1H), 8,17 - 8,20 (m, 2H), 7,59 (dd, 1H, J = 8,5, 1,6 Hz), 6,93 (d, 1H, J = 45,2 Hz), 3,19 (d, 3H, J = 1,2 Hz) Intermediário 5) Síntese de ácido 5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxílico (c) Síntese de 2-metil-4-(2-(metilsulfonil)propan-2-il)-1-nitrobenzeno[071] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylate (11.0 mg, 0.04 mmol ) as a starting material to obtain 5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxylic acid (6.7 mg, 64%). 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 8.17 - 8.20 (m, 2H), 7.59 (dd, 1H, J = 8.5, 1 .6 Hz), 6.93 (d, 1H, J = 45.2 Hz), 3.19 (d, 3H, J = 1.2 Hz) Intermediate 5) Synthesis of 5-(2-(methylsulfonyl) acid propan-2-yl)benzo[b]thiophene-2-carboxylic acid (c) Synthesis of 2-methyl-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene

[072]O procedimento de síntese do Intermediário 1-c foi repetido, exceto para o uso de 2-metil-4-((metilsulfonil)metil)-1-nitrobenzeno (500,0 mg, 2,18 mmol) como um material de partida para obter 2-metil-4-(2-(metilsulfonil)propan-2-il)-1- nitrobenzeno (308,0 mg, 55 %). RMN de 1H (400 MHz, CDCl3): δ 8,00 (d, 1H, J = 9,2 Hz), 7,62 - 7,63 (m, 2H), 2,65 (s, 3H), 2,61 (s, 3H), 1,88 (s, 6H) (d) Síntese de 2-(bromometil)-4-(2-(metilsulfonil)propan-2-il)-1-nitrobenzeno[072] The procedure for the synthesis of Intermediate 1-c was repeated, except for the use of 2-methyl-4-((methylsulfonyl)methyl)-1-nitrobenzene (500.0 mg, 2.18 mmol) as a material to obtain 2-methyl-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene (308.0 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H, J = 9.2 Hz), 7.62 - 7.63 (m, 2H), 2.65 (s, 3H), 2 .61 (s, 3H), 1.88 (s, 6H) (d) Synthesis of 2-(bromomethyl)-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene

[073]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 2-metil-4-(2-(metilsulfonil)propan-2-il)-1-nitrobenzeno (270,0 mg, 1,05 mmol) como um material de partida para obter 2-(bromometil)-4-(2- (metilsulfonil)propan-2-il)-1-nitrobenzeno (272,0 mg). RMN de 1H (400 MHz, CDCl3): δ 8,07 (d, 1H, J = 8,7 Hz), 7,84 (d, 1H, J = 2,2 Hz), 7,77 (dd, 1H, J = 8,7, 2,2 Hz), 4,86 (s, 2H), 2,63 (s, 3H), 1,91 (s, 6H) (e) Síntese de 5-(2-(metilsulfonil)propan-2-il)-2-nitrobenzaldeído[073] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 2-methyl-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene (270.0 mg, 1, 05 mmol) as a starting material to obtain 2-(bromomethyl)-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene (272.0 mg). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 1H, J = 8.7 Hz), 7.84 (d, 1H, J = 2.2 Hz), 7.77 (dd, 1H , J = 8.7, 2.2 Hz), 4.86 (s, 2H), 2.63 (s, 3H), 1.91 (s, 6H) (e) Synthesis of 5-(2-( methylsulfonyl)propan-2-yl)-2-nitrobenzaldehyde

[074]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 2-(bromometil)-4-(2-(metilsulfonil)propan-2-il)-1-nitrobenzeno (270,0 mg) como um material de partida para obter 5-(2-(metilsulfonil)propan-2-il)-2- nitrobenzaldeído (139,0 mg, rendimento de 2 etapas: 49 %). LC/MS (ESI+): 272 (M+1) RMN de 1H (400 MHz, CDCl3): δ 10,46 (s, 1H), 8,10 - 8,18 (m, 3H), 2,66 (s, 3H), 1,93 (s, 6H) (f) Síntese de 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila[074] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 2-(bromomethyl)-4-(2-(methylsulfonyl)propan-2-yl)-1-nitrobenzene (270.0 mg) as a starting material to obtain 5-(2-(methylsulfonyl)propan-2-yl)-2-nitrobenzaldehyde (139.0 mg, 2-step yield: 49%). LC/MS (ESI+): 272 (M+1) 1H NMR (400 MHz, CDCl3): δ 10.46 (s, 1H), 8.10 - 8.18 (m, 3H), 2.66 ( s, 3H), 1.93 (s, 6H) (f) Synthesis of methyl 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate

[075]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 5-(2-(metilsulfonil)propan-2-il)-2-nitrobenzaldeído (137,0 mg, 0,51 mmol) como um material de partida para obter 5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxilato de metila (140,0 mg, 89 %). RMN de 1H (400 MHz, CDCl3): δ 8,12 (d, 1H, J = 1,8 Hz), 8,08 (s, 1H), 7,90 (d, 1H, J = 8,7 Hz), 7,79 (dd, 1H, J = 8,7, 1,9 Hz), 3,96 (s, 3H), 2,55 (s, 3H), 1,93 (s, 6H) (g) Síntese de ácido 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxílico[075] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 5-(2-(methylsulfonyl)propan-2-yl)-2-nitrobenzaldehyde (137.0 mg, 0.51 mmol) as a starting material to obtain methyl 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (140.0 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 8.12 (d, 1H, J = 1.8 Hz), 8.08 (s, 1H), 7.90 (d, 1H, J = 8.7 Hz ), 7.79 (dd, 1H, J = 8.7, 1.9 Hz), 3.96 (s, 3H), 2.55 (s, 3H), 1.93 (s, 6H) (g ) Synthesis of 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid

[076]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (155,0 mg, 0,50 mmol) como um material de partida para obter ácido 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (115,0 mg, 78 %).RMN de 1H (400 MHz, DMSO-d6): δ 13,55 (brs, 1H), 8,25 (s, 1H), 8,14 (s, 1H), 8,07 (d, 1H, J = 8,7 Hz), 7,76 (dd, 1H, J = 8,8, 1,7 Hz), 2,73 (s, 3H), 1,83 (s, 6H) Intermediário 6) Síntese de ácido 5-(1- (metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxílico (h) Síntese de 2-metil-4-(1-(metilsulfonil)ciclopropil)-1-nitrobenzeno[076] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (155.0 mg , 0.50 mmol) as a starting material to obtain 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (115.0 mg, 78%).1H NMR (400 MHz, DMSO-d6): δ 13.55 (brs, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.07 (d, 1H, J = 8.7 Hz), 7.76 (dd, 1H, J = 8.8, 1.7 Hz), 2.73 (s, 3H), 1.83 (s, 6H) Intermediate 6) 5-(1 - (methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylic acid (h) Synthesis of 2-methyl-4-(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene

[077]2-Metil-4-((metilsulfonil)metil)-1-nitrobenzeno (500,0 mg, 2,18 mmols), 1,2-dibromoetano (0,3 mL, 3,27 mmols) e brometo de tetra-n-butilamônio (70,3 mg, 0,22 mmol) foram dissolvidos em tolueno (22,0 mL) e solução aquosa de NaOH 10 N (0,7 mL, 6,54 mmols) foi lentamente adicionada. A mistura de reação foi aquecida a 40 °C durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 4:1) para obter 2-metil-4-(1-(metilsulfonil)ciclopropil)-1- nitrobenzeno (92,0 mg, 17 %) como um óleo amarelo. RMN de 1H (400 MHz, CDCl3): δ 8,00 (d, 1H, J = 8,4 Hz), 7,58 (m, 1H), 7,53 (m, 1H), 2,79 (s, 3H), 2,62 (s, 3H), 1,89 - 1,92 (m, 2H), 1,30 - 1,33 (m, 2H) (i) Síntese de 2-(bromometil)-4-(1-(metilsulfonil)ciclopropil)-1-nitrobenzeno[077] 2-Methyl-4-((methylsulfonyl)methyl)-1-nitrobenzene (500.0 mg, 2.18 mmol), 1,2-dibromoethane (0.3 mL, 3.27 mmol) and sodium bromide tetra-n-butylammonium (70.3 mg, 0.22 mmol) was dissolved in toluene (22.0 mL) and 10N aqueous NaOH solution (0.7 mL, 6.54 mmol) was slowly added. The reaction mixture was heated at 40°C for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 4:1) to obtain 2-methyl-4-(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene (92.0 mg, 17%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H, J = 8.4 Hz), 7.58 (m, 1H), 7.53 (m, 1H), 2.79 (s , 3H), 2.62 (s, 3H), 1.89 - 1.92 (m, 2H), 1.30 - 1.33 (m, 2H) (i) Synthesis of 2-(bromomethyl)-4 -(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene

[078]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 2-metil-4-(1-(metilsulfonil)ciclopropil)-1-nitrobenzeno (95,0 mg, 0,37 mmol) como um material de partida para obter 2-(bromometil)-4-(1- (metilsulfonil)ciclopropil)-1-nitrobenzeno (102,0 mg). RMN de 1H (400 MHz, CDCl3): δ 8,05 (d, 1H, J = 8,4 Hz), 7,79 (d, 1H, J = 2,0 Hz), 7,69 (dd, 1H, J = 8,4, 2,0 Hz), 4,83 (s, 2H), 2,80 (s, 3H), 1,90 - 1,95 (m, 2H), 1,34 - 1,37 (m, 2H) (j) Síntese de 5-(1-(metilsulfonil)ciclopropil)-2-nitrobenzaldeído[078] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 2-methyl-4-(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene (95.0 mg, 0.37 mmol) as a starting material to obtain 2-(bromomethyl)-4-(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene (102.0 mg). 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 1H, J = 8.4 Hz), 7.79 (d, 1H, J = 2.0 Hz), 7.69 (dd, 1H , J = 8.4, 2.0 Hz), 4.83 (s, 2H), 2.80 (s, 3H), 1.90 - 1.95 (m, 2H), 1.34 - 1, 37 (m, 2H) (j) Synthesis of 5-(1-(methylsulfonyl)cyclopropyl)-2-nitrobenzaldehyde

[079]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 2-(bromometil)-4-(1-(metilsulfonil)ciclopropil)-1-nitrobenzeno (100,0 mg) como um material de partida para obter 5-(1-(metilsulfonil)ciclopropil)-2- nitrobenzaldeído (40,6 mg, rendimento de 2 etapas: 41 %). LC/MS (ESI+): 270 (M+1) RMN de 1H (400 MHz, CDCl3): δ 10,43 (s, 1H), 8,16 (d, 1H, J = 8,2 Hz), 8,03 - 8,07 (m, 2H), 2,80 (s, 3H), 1,96 - 1,99 (m, 2H), 1,35 - 1,39 (m, 2H) (k) Síntese de 5-(1-(metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxilato de metila[079] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 2-(bromomethyl)-4-(1-(methylsulfonyl)cyclopropyl)-1-nitrobenzene (100.0 mg) as a material of starting to obtain 5-(1-(methylsulfonyl)cyclopropyl)-2-nitrobenzaldehyde (40.6 mg, 2-step yield: 41%). LC/MS (ESI+): 270 (M+1) 1H NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 8.16 (d, 1H, J = 8.2 Hz), 8 .03 - 8.07 (m, 2H), 2.80 (s, 3H), 1.96 - 1.99 (m, 2H), 1.35 - 1.39 (m, 2H) (k) Synthesis of methyl 5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylate

[080]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 5-(1-(metilsulfonil)ciclopropil)-2-nitrobenzaldeído (40,0 mg, 0,15 mmol) como um material de partida para obter 5-(1-(metilsulfonil)ciclopropil)benzo[b]tiofeno- 2-carboxilato de metila (35,9 mg, 78 %). LC/MS (ESI+): 311 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,04 - 8,07 (m, 2H), 7,88 (m, 1H), 7,67 (m, 1H), 3,96 (s, 3H), 2,77 (s, 3H), 1,90 - 1,91 (m, 2H), 1,34 - 1,36 (m, 2H) (l) Síntese de ácido 5-(1-(metilsulfonil)ciclopropil)benzo[b]tiofeno-2- carboxílico[080] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 5-(1-(methylsulfonyl)cyclopropyl)-2-nitrobenzaldehyde (40.0 mg, 0.15 mmol) as a starting material to obtain methyl 5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylate (35.9 mg, 78%). LC/MS (ESI+): 311 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.04 - 8.07 (m, 2H), 7.88 (m, 1H), 7.67 ( m, 1H), 3.96 (s, 3H), 2.77 (s, 3H), 1.90 - 1.91 (m, 2H), 1.34 - 1.36 (m, 2H) (l ) Synthesis of 5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylic acid

[081]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(1-(metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxilato de metila (33,0 mg, 0,11 mmol) como um material de partida para obter ácido 5-(1- (metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxílico (21,9 mg, 70 %). LC/MS ESI (+): 297 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 13,57 (brs, 1H), 8,19 (s, 1H), 8,10 (s, 1H), 8,07 (d, 1H, J = 8,5 Hz), 7,67 (d, 1H, J = 8,9 Hz), 2,88 (s, 3H), 1,67 - 1,70 (m, 2H), 1,35 - 1,38 (m, 2H) Intermediário 7) Síntese de ácido 6-cloro-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxílico (m) Síntese de 1-(2-cloro-4-fluoro-5-metilfenil)etan-1-ona[081] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylate (33.0 mg, 0.11 mmol) as a starting material to obtain 5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxylic acid (21.9 mg, 70%). LC/MS ESI (+): 297 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 13.57 (brs, 1H), 8.19 (s, 1H), 8.10 (s , 1H), 8.07 (d, 1H, J = 8.5 Hz), 7.67 (d, 1H, J = 8.9 Hz), 2.88 (s, 3H), 1.67 - 1 .70 (m, 2H), 1.35 - 1.38 (m, 2H) Intermediate 7) Synthesis of 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxylic acid (m) Synthesis of 1-(2-chloro-4-fluoro-5-methylphenyl)ethan-1-one

[082]AlCl3 (5,8 g, 43,3 mmols) foi dissolvido em 1,2-dicloroetano (34,6 mL) e cloreto de acetila (3,1 mL, 43,3 mmols) foi adicionado às gotas a 0 °C. 4-Cloro-2- fluoro-1-metilbenzeno (5,0 g, 34,6 mmols) foi adicionado. A mistura de reação foi agitada a 0 °C durante 1 hora e depois a 60 °C durante 16 horas. Solução aquosa de HCl 1 N foi adicionada às gotas e a mistura de reação foi extraída com EtOAc. O extrato orgânico foi lavado com solução aquosa de NaHCO3 sat. e salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 1- (2-cloro-4-fluoro-5-metilfenil)etan-1-ona (4,9 g, 75 %) como um óleo amarelo.LC/MS ESI (+): 187 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,48 (d, 1H, J = 8,1 Hz), 7,10 (d, 1H, J = 9,1 Hz), 2,64 (s, 3H), 2,27 (s, 3H) (n) Síntese de 2-(2-cloro-4-fluoro-5-metilfenil)propan-2-ol[082]AlCl3 (5.8 g, 43.3 mmol) was dissolved in 1,2-dichloroethane (34.6 mL) and acetyl chloride (3.1 mL, 43.3 mmol) was added dropwise at 0 °C. 4-Chloro-2-fluoro-1-methylbenzene (5.0 g, 34.6 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour and then at 60 °C for 16 hours. Aqueous 1N HCl solution was added dropwise and the reaction mixture was extracted with EtOAc. The organic extract was washed with sat. NaHCO 3 aqueous solution. and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 1-(2-chloro-4-fluoro-5-methylphenyl)ethan-1-one (4.9 g, 75%) as a yellow oil. LC/MS ESI (+): 187 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.48 (d, 1H, J = 8.1 Hz) , 7.10 (d, 1H, J = 9.1 Hz), 2.64 (s, 3H), 2.27 (s, 3H) (n) Synthesis of 2-(2-chloro-4-fluoro- 5-methylphenyl)propan-2-ol

[083]1-(2-Cloro-4-fluoro-5-metilfenil)etan-1-ona (4,9 g, 26,00 mmols) foi dissolvida em THF (260,0 mL) e solução 3,0 M de brometo de metilmagnésio em Et2O (26,0 mL) foi adicionada às gotas a -8 °C. A mistura de reação foi agitada durante 16 horas, solução aquosa de HCl 1 N foi adicionada às gotas a 0 °C para extinguir a reação e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n- Hex:EtOAc = 2:1) para obter 2-(2-cloro-4-fluoro-5-metilfenil)propan-2-ol (4,3 g, 82 %) como um óleo incolor. RMN de 1H (400 MHz, CDCl3): δ 7,50 (d, 1H, J = 8,4 Hz), 7,04 (d, 1H, J = 9,1 Hz), 2,44 (s, 1H), 2,25 (d, 3H, J = 1,7 Hz), 1,70 (s, 6H) (o) Síntese de 2-(2-cloro-4-fluoro-5-metilfenil)propano-2-tiol[083]1-(2-Chloro-4-fluoro-5-methylphenyl)ethan-1-one (4.9 g, 26.00 mmol) was dissolved in THF (260.0 mL) and 3.0 M solution of methylmagnesium bromide in Et2O (26.0 mL) was added dropwise at -8 °C. The reaction mixture was stirred for 16 hours, 1N aqueous HCl solution was added dropwise at 0°C to quench the reaction, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 2:1) to obtain 2-(2-chloro-4-fluoro-5-methylphenyl)propan-2-ol (4, 3 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.50 (d, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 9.1 Hz), 2.44 (s, 1H ), 2.25 (d, 3H, J = 1.7 Hz), 1.70 (s, 6H) (o) Synthesis of 2-(2-chloro-4-fluoro-5-methylphenyl)propane-2- thiol

[084]2-(2-Cloro-4-fluoro-5-metilfenil)propan-2-ol (4,3 g, 21,40 mmols) e reagente de Lawesson (5,2 g, 12,80 mmols) foram dissolvidos em tolueno (107,0 mL) e H2O (0,5 mL) foi adicionada. A mistura de reação foi agitada a 50 °C durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com solução aquosa de NaHCO3 sat., seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:DCM = 4:1) para obter 2-(2-cloro-4-fluoro-5-metilfenil)propano-2- tiol (2,7 g, 59 %) como um óleo amarelo claro.RMN de 1H (400 MHz, CDCl3): δ 7,31 (d, 1H, J = 8,1 Hz), 7,08 (d, 1H, J = 9,1 Hz), 2,89 (s, 1H), 2,24 (s, 3H), 1,92 (s, 6H) (p) Síntese de (2-(2-cloro-4-fluoro-5-metilfenil)propan-2-il)(metil)sulfano[084]2-(2-Chloro-4-fluoro-5-methylphenyl)propan-2-ol (4.3 g, 21.40 mmol) and Lawesson's reagent (5.2 g, 12.80 mmol) were dissolved in toluene (107.0 mL) and H2O (0.5 mL) was added. The reaction mixture was stirred at 50°C for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with sat. NaHCO3 aqueous solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:DCM = 4:1) to obtain 2-(2-chloro-4-fluoro-5-methylphenyl)propane-2-thiol (2.7 g, 59%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.31 (d, 1H, J = 8.1 Hz), 7.08 (d, 1H, J = 9, 1 Hz), 2.89 (s, 1H), 2.24 (s, 3H), 1.92 (s, 6H) (p) Synthesis of (2-(2-chloro-4-fluoro-5-methylphenyl )propan-2-yl)(methyl)sulfan

[085]NaOH (357,0 mg, 8,92 mmols) foi dissolvido em EtOH (34,3 mL) e sulfato de dimetila (1,0 mL, 10,29 mmols) foi adicionado às gotas. 2-(2-Cloro-4- fluoro-5-metilfenil)propano-2-tiol (1,5 g, 6,86 mmols) foi adicionado e a mistura de reação foi agitada na temperatura ambiente durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:DCM = 6:1) para obter (2- (2-cloro-4-fluoro-5-metilfenil)propan-2-il)(metil)sulfano (1,5 g, 93 %) como um óleo incolor. RMN de 1H (400 MHz, CDCl3): δ 7,27 (d, 1H, J = 7,7 Hz), 7,08 (d, 1H, J = 9,2 Hz), 2,25 (d, 3H, J = 1,7 Hz), 1,81 - 1,83 (m, 9H) (q) Síntese de 1-cloro-5-fluoro-4-metil-2-(2-(metilsulfonil)propan-2-il)benzeno[085]NaOH (357.0 mg, 8.92 mmol) was dissolved in EtOH (34.3 mL) and dimethyl sulfate (1.0 mL, 10.29 mmol) was added dropwise. 2-(2-Chloro-4-fluoro-5-methylphenyl)propane-2-thiol (1.5 g, 6.86 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:DCM = 6:1) to obtain (2-(2-chloro-4-fluoro-5-methylphenyl)propan-2-yl)(methyl )sulfane (1.5 g, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J = 7.7 Hz), 7.08 (d, 1H, J = 9.2 Hz), 2.25 (d, 3H , J = 1.7 Hz), 1.81 - 1.83 (m, 9H) (q) Synthesis of 1-chloro-5-fluoro-4-methyl-2-(2-(methylsulfonyl)propan-2- yl)benzene

[086](2-(2-Cloro-4-fluoro-5-metilfenil)propan-2-il)(metil)sulfano (1,5 g, 6,36 mmols) foi dissolvido em AcOH (31,8 mL) e solução aquosa de H2O2 35 % em peso (6,4 mL) foi adicionada às gotas. A mistura de reação foi agitada na temperatura ambiente durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com solução aquosa de NaHCO3 sat. e salmoura, seco em Na2SO anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 4:1) para obter 1-cloro-5-fluoro-4-metil-2-(2-(metilsulfonil)propan-2-il)benzeno (1,6 g, 95 %) como um sólido branco. LC/MS ESI (+): 265 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,55 (d, 1H, J = 8,1 Hz), 7,09 (d, 1H, J = 9,0 Hz), 2,76 (s, 3H), 2,27 (s, 3H), 2,03 (s, 6H) (r) Síntese de 1-(bromometil)-4-cloro-2-fluoro-5-(2-(metilsulfonil)propan-2- il)benzeno[086](2-(2-Chloro-4-fluoro-5-methylphenyl)propan-2-yl)(methyl)sulfane (1.5 g, 6.36 mmol) was dissolved in AcOH (31.8 mL) and 35% by weight aqueous H 2 O 2 solution (6.4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with sat. NaHCO 3 aqueous solution. and brine, dried over anhydrous Na2SO and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 4:1) to obtain 1-chloro-5-fluoro-4-methyl-2-(2-(methylsulfonyl)propan-2 -yl)benzene (1.6 g, 95%) as a white solid. LC/MS ESI (+): 265 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J = 8.1 Hz), 7.09 (d, 1H, J = 9.0 Hz), 2.76 (s, 3H), 2.27 (s, 3H), 2.03 (s, 6H) (r) Synthesis of 1-(bromomethyl)-4-chloro-2- fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzene

[087]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 1-cloro-5-fluoro-4-metil-2-(2-(metilsulfonil)propan-2-il)benzeno (1,7 g, 6,35 mmols) como um material de partida para obter 1-(bromometil)-4-cloro-2-fluoro- 5-(2-(metilsulfonil)propan-2-il)benzeno (2,2 g). LC/MS ESI (+): 343 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,77 (d, 1H, J = 7,9 Hz), 7,18 (d, 1H, J = 9,1 Hz), 4,47 (s, 2H), 2,77 (s, 3H), 2,06 (s, 6H) (s) Síntese de 4-cloro-2-fluoro-5-(2-(metilsulfonil)propan-2-il)benzaldeído[087] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 1-chloro-5-fluoro-4-methyl-2-(2-(methylsulfonyl)propan-2-yl)benzene (1, 7 g, 6.35 mmol) as a starting material to obtain 1-(bromomethyl)-4-chloro-2-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzene (2.2 g) . LC/MS ESI (+): 343 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.77 (d, 1H, J = 7.9 Hz), 7.18 (d, 1H, J = 9.1 Hz), 4.47 (s, 2H), 2.77 (s, 3H), 2.06 (s, 6H) (s) Synthesis of 4-chloro-2-fluoro-5-(2 -(methylsulfonyl)propan-2-yl)benzaldehyde

[088]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 1-(bromometil)-4-cloro-2-fluoro-5-(2-(metilsulfonil)propan-2-il)benzeno (2,2 g) como um material de partida para obter 4-cloro-2-fluoro-5-(2- (metilsulfonil)propan-2-il)benzaldeído (1,0 g, rendimento de 2 etapas: 57 %). RMN de 1H (400 MHz, CDCl3): δ 10,29 (s, 1H), 8,22 (d, 1H, J = 7,4 Hz), 7,34 (d, 1H, J = 9,6 Hz), 2,78 (s, 3H), 2,09 (s, 6H) (t) Síntese de 6-cloro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila[088] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 1-(bromomethyl)-4-chloro-2-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzene ( 2.2 g) as a starting material to obtain 4-chloro-2-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (1.0 g, 2-step yield: 57%). 1H NMR (400 MHz, CDCl3): δ 10.29 (s, 1H), 8.22 (d, 1H, J = 7.4 Hz), 7.34 (d, 1H, J = 9.6 Hz ), 2.78 (s, 3H), 2.09 (s, 6H) (t) Synthesis of 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- methyl carboxylate

[089]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 4-cloro-2-fluoro-5-(2-(metilsulfonil)propan-2-il)benzaldeído (1,0 g, 3,59 mmols) como um material de partida para obter 6-cloro-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxilato de metila (1,1 g, 91 %). RMN de 1H (400 MHz, CDCl3): δ 8,27 (s, 1H), 8,03 (s, 1H), 7,94 (s, 1H), 3,96 (s, 3H), 2,79 (s, 3H), 2,14 (s, 6H) (u) Síntese de ácido 6-cloro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxílico[089] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 4-chloro-2-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (1.0 g, 3 .59 mmol) as a starting material to obtain methyl 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (1.1 g, 91%). 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 3.96 (s, 3H), 2.79 (s, 3H), 2,14 (s, 6H) (u) Synthesis of 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid

[090]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 6-cloro-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (1,1 g, 3,26 mmols) como um material de partida para obter ácido 6-cloro-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (998,0 mg, 92 %).RMN de 1H (400 MHz, DMSO-d6): δ 13,67 (brs, 1H), 8,44 (s, 1H), 8,26 (s, 1H), 8,14 (s, 1H), 2,88 (s, 3H), 2,04 (s, 6H) Intermediário 8) Síntese de ácido 5-(2-(metilsulfonil)propan-2-il)tieno[2,3- c]piridino-2-carboxílico (v) Síntese de 2-(bromometil)-4-metil-5-nitropiridina[090] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate ( 1.1 g, 3.26 mmol) as a starting material to obtain 6-chloro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (998.0 mg , 92%).1H NMR (400 MHz, DMSO-d6): δ 13.67 (brs, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 8.14 (s , 1H), 2.88 (s, 3H), 2.04 (s, 6H) Intermediate 8) Synthesis of 5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine acid -2-carboxylic acid (v) Synthesis of 2-(bromomethyl)-4-methyl-5-nitropyridine

[091]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 2,4-dimetil-5-nitropiridina (2,5 g, 16,43 mmols) como um material de partida para obter 2-(bromometil)-4-metil-5-nitropiridina (1,1 g, 28 %). LC/MS ESI (+): 231 (M+1) RMN de 1H (400 MHz, CDCl3): δ 9,11 (s, 1H), 7,74 (s, 1H), 4,75 (s, 2H), 2,59 (s, 3H) (w) Síntese de 4-metil-2-((metilsulfonil)metil)-5-nitropiridina[091] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 2,4-dimethyl-5-nitropyridine (2.5 g, 16.43 mmol) as a starting material to obtain 2-( bromomethyl)-4-methyl-5-nitropyridine (1.1 g, 28%). LC/MS ESI (+): 231 (M+1) 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 7.74 (s, 1H), 4.75 (s, 2H) ), 2.59 (s, 3H) (w) Synthesis of 4-methyl-2-((methylsulfonyl)methyl)-5-nitropyridine

[092]O procedimento de síntese do Intermediário 1-b foi repetido, exceto para o uso de 2-(bromometil)-4-metil-5-nitropiridina (1,1 g, 4,76 mmols) como um material de partida para obter 4-metil-2-((metilsulfonil)metil)-5-nitropiridina (980,0 mg, 89 %).LC/MS ESI (+): 231 (M+1) RMN de 1H (400 MHz, CDCl3): δ 9,15 (s, 1H) 7,50 (s, 1H), 4,46 (s, 2H), 2,98 (s, 3H), 2,69 (s, 3H) (x) Síntese de 4-metil-2-(2-(metilsulfonil)propan-2-il)-5-nitropiridina[092] The procedure for the synthesis of Intermediate 1-b was repeated, except for the use of 2-(bromomethyl)-4-methyl-5-nitropyridine (1.1 g, 4.76 mmol) as a starting material for obtain 4-methyl-2-((methylsulfonyl)methyl)-5-nitropyridine (980.0 mg, 89%). LC/MS ESI (+): 231 (M+1) 1H NMR (400 MHz, CDCl3) : δ 9.15 (s, 1H) 7.50 (s, 1H), 4.46 (s, 2H), 2.98 (s, 3H), 2.69 (s, 3H) (x) Synthesis of 4-methyl-2-(2-(methylsulfonyl)propan-2-yl)-5-nitropyridine

[093]4-Metil-2-((metilsulfonil)metil)-5-nitropiridina (980,0 mg, 4,25 mmols) foi dissolvida em DMF anidra (21,2 mL) e NaH 60 % em peso (426,0 mg, 10,64 mmols) e CH3I (0,8 mL, 12,75 mmols) foram adicionados a 0 °C. A mistura de reação foi agitada na temperatura ambiente durante 16 horas, H2O foi adicionada a 0 °C e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 2:1) para obter 4- metil-2-(2-(metilsulfonil)propan-2-il)-5-nitropiridina (290,0 mg, 26 %) como um sólido branco. LC/MS ESI (+): 259 (M+1) RMN de 1H (400 MHz, CDCl3): δ 9,14 (s, 1H) 7,65 (s, 1H), 2,82 (s, 3H), 2,69 (s, 3H), 1,92 (s, 6H) (y) Síntese de (E)-N,N-dimetil-2-(2-(2-(metilsulfonil)propan-2-il)-5-nitropiridin- 4-il)eteno-1-amina[093]4-Methyl-2-((methylsulfonyl)methyl)-5-nitropyridine (980.0 mg, 4.25 mmol) was dissolved in anhydrous DMF (21.2 mL) and 60 wt% NaH (426, 0 mg, 10.64 mmol) and CH3I (0.8 mL, 12.75 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, H2O was added at 0 °C and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 2:1) to obtain 4-methyl-2-(2-(methylsulfonyl)propan-2-yl)-5-nitropyridine (290 .0 mg, 26%) as a white solid. LC/MS ESI (+): 259 (M+1) 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H) 7.65 (s, 1H), 2.82 (s, 3H) , 2.69 (s, 3H), 1.92 (s, 6H) (y) Synthesis of (E)-N,N-dimethyl-2-(2-(2-(methylsulfonyl)propan-2-yl) -5-nitropyridin-4-yl)ethene-1-amine

[094]4-Metil-2-(2-(metilsulfonil)propan-2-il)-5-nitropiridina (250,0 mg, 0,97 mmol) foi dissolvida em DMF anidra (1,2 mL) e N,N-dimetilformamida dimetilacetal (1,3 mL, 9,68 mmols) foi adicionado. A mistura de reação foi agitada durante 1 hora, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:1) para obter (E)-N,N-dimetil-2-(2-(2-(metilsulfonil)propan-2-il)-5-nitropiridin-4- il)eteno-1-amina (250,0 mg, 82 %) como um sólido vermelho.RMN de 1H (400 MHz, CDCl3): δ 8,93 (s, 1H) 7,58 (s, 1H), 7,35 (d, 1H, J = 13,2 Hz), 5,98 (d, 1H, J = 13,2 Hz), 3,05 (s, 6H), 2,95 (s, 3H), 1,87 (s, 6H) (z) Síntese de 2-(2-(metilsulfonil)propan-2-il)-5-nitroisonicotinaldeído[094] 4-Methyl-2-(2-(methylsulfonyl)propan-2-yl)-5-nitropyridine (250.0 mg, 0.97 mmol) was dissolved in anhydrous DMF (1.2 mL) and N, N-dimethylformamide dimethylacetal (1.3 mL, 9.68 mmol) was added. The reaction mixture was stirred for 1 hour, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:1) to obtain (E)-N,N-dimethyl-2-(2-(2-(methylsulfonyl)propan-2 -yl)-5-nitropyridin-4-yl)ethene-1-amine (250.0 mg, 82%) as a red solid. 1H NMR (400 MHz, CDCl3): δ 8.93 (s, 1H) 7.58 (s, 1H), 7.35 (d, 1H, J = 13.2 Hz), 5.98 (d, 1H, J = 13.2 Hz), 3.05 (s, 6H), 2.95 (s, 3H), 1.87 (s, 6H) (z) Synthesis of 2-(2-(methylsulfonyl)propan-2-yl)-5-nitroisonicotinaldehyde

[095](E)-N,N-dimetil-2-(2-(2-(metilsulfonil)propan-2-il)-5-nitropiridin-4-il)eteno- 1-amina (250,0 mg, 0,80 mmol) foi dissolvida em THF (4,0 mL) e H2O (4,0 mL) e metaperiodato de sódio (512,0 mg, 2,39 mmols) foi adicionado. A mistura de reação foi agitada a 40 °C durante 5 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:1) para obter 2-(2-(metilsulfonil)propan-2-il)-5- nitroisonicotinaldeído (130,0 mg, 60 %) como um sólido amarelo.LC/MS ESI (+): 273 (M+1) RMN de 1H (400 MHz, CDCl3): δ 10,55 (s, 1H) 9,41 (s, 1H), 8,06 (s, 1H), 2,87 (s, 3H), 1,95 (s, 6H) (aa) Síntese de 5-(2-(metilsulfonil)propan-2-il)tieno[2,3-c]piridino-2-carboxilato de metila[095](E)-N,N-dimethyl-2-(2-(2-(methylsulfonyl)propan-2-yl)-5-nitropyridin-4-yl)ethene-1-amine (250.0 mg, 0.80 mmol) was dissolved in THF (4.0 mL) and H2O (4.0 mL) and sodium metaperiodate (512.0 mg, 2.39 mmol) was added. The reaction mixture was stirred at 40°C for 5 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:1) to obtain 2-(2-(methylsulfonyl)propan-2-yl)-5-nitroisonicotinaldehyde (130.0 mg, 60%) as a yellow solid. LC/MS ESI (+): 273 (M+1) 1H NMR (400 MHz, CDCl3): δ 10.55 (s, 1H) 9.41 (s, 1H), 8.06 (s, 1H), 2.87 (s, 3H), 1.95 (s, 6H) (aa) Synthesis of 5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3 methyl -c]pyridine-2-carboxylate

[096]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 2-(2-(metilsulfonil)propan-2-il)-5-nitroisonicotinaldeído (130,0 mg, 0,48 mmol) como um material de partida para obter 5-(2-(metilsulfonil)propan-2- il)tieno[2,3-c]piridino-2-carboxilato de metila (110,0 mg, 74 %). LC/MS ESI (+): 314 (M+1) RMN de 1H (400 MHz, CDCl3): δ 9,16 (s, 1H) 8,10 (s, 1H), 8,07 (s, 1H), 4,00 (s, 3H), 2,82 (s, 3H), 1,98 (s, 6H) (bb) Síntese de ácido 5-(2-(metilsulfonil)propan-2-il)tieno[2,3-c]piridino-2- carboxílico[096] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 2-(2-(methylsulfonyl)propan-2-yl)-5-nitroisonicotinaldehyde (130.0 mg, 0.48 mmol) as a starting material to obtain methyl 5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine-2-carboxylate (110.0 mg, 74%). LC/MS ESI (+): 314 (M+1) 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H) 8.10 (s, 1H), 8.07 (s, 1H) , 4.00 (s, 3H), 2.82 (s, 3H), 1.98 (s, 6H) (bb) 5-(2-(Methylsulfonyl)propan-2-yl)thieno[2] acid synthesis ,3-c]pyridine-2-carboxylic

[097]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(2-(metilsulfonil)propan-2-il)tieno[2,3-c]piridino-2-carboxilato de metila (110,0 mg, 7,64 mmols) como um material de partida para obter ácido 5-(2- (metilsulfonil)propan-2-il)tieno[2,3-c]piridino-2-carboxílico (100,0 mg, 95 %). LC/MS ESI (+): 300 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 9,37 (s, 1H) 8,28 (s, 1H), 8,16 (s, 1H), 2,86 (s, 3H), 1,86 (s, 6H) Intermediário 9) Síntese de ácido 6-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxílico (cc) Síntese de 2-fluoro-1-metil-4-((metilsulfonil)metil)benzeno[097] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine-2-carboxylate ( 110.0 mg, 7.64 mmol) as a starting material to obtain 5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine-2-carboxylic acid (100.0 mg , 95%). LC/MS ESI (+): 300 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H) 8.28 (s, 1H), 8.16 (s, 1H), 2.86 (s, 3H), 1.86 (s, 6H) Intermediate 9) Synthesis of 6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid ( cc) Synthesis of 2-fluoro-1-methyl-4-((methylsulfonyl)methyl)benzene

[098]O procedimento de síntese do Intermediário 1-b foi repetido, exceto para o uso de 4-(bromometil)-2-fluoro-1-metilbenzeno (1,0 g, 4,92 mmol) como um material de partida para obter 2-fluoro-1-metil-4-((metilsulfonil)metil)benzeno (813,0 mg, 82 %). RMN de 1H (400 MHz, CDCl3): δ 7,23 (t, 1H, J = 8,1 Hz), 7,07 - 7,10 (m, 2H), 4,20 (s, 2H), 2,78 (s, 3H), 2,29 (s, 3H) (dd) Síntese de 2-fluoro-1-metil-4-(2-(metilsulfonil)propan-2-il)benzeno[098] The procedure for the synthesis of Intermediate 1-b was repeated, except for the use of 4-(bromomethyl)-2-fluoro-1-methylbenzene (1.0 g, 4.92 mmol) as a starting material for obtain 2-fluoro-1-methyl-4-((methylsulfonyl)methyl)benzene (813.0 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 7.23 (t, 1H, J = 8.1 Hz), 7.07 - 7.10 (m, 2H), 4.20 (s, 2H), 2 .78 (s, 3H), 2.29 (s, 3H) (dd) Synthesis of 2-Fluoro-1-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene

[099]O procedimento de síntese do Intermediário 1-c foi repetido, exceto para o uso de 2-fluoro-1-metil-4-((metilsulfonil)metil)benzeno (813,0 mg, 4,02 mmols) como um material de partida para obter 2-fluoro-1-metil-4-(2-(metilsulfonil)propan-2- il)benzeno (620 mg, 67 %). RMN de 1H (400 MHz, CDCl3): δ 7,26 - 7,32 (m, 2H), 7,21 (t, 1H, J = 8,4 Hz), 2,54 (s, 3H), 2,28 (s, 3H), 1,82 (s, 6H) (ee) Síntese de 1-(bromometil)-2-fluoro-4-(2-(metilsulfonil)propan-2-il)benzeno[099] The procedure for the synthesis of Intermediate 1-c was repeated, except for the use of 2-fluoro-1-methyl-4-((methylsulfonyl)methyl)benzene (813.0 mg, 4.02 mmol) as a starting material to obtain 2-fluoro-1-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene (620 mg, 67%). 1H NMR (400 MHz, CDCl3): δ 7.26 - 7.32 (m, 2H), 7.21 (t, 1H, J = 8.4 Hz), 2.54 (s, 3H), 2 .28 (s, 3H), 1.82 (s, 6H) (ee) Synthesis of 1-(bromomethyl)-2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzene

[0100]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 2-fluoro-1-metil-4-(2-(metilsulfonil)propan-2-il)benzeno (620,0 mg, 2,69 mmols) para obter 1-(bromometil)-2-fluoro-4-(2-(metilsulfonil)propan-2-il)benzeno (680,0 mg, 79 %). RMN de 1H (400 MHz, CDCl3): δ 7,35 - 7,46 (m, 3H), 4,51 (s, 2H), 2,58 (s, 3H), 1,84 (s, 6H) (ff) Síntese de 2-fluoro-4-(2-(metilsulfonil)propan-2-il)benzaldeído[0100] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 2-fluoro-1-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene (620.0 mg, 2 .69 mmol) to obtain 1-(bromomethyl)-2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzene (680.0 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 7.35 - 7.46 (m, 3H), 4.51 (s, 2H), 2.58 (s, 3H), 1.84 (s, 6H) (ff) Synthesis of 2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde

[0101]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 1-(bromometil)-2-fluoro-4-(2-(metilsulfonil)propan-2-il)benzeno (650,0 mg, 2,10 mmols) como um material de partida para obter 2-fluoro-4-(2- (metilsulfonil)propan-2-il)benzaldeído (330,0 mg, 64 %). RMN de 1H (400 MHz, CDCl3): δ 10,23 (s, 1H), 7,88 (t, 1H, J = 8,3 Hz), 7,60 - 7,64 (m, 2H), 2,78 (s, 3H), 1,78 (s, 6H) (gg) Síntese de 6-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila[0101] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 1-(bromomethyl)-2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzene (650.0 mg , 2.10 mmol) as a starting material to obtain 2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (330.0 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 7.88 (t, 1H, J = 8.3 Hz), 7.60 - 7.64 (m, 2H), 2 .78 (s, 3H), 1.78 (s, 6H) (gg) Synthesis of methyl 6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate

[0102]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 2-fluoro-4-(2-(metilsulfonil)propan-2-il)benzaldeído (350,0 mg, 1,43 mmol) como um material de partida para obter 6-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxilato de metila (265,0 mg, 59 %). RMN de 1H (400 MHz, CDCl3): δ 8,33 (s, 1H), 8,22 (s, 1H), 8,04 (d, 1H, J = 8,6 Hz), 7,73 (dd, 1H, J = 8,6, 1,7 Hz), 3,90 (s, 3H), 2,74 (s, 3H), 1,84 (s, 6H) (hh) Síntese de ácido 6-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxílico[0102] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 2-fluoro-4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (350.0 mg, 1.43 mmol) as a starting material to obtain methyl 6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (265.0 mg, 59%). 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 8.22 (s, 1H), 8.04 (d, 1H, J = 8.6 Hz), 7.73 (dd , 1H, J = 8.6, 1.7 Hz), 3.90 (s, 3H), 2.74 (s, 3H), 1.84 (s, 6H) (hh) Acid Synthesis 6-( 2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid

[0103]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 6-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (265,0 mg, 0,85 mmol) como um material de partida para obter ácido 6-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (230,0 mg, 91 %). LC/MS ESI (-): 297 (M-1) Intermediário 10) Síntese de ácido 5-(4-(metilsulfonil)tetra-hidro-2H-piran-4- il)benzo[b]tiofeno-2-carboxílico (ii) Síntese de 4-(4-fluoro-3-metilfenil)tetra-hidro-2H-piran-4-ol[0103] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (265.0 mg , 0.85 mmol) as a starting material to obtain 6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (230.0 mg, 91%). LC/MS ESI (-): 297 (M-1) Intermediate 10) Synthesis of 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid ( ii) Synthesis of 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-ol

[0104]4-Bromo-1-fluoro-2-metilbenzeno (1,0 g, 5,29 mmols) foi dissolvido em THF anidro (26,0 mL) e solução 1,6 M de n-BuLi em THF (3,5 mL, 5,55 mmols) e tetra-hidro-4H-piran-4-ona (556,0 mg, 5,55 mmols) foram adicionadas a -78 °C. A mistura de reação foi agitada a 0 °C durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:1) para obter 4-(4-fluoro-3- metilfenil)tetra-hidro-2H-piran-4-ol (800,0 mg, 72 %) como um sólido branco. RMN de 1H (400 MHz, CDCl3): δ 7,31 (dd, 1H, J = 7,3, 2,2 Hz), 7,26 (m, 1H), 6,99 (t, 1H, J = 8,9 Hz), 3,84 - 3,98 (m, 4H), 2,29 (s, 3H), 2,08 - 2,18 (m, 2H), 1,65 - 1,69 (m, 3H) (jj) Síntese de 4-(4-fluoro-3-metilfenil)tetra-hidro-2H-piran-4-tiol[0104]4-Bromo-1-fluoro-2-methylbenzene (1.0 g, 5.29 mmol) was dissolved in anhydrous THF (26.0 mL) and 1.6 M solution of n-BuLi in THF (3 .5 mL, 5.55 mmol) and tetrahydro-4H-pyran-4-one (556.0 mg, 5.55 mmol) were added at -78 °C. The reaction mixture was stirred at 0°C for 2 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:1) to obtain 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-ol (800 .0 mg, 72%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.31 (dd, 1H, J = 7.3, 2.2 Hz), 7.26 (m, 1H), 6.99 (t, 1H, J = 8.9 Hz), 3.84 - 3.98 (m, 4H), 2.29 (s, 3H), 2.08 - 2.18 (m, 2H), 1.65 - 1.69 (m , 3H) (jj) Synthesis of 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-thiol

[0105]O procedimento de síntese do Intermediário 7-c foi repetido, exceto para o uso de 4-(4-fluoro-3-metilfenil)tetra-hidro-2H-piran-4-ol (800,0 mg, 3,80 mmols) como um material de partida para obter 4-(4-fluoro-3-metilfenil)tetra-hidro- 2H-piran-4-tiol (450,0 mg, 52 %).RMN de 1H (400 MHz, DMSO-d6): δ, 7,40 (dd, 1H, J = 7,4, 2,4 Hz), 7,32 (m, 1H), 7,10 (t, 1H, J = 8,9 Hz), 3,76 - 3,82 (m, 2H), 3,65 - 3,69 (m, 2H), 3,26 (s, 1H), 2,24 (s, 3H), 2,08 - 2,18 (m, 4H) (kk) Síntese de 4-(4-fluoro-3-metilfenil)-4-(metiltio)tetra-hidro-2H-pirano[0105] The procedure for the synthesis of Intermediate 7-c was repeated, except for the use of 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-ol (800.0 mg, 3, 80 mmol) as a starting material to obtain 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-thiol (450.0 mg, 52%). 1H NMR (400 MHz, DMSO -d6): δ, 7.40 (dd, 1H, J = 7.4, 2.4 Hz), 7.32 (m, 1H), 7.10 (t, 1H, J = 8.9 Hz) , 3.76 - 3.82 (m, 2H), 3.65 - 3.69 (m, 2H), 3.26 (s, 1H), 2.24 (s, 3H), 2.08 - 2 .18 (m, 4H) (kk) Synthesis of 4-(4-fluoro-3-methylphenyl)-4-(methylthio)tetrahydro-2H-pyran

[0106]O procedimento de síntese do Intermediário 7-d foi repetido, exceto para o uso de 4-(4-fluoro-3-metilfenil)tetra-hidro-2H-piran-4-tiol (450,0 g, 1,99 mmol) como um material de partida para obter 4-(4-fluoro-3-metilfenil)-4-(metiltio)tetra- hidro-2H-pirano (300,0 mg, 63 %).RMN de 1H (400 MHz, DMSO-d6): δ 7,33 (d, 1H, J = 7,4 Hz), 7,25 (m, 1H), 7,09 (t, 1H, J = 9,0 Hz), 3,77 - 3,82 (m, 2H), 3,57 - 3,62 (m, 2H), 2,24 (s, 3H), 2,04 - 2,12 (m, 4H), 1,60 (s, 3H) (ll) Síntese de 4-(4-fluoro-3-metilfenil)-4-(metilsulfonil)tetra-hidro-2H-pirano[0106] The procedure for the synthesis of Intermediate 7-d was repeated, except for the use of 4-(4-fluoro-3-methylphenyl)tetrahydro-2H-pyran-4-thiol (450.0 g, 1, 99 mmol) as a starting material to obtain 4-(4-fluoro-3-methylphenyl)-4-(methylthio)tetrahydro-2H-pyran (300.0 mg, 63%). 1H NMR (400 MHz , DMSO-d6): δ 7.33 (d, 1H, J = 7.4 Hz), 7.25 (m, 1H), 7.09 (t, 1H, J = 9.0 Hz), 3, 77 - 3.82 (m, 2H), 3.57 - 3.62 (m, 2H), 2.24 (s, 3H), 2.04 - 2.12 (m, 4H), 1.60 ( s, 3H) (ll) Synthesis of 4-(4-fluoro-3-methylphenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran

[0107]O procedimento de síntese do Intermediário 7-e foi repetido, exceto para o uso de 4-(4-fluoro-3-metilfenil)-4-(metiltio)tetra-hidro-2H-piran (300,0 mg, 1,25 mmol) como um material de partida para obter 4-(4-fluoro-3-metilfenil)-4- (metilsulfonil)tetra-hidro-2H-pirano (300,0 mg, 89 %). RMN de 1H (400 MHz, CDCl3): δ 7,39 (dd, 1H, J = 7,0, 2,4 Hz), 7,33 (m, 1H), 7,10 (t, 1H, J = 8,8 Hz), 3,98 - 4,02 (m, 2H), 3,40 (t, 2H, J = 11,7 Hz), 2,55 - 2,63 (m, 2H), 2,42 - 2,47 (m, 5H), 2,33 (s, 3H) (mm) Síntese de 4-(3-(bromometil)-4-fluorofenil)-4-(metilsulfonil)tetra-hidro-2H- pirano[0107] The procedure for the synthesis of Intermediate 7-e was repeated, except for the use of 4-(4-fluoro-3-methylphenyl)-4-(methylthio)tetrahydro-2H-pyran (300.0 mg, 1.25 mmol) as a starting material to obtain 4-(4-fluoro-3-methylphenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran (300.0 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 7.39 (dd, 1H, J = 7.0, 2.4 Hz), 7.33 (m, 1H), 7.10 (t, 1H, J = 8.8 Hz), 3.98 - 4.02 (m, 2H), 3.40 (t, 2H, J = 11.7 Hz), 2.55 - 2.63 (m, 2H), 2, 42 - 2.47 (m, 5H), 2.33 (s, 3H) (mm) Synthesis of 4-(3-(bromomethyl)-4-fluorophenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran

[0108]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 4-(4-fluoro-3-metilfenil)-4-(metilsulfonil)tetra-hidro-2H-pirano (300,0 mg, 1,10 mmol) como um material de partida para obter 4-(3-(bromometil)-4- fluorofenil)-4-(metilsulfonil)tetra-hidro-2H-pirano (340,0 mg, 88 %). RMN de 1H (400 MHz, CDCl3): δ 7,59 (dd, 1H, J = 6,9, 2,6 Hz), 7,50 (m, 1H), 7,19 (t, 1H, J = 8,9 Hz), 4,54 (s, 2H), 3,98 - 4,02 (m, 2H), 3,36 - 3,42 (m, 2H), 2,55 - 2,65 (m, 2H), 2,42 - 2,50 (m, 5H) (nn) Síntese de 2-fluoro-5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4- il)benzaldeído[0108] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 4-(4-fluoro-3-methylphenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran (300.0 mg, 1.10 mmol) as a starting material to obtain 4-(3-(bromomethyl)-4-fluorophenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran (340.0 mg, 88%). 1H NMR (400 MHz, CDCl3): δ 7.59 (dd, 1H, J = 6.9, 2.6 Hz), 7.50 (m, 1H), 7.19 (t, 1H, J = 8.9 Hz), 4.54 (s, 2H), 3.98 - 4.02 (m, 2H), 3.36 - 3.42 (m, 2H), 2.55 - 2.65 (m , 2H), 2.42 - 2.50 (m, 5H) (nn) Synthesis of 2-fluoro-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzaldehyde

[0109]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 4-(3-(bromometil)-4-fluorofenil)-4-(metilsulfonil)tetra-hidro-2H-pirano (350,0 mg, 1,00 mmol) como um material de partida para obter 2-fluoro-5-(4- (metilsulfonil)tetra-hidro-2H-pirano-4-il)benzaldeído (220,0 mg, 76 %).LC/MS ESI (-): 285 (M-1) (oo) Síntese de 5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4-il)benzo[b]tiofeno-2- carboxilato de metila[0109] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 4-(3-(bromomethyl)-4-fluorophenyl)-4-(methylsulfonyl)tetrahydro-2H-pyran (350.0 mg, 1.00 mmol) as a starting material to obtain 2-fluoro-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzaldehyde (220.0 mg, 76%).LC /MS ESI (-): 285 (M-1) (oo) Synthesis of methyl 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate

[0110]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 2-fluoro-5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4-il)benzaldeído (110,0 mg, 0,38 mmol) como um material de partida para obter 5-(4- (metilsulfonil)tetra-hidro-2H-pirano-4-il)benzo[b]tiofeno-2-carboxilato de metila (124,0 mg, 91 %). RMN de 1H (400 MHz, CDCl3): δ, 8,06 - 8,09 (m, 2H), 7,97 (d, 1H, J = 8,7 Hz), 7,66 (dd, 1H, J = 8,7, 1,9 Hz), 4,03 - 4,06 (m, 2H), 3,97 (s, 3H), 3,43 (t, 2H, J = 11,6 Hz), 2,56 - 2,72 (m, 4H), 2,49 (s, 3H) (pp) Síntese de ácido 5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4- il)benzo[b]tiofeno-2-carboxílico[0110] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 2-fluoro-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzaldehyde (110.0 mg , 0.38 mmol) as a starting material to obtain methyl 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (124.0 mg, 91 %). 1H NMR (400 MHz, CDCl3): δ, 8.06 - 8.09 (m, 2H), 7.97 (d, 1H, J = 8.7 Hz), 7.66 (dd, 1H, J = 8.7, 1.9 Hz), 4.03 - 4.06 (m, 2H), 3.97 (s, 3H), 3.43 (t, 2H, J = 11.6 Hz), 2 .56 - 2.72 (m, 4H), 2.49 (s, 3H) (pp) Acid Synthesis 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b] thiophene-2-carboxylic acid

[0111]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4-il)benzo[b]tiofeno-2- carboxilato de metila (124,0 mg, 0,35 mmol) como um material de partida para obter ácido 5-(4-(metilsulfonil)tetra-hidro-2H-pirano-4-il)benzo[b]tiofeno-2-carboxílico (104,0 mg, 87 %). LC/MS ESI (-): 339 (M-1) Intermediário 11) Síntese de ácido 6-(2-(metilsulfonil)propan-2-il)-1H-indol-2- carboxílico (qq) Síntese de 2-(3-bromo-4-metilfenil)propan-2-ol[0111] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate methyl (124.0 mg, 0.35 mmol) as a starting material to obtain 5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid ( 104.0 mg, 87%). LC/MS ESI (-): 339 (M-1) Intermediate 11) Synthesis of 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylic acid (qq) Synthesis of 2-( 3-bromo-4-methylphenyl)propan-2-ol

[0112]O procedimento de síntese do Intermediário 7-b foi repetido, exceto para o uso de 1-(3-bromo-4-metilfenil)etan-1-ona (1,0 g, 4,69 mmols) como um material de partida para obter 2-(3-bromo-4-metilfenil)propan-2-ol (1,0 g, 96 %).RMN de 1H (400 MHz, CDCl3): δ 7,67 (d, 1H, J = 1,8 Hz), 7,31 (dd, 1H, J = 7,9, 1,8 Hz), 7,20 (d, 1H, J = 7,9 Hz), 2,38 (s, 3H), 1,70 (s, 1H), 1,56 (s, 6H) (rr) Síntese de 2-(3-bromo-4-metilfenil)propano-2-tiol[0112] The procedure for the synthesis of Intermediate 7-b was repeated, except for the use of 1-(3-bromo-4-methylphenyl)ethan-1-one (1.0 g, 4.69 mmol) as a material stock to obtain 2-(3-bromo-4-methylphenyl)propan-2-ol (1.0 g, 96%). 1H NMR (400 MHz, CDCl 3 ): δ 7.67 (d, 1H, J = 1.8 Hz), 7.31 (dd, 1H, J = 7.9, 1.8 Hz), 7.20 (d, 1H, J = 7.9 Hz), 2.38 (s, 3H ), 1.70 (s, 1H), 1.56 (s, 6H) (rr) Synthesis of 2-(3-bromo-4-methylphenyl)propane-2-thiol

[0113]O procedimento de síntese do Intermediário 7-c foi repetido, exceto para o uso de 2-(3-bromo-4-metilfenil)propan-2-ol (1,0 g, 4,50 mmols) como um material de partida para obter 2-(3-bromo-4-metilfenil)propano-2-tiol (1,0 g, 92 %).RMN de 1H (400 MHz, CDCl3): δ 7,71 (s, 1H), 7,40 (d, 1H, J = 8,0 Hz), 7,18 (d, 1H, J = 8,0 Hz), 2,37 (s, 3H), 2,24 (s, 1H), 1,79 (s, 6H) (ss) Síntese de (2-(3-bromo-4-metilfenil)propan-2-il)(metil)sulfano[0113] The procedure for the synthesis of Intermediate 7-c was repeated, except for the use of 2-(3-bromo-4-methylphenyl)propan-2-ol (1.0 g, 4.50 mmol) as a material stock to obtain 2-(3-bromo-4-methylphenyl)propane-2-thiol (1.0 g, 92%). 1H NMR (400 MHz, CDCl 3 ): δ 7.71 (s, 1H), 7.40 (d, 1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz), 2.37 (s, 3H), 2.24 (s, 1H), 1.79 (s, 6H) (ss) Synthesis of (2-(3-bromo-4-methylphenyl)propan-2-yl)(methyl)sulfan

[0114]O procedimento de síntese do Intermediário 7-d foi repetido, exceto para o uso de 2-(3-bromo-4-metilfenil)propano-2-tiol (1,0 g, 4,08 mmols) como um material de partida para obter (2-(3-bromo-4-metilfenil)propan-2-il)(metil)sulfano (872,7 mg, 83 %).RMN de 1H (400 MHz, CDCl3): δ 7,65 (d, 1H, J = 2,0 Hz), 7,36 (dd, 1H, J = 8,0, 2,0 Hz), 7,18 (d, 1H, J = 8,0 Hz), 2,37 (s, 3H), 1,79 (s, 3H), 1,66 (s, 6H) (tt) Síntese de 2-bromo-1-metil-4-(2-(metilsulfonil)propan-2-il)benzeno[0114] The procedure for the synthesis of Intermediate 7-d was repeated, except for the use of 2-(3-bromo-4-methylphenyl)propane-2-thiol (1.0 g, 4.08 mmol) as a material stock to obtain (2-(3-bromo-4-methylphenyl)propan-2-yl)(methyl)sulfane (872.7 mg, 83%).1H NMR (400 MHz, CDCl3): δ 7.65 (d, 1H, J = 2.0 Hz), 7.36 (dd, 1H, J = 8.0, 2.0 Hz), 7.18 (d, 1H, J = 8.0 Hz), 2 .37 (s, 3H), 1.79 (s, 3H), 1.66 (s, 6H) (tt) Synthesis of 2-bromo-1-methyl-4-(2-(methylsulfonyl)propan-2- yl)benzene

[0115]O procedimento de síntese do Intermediário 7-e foi repetido, exceto para o uso de (2-(3-bromo-4-metilfenil)propan-2-il)(metil)sulfano (871,0 mg, 3,36 mmols) como um material de partida para obter 2-bromo-1-metil-4-(2- (metilsulfonil)propan-2-il)benzeno (973,7 mg, quant). RMN de 1H (400 MHz, CDCl3): δ 7,76 (s, 1H), 7,51 (d, 1H, J = 8,1 Hz), 7,27 (d, 1H, J = 8,1 Hz), 2,56 (s, 3H), 2,41 (s, 3H), 1,82 (s, 6H) (uu) Síntese de 2-bromo-1-(bromometil)-4-(2-(metilsulfonil)propan-2- il)benzeno[0115] The synthesis procedure for Intermediate 7-e was repeated, except for the use of (2-(3-bromo-4-methylphenyl)propan-2-yl)(methyl)sulfane (871.0 mg, 3, 36 mmol) as a starting material to obtain 2-bromo-1-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene (973.7 mg, quant). 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.51 (d, 1H, J = 8.1 Hz), 7.27 (d, 1H, J = 8.1 Hz ), 2.56 (s, 3H), 2.41 (s, 3H), 1.82 (s, 6H) (uu) Synthesis of 2-bromo-1-(bromomethyl)-4-(2-(methylsulfonyl) )propan-2-yl)benzene

[0116]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 2-bromo-1-metil-4-(2-(metilsulfonil)propan-2-il)benzeno (972,0 mg, 3,34 mmols) como um material de partida para obter 2-bromo-1-(bromometil)-4-(2- (metilsulfonil)propan-2-il)benzeno (894,4 mg, 72 %). RMN de 1H (400 MHz, CDCl3): δ 7,82 (d, 1H, J = 2,0 Hz), 7,61 (dd, 1H, J = 8,2, 2,0 Hz), 7,50 (d, 1H, J = 8,2 Hz), 4,59 (s, 2H), 2,59 (s, 3H), 1,84 (s, 6H) (vv) Síntese de 2-bromo-4-(2-(metilsulfonil)propan-2-il)benzaldeído[0116] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 2-bromo-1-methyl-4-(2-(methylsulfonyl)propan-2-yl)benzene (972.0 mg, 3 .34 mmol) as a starting material to obtain 2-bromo-1-(bromomethyl)-4-(2-(methylsulfonyl)propan-2-yl)benzene (894.4 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 1H, J = 2.0 Hz), 7.61 (dd, 1H, J = 8.2, 2.0 Hz), 7.50 (d, 1H, J = 8.2 Hz), 4.59 (s, 2H), 2.59 (s, 3H), 1.84 (s, 6H) (vv) Synthesis of 2-bromo-4- (2-(methylsulfonyl)propan-2-yl)benzaldehyde

[0117]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 2-bromo-1-(bromometil)-4-(2-(metilsulfonil)propan-2-il)benzeno (890,0 mg, 2,41 mmols) como um material de partida para obter 2-bromo-4-(2- (metilsulfonil)propan-2-il)benzaldeído (475,9 mg, 65 %). RMN de 1H (400 MHz, CDCl3): δ 10,36 (s, 1H), 7,94 (d, 1H, J = 8,3 Hz), 7,92 (d, 1H, J = 1,8 Hz), 7,74 (dd, 1H, J = 8,3, 1,2 Hz), 2,62 (s, 3H), 1,88 (s, 6H) (ww) Síntese de (Z)-2-(((benzilóxi)carbonil)amino)-3-(2-bromo-4-(2- (metilsulfonil)propan-2-il)fenil)acrilato de metila[0117] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of 2-bromo-1-(bromomethyl)-4-(2-(methylsulfonyl)propan-2-yl)benzene (890.0 mg , 2.41 mmol) as a starting material to obtain 2-bromo-4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (475.9 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 7.94 (d, 1H, J = 8.3 Hz), 7.92 (d, 1H, J = 1.8 Hz ), 7.74 (dd, 1H, J = 8.3, 1.2 Hz), 2.62 (s, 3H), 1.88 (s, 6H) (ww) Synthesis of (Z)-2- Methyl (((benzyloxy)carbonyl)amino)-3-(2-bromo-4-(2-(methylsulfonyl)propan-2-yl)phenyl)acrylate

[0118]2-Bromo-4-(2-(metilsulfonil)propan-2-il)benzaldeído (441,0 mg, 1,45 mmol), 2-(((benzilóxi)carbonil)amino)-2-(dimetoxifosforil)acetato de metila (622,0 mg, 1,88 mmol) e DBU (330,0 mg, 2,17 mmol) foram dissolvidos em CH2Cl2 (14,5 mL). A mistura de reação foi agitada na temperatura ambiente durante 30 minutos, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:1) para obter (Z)-2-(((benzilóxi)carbonil)amino)-3-(2-bromo-4-(2-(metilsulfonil)propan-2- il)fenil)acrilato de metila (570,0 mg, 77 %). LC/MS ESI (+): 510 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,82 (s, 1H), 7,51 (s, 2H), 7,32 - 7,37 (m, 4H), 7,26 - 7,29 (m, 2H), 6,55 (brs, 1H), 5,04 (s, 2H), 3,87 (s, 3H), 2,53 (s, 3H), 1,82 (s, 6H) (xx) Síntese de 6-(2-(metilsulfonil)propan-2-il)-1H-indol-2-carboxilato de metila[0118] 2-Bromo-4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde (441.0 mg, 1.45 mmol), 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl )methyl acetate (622.0 mg, 1.88 mmol) and DBU (330.0 mg, 2.17 mmol) were dissolved in CH 2 Cl 2 (14.5 mL). The reaction mixture was stirred at room temperature for 30 minutes, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel amine, n-Hex:EtOAc = 1:1) to obtain (Z)-2-(((benzyloxy)carbonyl)amino)-3-(2-bromo- Methyl 4-(2-(methylsulfonyl)propan-2-yl)phenyl)acrylate (570.0 mg, 77%). LC/MS ESI (+): 510 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.51 (s, 2H), 7.32 - 7.37 (m, 4H), 7.26 - 7.29 (m, 2H), 6.55 (brs, 1H), 5.04 (s, 2H), 3.87 (s, 3H), 2.53 ( s, 3H), 1.82 (s, 6H) (xx) Synthesis of methyl 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylate

[0119](Z)-2-(((Benzilóxi)carbonil)amino)-3-(2-bromo-4-(2- (metilsulfonil)propan-2-il)fenil)acrilato de metila (570,0 mg, 1,12 mmol), CuI (42,5 mg, 0,22 mmol), L-prolina (51,4 mg, 0,45 mmol) e K2CO3 (463,0 mg, 3,35 mmols) foram dissolvidos em 1,4-dioxano (5,6 mL). A mistura de reação foi agitada a 100 °C durante 2 dias, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:1) para obter 6-(2-(metilsulfonil)propan-2-il)-1H-indol-2- carboxilato de metila (227,0 mg, 69 %).RMN de 1H (400 MHz, DMSO-d6): δ 12,02 (s, 1H), 7,67 - 7,69 (m, 2H), 7,37 (dd, 1H, J = 8,6, 1,8 Hz), 7,16 (d, 1H, J = 1,5 Hz), 3,88 (s, 3H), 2,68 (s, 3H), 1,80 (s, 6H) (yy) Síntese de cloridreto do ácido 6-(2-(metilsulfonil)propan-2-il)-1H-indol-2- carboxílicoMethyl [0119](Z)-2-(((Benzyloxy)carbonyl)amino)-3-(2-bromo-4-(2-(methylsulfonyl)propan-2-yl)phenyl)acrylate (570.0 mg , 1.12 mmol), CuI (42.5 mg, 0.22 mmol), L-proline (51.4 mg, 0.45 mmol) and K2CO3 (463.0 mg, 3.35 mmol) were dissolved in 1,4-dioxane (5.6 mL). The reaction mixture was stirred at 100°C for 2 days, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 1:1) to obtain 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylate of methyl (227.0 mg, 69%). 1H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 7.67 - 7.69 (m, 2H), 7.37 ( dd, 1H, J = 8.6, 1.8 Hz), 7.16 (d, 1H, J = 1.5 Hz), 3.88 (s, 3H), 2.68 (s, 3H), 1.80 (s, 6H) (yy) Synthesis of 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylic acid hydrochloride

[0120]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 6-(2-(metilsulfonil)propan-2-il)-1H-indol-2-carboxilato de metila (227,0 mg, 0,77 mmol) como um material de partida para obter cloridreto do ácido 6-(2- (metilsulfonil)propan-2-il)-1H-indol-2-carboxílico (170,0 mg, 79 %).RMN de 1H (400 MHz, DMSO-d6): δ 13,02 (brs, 1H), 11,82 (s, 1H), 7,64 - 7,67 (m, 2H), 7,35 (dd, 1H, J = 8,8, 1,6 Hz), 7,07 (d, 1H, J = 1,6 Hz), 2,67 (s, 3H), 1,80 (s, 6H) Intermediário 12) Síntese de ácido 5-(2-((2-metoxietil)sulfonil)propan-2- il)benzo[b]tiofeno-2-carboxílico (zz) Síntese de 2-(4-fluoro-3-metilfenil)propan-2-ol[0120] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylate (227.0 mg, 0.77 mmol) as a starting material to obtain 6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxylic acid hydrochloride (170.0 mg, 79%).1H NMR (400 MHz, DMSO-d6): δ 13.02 (brs, 1H), 11.82 (s, 1H), 7.64 - 7.67 (m, 2H), 7.35 (dd, 1H, J = 8.8, 1.6 Hz), 7.07 (d, 1H, J = 1.6 Hz), 2.67 (s, 3H), 1.80 (s, 6H) Intermediate 12) Acid synthesis 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic (zz) Synthesis of 2-(4-fluoro-3-methylphenyl)propan-2-ol

[0121]O procedimento de síntese do Intermediário 7-b foi repetido, exceto para o uso de 1-(4-fluoro-3-metilfenil)etan-1-ona (1,0 g, 6,57 mmol) como um material de partida para obter 2-(4-fluoro-3-metilfenil)propan-2-ol (872,0 mg, 79 %).RMN de 1H (400 MHz, CDCl3): δ 7,31 (dd, 1H, J = 7,4, 2,1 Hz), 7,25 (m, 1H), 6,95 (t, 1H, J = 8,9 Hz), 2,28 (s, 3H), 1,71 (s, 1H), 1,57 (s, 6H) (aaa) Síntese de 2-(4-fluoro-3-metilfenil)propano-2-tiol[0121] The procedure for the synthesis of Intermediate 7-b was repeated, except for the use of 1-(4-fluoro-3-methylphenyl)ethan-1-one (1.0 g, 6.57 mmol) as a material stock to obtain 2-(4-fluoro-3-methylphenyl)propan-2-ol (872.0 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 7.31 (dd, 1H, J = 7.4, 2.1 Hz), 7.25 (m, 1H), 6.95 (t, 1H, J = 8.9 Hz), 2.28 (s, 3H), 1.71 (s , 1H), 1.57 (s, 6H) (aaa) Synthesis of 2-(4-fluoro-3-methylphenyl)propane-2-thiol

[0122]O procedimento de síntese do Intermediário 7-c foi repetido, exceto para o uso de 2-(4-fluoro-3-metilfenil)propan-2-ol (872,0 mg, 5,18 mmols) como um material de partida para obter 2-(4-fluoro-3-metilfenil)propano-2-tiol (955,0 mg, 85 %).RMN de 1H (400 MHz, CDCl3): δ 7,37 (dd, 1H, J = 7,1, 2,3 Hz), 7,32 (m, 1H), 6,93 (t, 1H, J = 8,9 Hz), 2,28 (s, 3H), 2,24 (s, 1H), 1,81 (s, 6H) (bbb) Síntese de (2-(4-fluoro-3-metilfenil)propan-2-il)(2-metoxietil)sulfano[0122] The procedure for the synthesis of Intermediate 7-c was repeated, except for the use of 2-(4-fluoro-3-methylphenyl)propan-2-ol (872.0 mg, 5.18 mmol) as a material stock to obtain 2-(4-fluoro-3-methylphenyl)propane-2-thiol (955.0 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.37 (dd, 1H, J = 7.1, 2.3 Hz), 7.32 (m, 1H), 6.93 (t, 1H, J = 8.9 Hz), 2.28 (s, 3H), 2.24 (s , 1H), 1.81 (s, 6H) (bbb) Synthesis of (2-(4-fluoro-3-methylphenyl)propan-2-yl)(2-methoxyethyl)sulfane

[0123]2-(4-Fluoro-3-metilfenil)propano-2-tiol (400,0 mg, 2,17 mmols) foi dissolvido em DMF anidra (16,3 mL) e 1-bromo-2-metoxietano (392,0 mg, 2,82 mmols) e Cs2CO3 (1,4 g, 4,34 mmols) foram adicionados. A mistura de reação foi agitada a 70 °C durante 5 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter (2-(4-fluoro-3-metilfenil)propan-2-il)(2-metoxietil)sulfano (420,0 mg, 80 %) como um sólido branco.RMN de 1H (400 MHz, CDCl3): δ 7,34 (dd, 1H, J = 7,4, 2,3 Hz), 7,29 (m, 1H), 6,92 (t, 1H, J = 8,9 Hz), 3,32 (t, 2H, J = 6,7 Hz), 3,26 (s, 3H), 2,43 (t, 2H, J = 6,7 Hz), 2,27 (s, 3H), 1,68 (s, 6H) (ccc) Síntese de 1-fluoro-4-(2-((2-metoxietil)sulfonil)propan-2-il)-2-metilbenzeno[0123] 2-(4-Fluoro-3-methylphenyl)propane-2-thiol (400.0 mg, 2.17 mmol) was dissolved in anhydrous DMF (16.3 mL) and 1-bromo-2-methoxyethane ( 392.0 mg, 2.82 mmol) and Cs2CO3 (1.4 g, 4.34 mmol) were added. The reaction mixture was stirred at 70°C for 5 hours, cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain (2-(4-fluoro-3-methylphenyl)propan-2-yl)(2-methoxyethyl)sulfane (420.0 mg, 80%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.34 (dd, 1H, J = 7.4, 2.3 Hz), 7.29 (m , 1H), 6.92 (t, 1H, J = 8.9 Hz), 3.32 (t, 2H, J = 6.7 Hz), 3.26 (s, 3H), 2.43 (t , 2H, J = 6.7 Hz), 2.27 (s, 3H), 1.68 (s, 6H) (tcc) Synthesis of 1-Fluoro-4-(2-((2-methoxyethyl)sulfonyl) propan-2-yl)-2-methylbenzene

[0124]O procedimento de síntese do Intermediário 7-e foi repetido, exceto para o uso de (2-(4-fluoro-3-metilfenil)propan-2-il)(2-metoxietil)sulfano (420,0 mg, 1,73 mmol) como um material de partida para obter 1-fluoro-4-(2-((2- metoxietil)sulfonil)propan-2-il)-2-metilbenzeno (410,0 mg, 86 %). RMN de 1H (400 MHz, CDCl3): δ 7,32 - 7,40 (m, 2H), 7,02 (t, 1H, J = 8,9 Hz), 3,64 (t, 2H, J = 6,7 Hz), 3,29 (s, 3H), 2,91 (t, 2H, J = 6,7 Hz), 2,30 (s, 3H), 1,82 (s, 6H) (ddd) Síntese de 2-(bromometil)-1-fluoro-4-(2-((2-metoxietil)sulfonil)propan-2- il)benzeno[0124] The procedure for the synthesis of Intermediate 7-e was repeated, except for the use of (2-(4-fluoro-3-methylphenyl)propan-2-yl)(2-methoxyethyl)sulfane (420.0 mg, 1.73 mmol) as a starting material to obtain 1-fluoro-4-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)-2-methylbenzene (410.0 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 7.32 - 7.40 (m, 2H), 7.02 (t, 1H, J = 8.9 Hz), 3.64 (t, 2H, J = 6.7 Hz), 3.29 (s, 3H), 2.91 (t, 2H, J = 6.7 Hz), 2.30 (s, 3H), 1.82 (s, 6H) (ddd ) Synthesis of 2-(bromomethyl)-1-fluoro-4-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzene

[0125]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de 1-fluoro-4-(2-((2-metoxietil)sulfonil)propan-2-il)-2-metilbenzeno (410,0 mg, 1,49 mmol) como um material de partida para obter 2-(bromometil)-1-fluoro-4-(2- ((2-metoxietil)sulfonil)propan-2-il)benzeno (40,0 mg, 8 %). RMN de 1H (400 MHz, CDCl3): δ 7,65 (dd, 1H, J = 7,0, 2,6 Hz), 7,58 (m, 1H), 7,10 (t, 1H, J = 9,0 Hz), 4,52 (s, 2H), 3,64 (t, 2H, J = 6,5 Hz), 3,29 (s, 3H), 2,93 (t, 2H, J = 6,5 Hz), 1,84 (s, 6H) (eee) Síntese de 2-fluoro-5-(2-((2-metoxietil)sulfonil)propan-2-il)benzaldeído[0125] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of 1-fluoro-4-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)-2-methylbenzene (410, 0 mg, 1.49 mmol) as a starting material to obtain 2-(bromomethyl)-1-fluoro-4-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzene (40.0 mg , 8%). 1H NMR (400 MHz, CDCl3): δ 7.65 (dd, 1H, J = 7.0, 2.6 Hz), 7.58 (m, 1H), 7.10 (t, 1H, J = 9.0 Hz), 4.52 (s, 2H), 3.64 (t, 2H, J = 6.5 Hz), 3.29 (s, 3H), 2.93 (t, 2H, J = 6.5 Hz), 1.84 (s, 6H) (eee) Synthesis of 2-Fluoro-5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzaldehyde

[0126]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de 2-(bromometil)-1-fluoro-4-(2-((2-metoxietil)sulfonil)propan-2-il)benzeno (60,0 mg, 0,17 mmol) como um material de partida para obter 2-fluoro-5-(2-((2- metoxietil)sulfonil)propan-2-il)benzaldeído (36,0 mg, 74 %).RMN de 1H (400 MHz, CDCl3): δ 10,30 (s, 1H), 7,99 (dd, 1H, J = 6,4, 2,7 Hz), 7,93 (m, 1H), 7,17 (t, 1H, J = 9,2 Hz), 3,62 (t, 2H, J = 6,4 Hz), 3,23 (s, 3H), 2,87 (t, 2H, J = 6,4 Hz), 1,80 (s, 6H) (fff) Síntese de 5-(2-((2-metoxietil)sulfonil)propan-2-il)benzo[b]tiofeno-2- carboxilato de metila[0126] The synthesis procedure for Intermediate 1-e was repeated, except for the use of 2-(bromomethyl)-1-fluoro-4-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzene (60.0 mg, 0.17 mmol) as a starting material to obtain 2-fluoro-5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzaldehyde (36.0 mg, 74% ).1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 7.99 (dd, 1H, J = 6.4, 2.7 Hz), 7.93 (m, 1H) , 7.17 (t, 1H, J = 9.2 Hz), 3.62 (t, 2H, J = 6.4 Hz), 3.23 (s, 3H), 2.87 (t, 2H, J = 6.4 Hz), 1.80 (s, 6H) (fff) Synthesis of 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate methyl

[0127]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de 2-fluoro-5-(2-((2-metoxietil)sulfonil)propan-2-il)benzaldeído (36,0 mg, 0,13 mmol) como um material de partida para obter 5-(2-((2- metoxietil)sulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (30,0 mg, 67 %). RMN de 1H (400 MHz, CDCl3): δ 8,10 (s, 1H), 8,07 (s, 1H), 7,90 (d, 1H, J = 8,7 Hz), 7,78 (dd, 1H, J = 8,7, 2,0 Hz), 3,96 (s, 3H), 3,63 (t, 2H, J = 6,4 Hz), 3,25 (s, 3H), 2,91 (t, 2H, J = 6,4 Hz), 1,93 (s, 6H) (ggg) Síntese de ácido 5-(2-((2-metoxietil)sulfonil)propan-2-il)benzo[b]tiofeno-2- carboxílico[0127] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of 2-fluoro-5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzaldehyde (36.0 mg, 0.13 mmol) as a starting material to obtain methyl 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (30.0 mg, 67% ). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 8.07 (s, 1H), 7.90 (d, 1H, J = 8.7 Hz), 7.78 (dd , 1H, J = 8.7, 2.0 Hz), 3.96 (s, 3H), 3.63 (t, 2H, J = 6.4 Hz), 3.25 (s, 3H), 2 .91 (t, 2H, J = 6.4 Hz), 1.93 (s, 6H) (ggg) Synthesis of 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxylic

[0128]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(2-((2-metoxietil)sulfonil)propan-2-il)benzo[b]tiofeno-2-carboxilato de metila (30,0 mg, 0,08 mmol) como um material de partida para obter ácido 5-(2-((2- metoxietil)sulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (27,0 mg, 94 %).LC/MS ESI (-): 341 (M-1) Intermediário 13) Síntese de ácido 5-((S- metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxílico (hhh) Síntese de (4-fluoro-3-metilbenzil)(metil)sulfano[0128] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylate (30.0 mg, 0.08 mmol) as a starting material to obtain 5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (27, 0 mg, 94%. LC/MS ESI (-): 341 (M-1) Intermediate 13) Synthesis of 5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylic acid (hhh) Synthesis of (4-fluoro-3-methylbenzyl)(methyl)sulfane

[0129]4-(Bromometil)-1-fluoro-2-metilbenzeno (1,0 g, 4,92 mmols) e metanotiolato de sódio (380,0 mg, 5,42 mmols) foram dissolvidos em DMF (24,6 mL). A mistura de reação foi agitada na temperatura ambiente durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex : CH2Cl2 = 4 : 1) para obter (4-fluoro-3-metilbenzil)(metil)sulfano (709,0 mg, 85 %) como um líquido incolor.RMN de 1H (400 MHz, CDCl3): δ 7,12 (d, 1H, J = 7,3 Hz), 7,06 (m, 1H), 6,93 (m, 1H), 3,61 (s, 2H), 2,26 (s, 3H), 1,99 (s, 3H) (iii) Síntese de (E)-N-((4-fluoro-3-metilbenzil)(metil)-À4-sulfanilideno)-4- nitrobenzenossulfonamida[0129]4-(Bromomethyl)-1-fluoro-2-methylbenzene (1.0 g, 4.92 mmol) and sodium methanethiolate (380.0 mg, 5.42 mmol) were dissolved in DMF (24.6 mmol) mL). The reaction mixture was stirred at room temperature for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : CH 2 Cl 2 = 4 : 1) to obtain (4-fluoro-3-methylbenzyl)(methyl)sulfane (709.0 mg, 85%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.12 (d, 1H, J = 7.3 Hz), 7.06 (m, 1H), 6.93 (m, 1H), 3, 61 (s, 2H), 2.26 (s, 3H), 1.99 (s, 3H) (iii) Synthesis of (E)-N-((4-fluoro-3-methylbenzyl)(methyl)-À4 -sulfanylidene)-4-nitrobenzenesulfonamide

[0130](4-Fluoro-3-metilbenzil)(metil)sulfano (600,0 mg, 3,52 mmols), 4- nitrobenzenossulfonamida (869,0 mg, 4,39 mmols) e (diacetóxi-iodo)benzeno (1,7 g, 5,37 mmols) foram dissolvidos em CH3CN (35,8 mL). A mistura de reação foi agitada a 90 °C durante 16 horas, esfriada até a temperatura ambiente e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, CH3CN : H2O) para obter (E)-N-((4-fluoro-3- metilbenzil)(metil)-À4-sulfanilideno)-4-nitrobenzenossulfonamida (606,0 mg, 46 %).LC/MS ESI (+): 371 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,18 (d, 2H, J = 8,9 Hz), 7,88 (d, 2H, J = 8,9 Hz), 7,01 - 7,05 (m, 2H), 6,91 (m, 1H), 4,16 (d, 1H, J = 12,8 Hz), 4,07 (d, 1H, J = 12,8 Hz), 2,66 (s, 3H), 2,20 (d, 3H, J = 1,9 Hz) (jjj) Síntese de N-((4-fluoro-3-metilbenzil)(metil)(oxo)-À6-sulfanilideno)-4- nitrobenzenossulfonamida[0130](4-Fluoro-3-methylbenzyl)(methyl)sulfane (600.0 mg, 3.52 mmol), 4-nitrobenzenesulfonamide (869.0 mg, 4.39 mmol) and (diacetoxyiodo)benzene ( 1.7 g, 5.37 mmol) was dissolved in CH 3 CN (35.8 mL). The reaction mixture was stirred at 90°C for 16 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, CH3CN : H2O) to obtain (E)-N-((4-fluoro-3-methylbenzyl)(methyl)-α4-sulfanylidene)-4- nitrobenzenesulfonamide (606.0 mg, 46 %).LC/MS ESI (+): 371 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.18 (d, 2H, J = 8.9 Hz ), 7.88 (d, 2H, J = 8.9 Hz), 7.01 - 7.05 (m, 2H), 6.91 (m, 1H), 4.16 (d, 1H, J = 12.8 Hz), 4.07 (d, 1H, J = 12.8 Hz), 2.66 (s, 3H), 2.20 (d, 3H, J = 1.9 Hz) (jjj) Synthesis of N-((4-fluoro-3-methylbenzyl)(methyl)(oxo)-Δ6-sulfanylidene)-4-nitrobenzenesulfonamide

[0131](E)-N-((4-fluoro-3-metilbenzil)(metil)-À4-sulfanilideno)-4- nitrobenzenossulfonamida (600,0 mg, 1,62 mmol), RuCla^HaO (36,5 mg, 0,16 mmol) e NaIO4 (520,0 mg, 2,43 mmols) foram dissolvidos em uma mistura de CH2Cl2/H2O (16,3 mL, 10/3 v/v). A mistura de reação foi agitada na temperatura ambiente durante 16 horas, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:2) para obter N-((4-fluoro-3-metilbenzil)(metil)(oxo)-À6- sulfanilideno)-4-nitrobenzenossulfonamida (546,0 mg, 87 %). RMN de 1H (400 MHz, CDCl3): δ 8,32 (d, 2H, J = 9,0 Hz), 8,14 (d, 2H, J = 9,0 Hz), 7,30 (dd, 1H, J = 6,9, 1,9 Hz), 7,25 (m, 1H), 7,08 (m, 1H), 4,69 (s, 2H), 3,09 (s, 3H), 2,31 (d, 3H, J = 1,8 Hz) (kkk) Síntese de N-((3-(bromometil)-4-fluorobenzil)(metil)(oxo)-À6-sulfanilideno)-4-nitrobenzenossulfonamida[0131](E)-N-((4-fluoro-3-methylbenzyl)(methyl)-α4-sulfanylidene)-4-nitrobenzenesulfonamide (600.0 mg, 1.62 mmol), RuCla^HaO (36.5 mg, 0.16 mmol) and NaIO4 (520.0 mg, 2.43 mmol) were dissolved in a mixture of CH2Cl2/H2O (16.3 mL, 10/3 v/v). The reaction mixture was stirred at room temperature for 16 hours, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel amine, n-Hex:EtOAc = 1:2) to obtain N-((4-fluoro-3-methylbenzyl)(methyl)(oxo)-Δ6-sulfanilidene) -4-nitrobenzenesulfonamide (546.0 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 2H, J = 9.0 Hz), 8.14 (d, 2H, J = 9.0 Hz), 7.30 (dd, 1H , J = 6.9, 1.9 Hz), 7.25 (m, 1H), 7.08 (m, 1H), 4.69 (s, 2H), 3.09 (s, 3H), 2 ,31 (d, 3H, J = 1.8 Hz) (kkk) Synthesis of N-((3-(bromomethyl)-4-fluorobenzyl)(methyl)(oxo)-Δ6-sulfanylidene)-4-nitrobenzenesulfonamide

[0132]O procedimento de síntese do Intermediário 1-d foi repetido, exceto para o uso de N-((4-fluoro-3-metilbenzil)(metil)(oxo)-À6-sulfanilideno)-4-nitrobenzeno sulfonamida (546,0 mg, 1,41 mmol) como um material de partida para obter N-((3- (bromometil)-4-fluorobenzil)(metil)(oxo)-À6-sulfanilideno)-4-nitrobenzenossulfonamida (657,0 mg, quant). RMN de 1H (400 MHz, CDCl3): δ 8,32 (d, 2H, J = 9,0 Hz), 8,13 (d, 2H, J = 9,0 Hz), 7,52 (m, 1H), 7,43 (m, 1H), 7,17 (m, 1H), 4,72 (s, 2H), 4,51 (s, 2H), 3,13 (s, 3H) (lll) Síntese de N-((4-fluoro-3-formilbenzil)(metil)(oxo)-À6-sulfanilideno)-4- nitrobenzenossulfonamida[0132] The procedure for the synthesis of Intermediate 1-d was repeated, except for the use of N-((4-fluoro-3-methylbenzyl)(methyl)(oxo)-À6-sulfanylidene)-4-nitrobenzenesulfonamide (546 .0 mg, 1.41 mmol) as a starting material to obtain N-((3-(bromomethyl)-4-fluorobenzyl)(methyl)(oxo)-Δ6-sulfanylidene)-4-nitrobenzenesulfonamide (657.0 mg , amount). 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 2H, J = 9.0 Hz), 8.13 (d, 2H, J = 9.0 Hz), 7.52 (m, 1H ), 7.43 (m, 1H), 7.17 (m, 1H), 4.72 (s, 2H), 4.51 (s, 2H), 3.13 (s, 3H) (III) Synthesis of N-((4-fluoro-3-formylbenzyl)(methyl)(oxo)-Δ6-sulfanylidene)-4-nitrobenzenesulfonamide

[0133]O procedimento de síntese do Intermediário 1-e foi repetido, exceto para o uso de N-((3-(bromometil)-4-fluorobenzil)(metil)(oxo)-À6-sulfanilideno)-4- nitrobenzenossulfonamida (657,0 mg, 1,41 mmol) como um material de partida para obter N-((4-fluoro-3-formilbenzil)(metil)(oxo)-À6-sulfanilideno)-4- nitrobenzenossulfonamida (357,7 mg, 63 %). RMN de 1H (400 MHz, CDCl3): δ 10,38 (s, 1H), 8,33 (d, 2H, J = 8,8 Hz), 8,14 (d, 2H, J = 8,8 Hz), 7,92 (dd, 1H, J = 6,2, 2,4 Hz), 7,82 - 7,86 (m, 1H), 7,34 (m, 1H), 4,75 - 4,83 (m, 2H), 3,14 (s, 3H) (mmm) Síntese de 5-((S-metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxilato de metila[0133] The procedure for the synthesis of Intermediate 1-e was repeated, except for the use of N-((3-(bromomethyl)-4-fluorobenzyl)(methyl)(oxo)-À6-sulfanylidene)-4-nitrobenzenesulfonamide ( 657.0 mg, 1.41 mmol) as a starting material to obtain N-((4-fluoro-3-formylbenzyl)(methyl)(oxo)-Δ6-sulfanylidene)-4-nitrobenzenesulfonamide (357.7 mg, 63 %). 1H NMR (400 MHz, CDCl3): δ 10.38 (s, 1H), 8.33 (d, 2H, J = 8.8 Hz), 8.14 (d, 2H, J = 8.8 Hz ), 7.92 (dd, 1H, J = 6.2, 2.4 Hz), 7.82 - 7.86 (m, 1H), 7.34 (m, 1H), 4.75 - 4, 83 (m, 2H), 3.14 (s, 3H) (mmm) Synthesis of methyl 5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylate

[0134]O procedimento de síntese do Intermediário 1-f foi repetido, exceto para o uso de N-((4-fluoro-3-formilbenzil)(metil)(oxo)-À6-sulfanilideno)-4- nitrobenzenossulfonamida (306,0 mg, 0,77 mmol) como um material de partida para obter 5-((S-metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxilato de metila (139,0 mg, 65 %).LC/MS ESI (+): 284 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,08 (s, 1H), 7,91 - 7,93 (m, 2H), 7,51 (dd, 1H, J = 8,5, 1,7 Hz), 4,52 (d, 1H, J = 13,1 Hz), 4,36 (d, 1H, J = 13,1 Hz), 3,97 (s, 3H), 3,77 (s, 1H), 2,97 (s, 3H) (nnn) Síntese de ácido 5-((S-metilsulfonimidoil)metil)benzo[b]tiofeno-2- carboxílico[0134] The procedure for the synthesis of Intermediate 1-f was repeated, except for the use of N-((4-fluoro-3-formylbenzyl)(methyl)(oxo)-À6-sulfanylidene)-4-nitrobenzenesulfonamide (306, 0 mg, 0.77 mmol) as a starting material to obtain methyl 5-(((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylate (139.0 mg, 65%). LC/MS ESI (+): 284 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.91 - 7.93 (m, 2H), 7.51 (dd, 1H , J = 8.5, 1.7 Hz), 4.52 (d, 1H, J = 13.1 Hz), 4.36 (d, 1H, J = 13.1 Hz), 3.97 (s , 3H), 3.77 (s, 1H), 2.97 (s, 3H) (nnn) Synthesis of 5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylic acid

[0135]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-((S-metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxilato de metila (137,0 mg, 0,48 mmol) como um material de partida para obter ácido 5-((S- metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxílico (93,4 mg, 46 %).LC/MS ESI (+): 270 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 8,13 (s, 1H), 8,06 (d, 1H, J = 8,3 Hz), 8,04 (s, 1H), 7,57 (dd, 1H, J = 8,4, 1,4 Hz), 4,55 - 4,57 (m, 3H), 2,86 (d, 3H, J = 3,5 Hz) Intermediário 14) Síntese de ácido 5-(1,1-dioxidotetra-hidrotiofen-2- il)benzo[b]tiofeno-2-carboxílico (a) Síntese de 5-(1,1-dioxidotetra-hidrotiofen-2-il)benzo[b]tiofeno-2- carboxilato de metila[0135] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylate (137.0 mg, 0.48 mmol) as a starting material to obtain 5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxylic acid (93.4 mg, 46%). LC/MS ESI (+): 270 (M +1) 1H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 8.06 (d, 1H, J = 8.3 Hz), 8.04 (s, 1H), 7.57 (dd, 1H, J = 8.4, 1.4 Hz), 4.55 - 4.57 (m, 3H), 2.86 (d, 3H, J = 3.5 Hz) Intermediate 14 ) Synthesis of 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[ methyl b]thiophene-2-carboxylate

[0136]1,1-Dióxido de tetra-hidrotiofeno (124,0 mg, 1,03 mmol) foi dissolvido em THF anidro (7,3 mL) e solução 1 M de lítio bis(trimetilsilil)amida em THF (1,5 mL, 1,55 mmol) foi adicionada às gotas a -20 °C. A mistura de reação foi agitada na temperatura ambiente durante 30 minutos e ZnCl2 (211,0 mg, 1,55 mmol) foi adicionado -20 °C. A mistura de reação foi lentamente aquecida até a temperatura ambiente, 5-bromobenzo[b]tiofeno-2-carboxilato de metila (200,0 mg, 0,74 mmol), Pd(OAc)2 (8,3 mg, 0,04 mmol) e XPhos (35,2 mg, 0,07 mmol) foram adicionados e agitados a 65 °C durante 5 horas. A mistura de reação foi esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n- Hex:EtOAc = 9:1) para obter 5-(1,1-dioxidotetra-hidrotiofen-2-il)benzo[b]tiofeno-2- carboxilato de metila (60,0 mg, 26 %) como um sólido branco amarelado.RMN de 1H (400 MHz, CDCl3): δ 8,06 (s, 1H), 7,89 - 7,91 (m, 2H), 7,49 (dd, 1H, J = 8,4, 2,0 Hz), 4,30 (m, 1H), 3,95 (s, 3H), 2,95 - 3,35 (m, 3H), 2,22 - 2,58 (m, 3H) (b) Síntese de ácido 5-(1,1-dioxidotetra-hidrotiofen-2-il)benzo[b]tiofeno-2- carboxílico[0136] Tetrahydrothiophene 1,1-dioxide (124.0 mg, 1.03 mmol) was dissolved in anhydrous THF (7.3 mL) and 1 M solution of lithium bis(trimethylsilyl)amide in THF (1, 5 mL, 1.55 mmol) was added dropwise at -20 °C. The reaction mixture was stirred at room temperature for 30 minutes and ZnCl2 (211.0 mg, 1.55 mmol) was added at -20 °C. The reaction mixture was slowly warmed to room temperature, methyl 5-bromobenzo[b]thiophene-2-carboxylate (200.0 mg, 0.74 mmol), Pd(OAc)2 (8.3 mg, 0. 04 mmol) and XPhos (35.2 mg, 0.07 mmol) were added and stirred at 65°C for 5 hours. The reaction mixture was cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxylate of methyl (60.0 mg, 26%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.89 - 7.91 (m, 2H), 7.49 (dd, 1H, J = 8.4, 2.0 Hz), 4.30 (m, 1H), 3.95 (s, 3H), 2.95 - 3.35 (m, 3H) , 2.22 - 2.58 (m, 3H) (b) Synthesis of 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxylic acid

[0137]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(1,1-dioxidotetra-hidrotiofen-2-il)benzo[b]tiofeno-2-carboxilato de metila (70,0 mg, 0,23 mmol) como um material de partida para obter ácido 5-(1,1- dioxidotetra-hidrotiofen-2-il)benzo[b]tiofeno-2-carboxílico (60,0 mg, 90 %) como um sólido branco.LC/MS ESI (-): 295 (M-1) RMN de 1H (400 MHz, DMSO-d6): δ 13,55 (s, 1H), 8,13 (s, 1H), 8,08 (d, 1H, J = 8,5 Hz), 8,02 (s, 1H), 7,51 (d, 1H, J = 8,4 Hz), 4,50 (m, 1H), 3,17 - 3,36 (m, 2H), 2,38 - 2,46 (m, 2H), 2,13 - 2,28 (m, 2H) Intermediário 15) Síntese de ácido 5-(1,1-dioxidotetra-hidro-2H-tiopiran-2- il)benzo[b]tiofeno-2-carboxílico (a) Síntese de 5-(1,1-dioxidotetra-hidro-2H-tiopiran-2-il)benzo[b]tiofeno-2- carboxilato de metila[0137] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxylate (70.0 mg, 0.23 mmol) as a starting material to obtain 5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxylic acid (60.0 mg, 90%) as a white solid. LC/MS ESI (-): 295 (M-1) 1H NMR (400 MHz, DMSO-d6): δ 13.55 (s, 1H), 8.13 (s, 1H), 8, 08 (d, 1H, J = 8.5 Hz), 8.02 (s, 1H), 7.51 (d, 1H, J = 8.4 Hz), 4.50 (m, 1H), 3, 17 - 3.36 (m, 2H), 2.38 - 2.46 (m, 2H), 2.13 - 2.28 (m, 2H) Intermediate 15) Synthesis of 5-(1,1-dioxidotetra) acid -hydro-2H-thiopyran-2-yl)benzo[b]thiophene-2-carboxylic (a) Synthesis of 5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene- 2-methyl carboxylate

[0138]O procedimento de síntese do Intermediário 14-um foi repetido, exceto para o uso de 5-bromobenzo[b]tiofeno-2-carboxilato de metila (95,0 mg, 0,35 mmol) e 1,1-dióxido de tetra-hidro-2H-tiopirano (66,0 mg, 0,49 mmol) como um material de partida para obter 5-(1,1-dioxidotetra-hidro-2H-tiopiran-2-il)benzo[b]tiofeno-2- carboxilato de metila (26,0 mg, 23 %) como um sólido branco amarelado.RMN de 1H (400 MHz, CDCl3): δ 8,06 (s, 1H), 7,95 (s, 1H), 7,89 (d, 1H, J = 8,5 Hz), 7,53 (d, 1H, J = 8,5 Hz), 4,15 (m, 1H), 3,95 (s, 3H), 3,09 - 3,29 (m, 2H), 1,56 - 2,59 (m, 6H) (b) Síntese de ácido 5-(1,1-dioxidotetra-hidro-2H-tiopiran-2- il)benzo[b]tiofeno-2-carboxílico[0138] The procedure for the synthesis of Intermediate 14-one was repeated, except for the use of methyl 5-bromobenzo[b]thiophene-2-carboxylate (95.0 mg, 0.35 mmol) and 1,1-dioxide of tetrahydro-2H-thiopyran (66.0 mg, 0.49 mmol) as a starting material to obtain 5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene methyl -2-carboxylate (26.0 mg, 23%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.95 (s, 1H), 7.89 (d, 1H, J = 8.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 4.15 (m, 1H), 3.95 (s, 3H), 3.09 - 3.29 (m, 2H), 1.56 - 2.59 (m, 6H) (b) Synthesis of 5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl) acid benzo[b]thiophene-2-carboxylic acid

[0139]O procedimento de síntese do Intermediário 1-g foi repetido, exceto para o uso de 5-(1,1-dioxidotetra-hidro-2H-tiopiran-2-il)benzo[b]tiofeno-2-carboxilato de metila (26,0 mg, 0,08 mmol) como um material de partida para obter ácido 5-(1,1- dioxidotetra-hidro-2H-tiopiran-2-il)benzo[b]tiofeno-2-carboxílico (22,0 mg, 88 %) como um sólido branco.LC/MS ESI (-): 309 (M-1) Exemplo 1) Síntese de N-(3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida (a) Síntese de cloreto de 3-cloro-5-nitrobenzoila[0139] The procedure for the synthesis of Intermediate 1-g was repeated, except for the use of methyl 5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene-2-carboxylate (26.0 mg, 0.08 mmol) as a starting material to obtain 5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene-2-carboxylic acid (22, 0 mg, 88%) as a white solid. LC/MS ESI (-): 309 (M-1) Example 1) Synthesis of N-(3-chloro-5-(2-(3-ethoxy-5-( trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-chloro-5-nitrobenzoyl chloride

[0140]Ácido 3-cloro-5-nitrobenzoico (5,0 g, 24,81 mmols) foi dissolvido em SOCl2 (10,0 mL, 137,00 mmols) e uma quantidade catalítica de DMF anidra foi adicionada. A mistura de reação foi submetida ao refluxo a 110 °C durante 2 horas e concentrada sob pressão reduzida para obter cloreto de 3-cloro-5-nitrobenzoila (5,3 g, quant.) como um líquido amarelo sem purificação.(b) Síntese de (3-cloro-5-nitrofenil)(3-metóxi-5-(trifluorometóxi)fenil)metanona[0140] 3-Chloro-5-nitrobenzoic acid (5.0 g, 24.81 mmol) was dissolved in SOCl 2 (10.0 mL, 137.00 mmol) and a catalytic amount of anhydrous DMF was added. The reaction mixture was refluxed at 110 °C for 2 hours and concentrated under reduced pressure to obtain 3-chloro-5-nitrobenzoyl chloride (5.3 g, quant.) as a yellow liquid without purification. (b) Synthesis of (3-chloro-5-nitrophenyl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone

[0141]Cloreto de 3-cloro-5-nitrobenzoila (5,0 g, 22,70 mmols) foi dissolvido em Et2O anidro (230,0 mL) e ácido (3-metóxi-5-(trifluorometóxi)fenil)borônico (5,4 g, 22,70 mmols), Pd(dba)2 (1,3 g, 2,27 mmols), PPh3 (1,2 g, 4,54 mmols) e tiofeno-2- carboxilato de cobre (4,3 g, 22,70 mmols) foram adicionados. A mistura de reação foi agitada na temperatura ambiente durante 15 horas, filtrada através de Celite e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 9:1) para obter (3-cloro- 5-nitrofenil)(3-metóxi-5-(trifluorometóxi)fenil)metanona (4,2 g, 41 %) como um óleo amarelo.RMN de 1H (400 MHz, CDCl3): δ 8,49 (s, 1H), 8,46 (s, 1H), 8,10 (s, 1H), 7,26 (s, 1H), 7,18 (s, 1H), 7,05 (s, 1H), 3,90 (s, 3H) (c) Síntese de 1-cloro-3-(dicloro(3-metóxi-5-(trifluorometóxi)fenil)metil)-5- nitrobenzeno[0141] 3-Chloro-5-nitrobenzoyl chloride (5.0 g, 22.70 mmol) was dissolved in anhydrous Et2O (230.0 mL) and (3-methoxy-5-(trifluoromethoxy)phenyl)boronic acid ( 5.4 g, 22.70 mmol), Pd(dba)2 (1.3 g, 2.27 mmol), PPh3 (1.2 g, 4.54 mmol) and copper thiophene-2-carboxylate (4 .3 g, 22.70 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 9:1) to obtain (3-chloro-5-nitrophenyl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone ( 4.2 g, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.46 (s, 1H), 8.10 (s, 1H) , 7.26 (s, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 3.90 (s, 3H) (c) Synthesis of 1-chloro-3-(dichloro( 3-methoxy-5-(trifluoromethoxy)phenyl)methyl)-5-nitrobenzene

[0142](3-Cloro-5-nitrofenil)(3-metóxi-5-(trifluorometóxi)fenil)metanona (4,0 g, 10,65 mmols) foi dissolvido em 1,2-dibromoetano (106,0 mL) e PCl5 (11,1 g, 53,24 mmols) foi adicionado. A mistura de reação foi agitada a 110 °C durante 24 horas e esfriada até a temperatura ambiente. A mistura de reação foi vertida em uma solução de NaHCO3 em água gelada, vigorosamente agitada e extraída com CH2Cl2. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 20:1) para obter 1-cloro-3-(dicloro(3-metóxi-5-(trifluorometóxi)fenil)metil)-5-nitrobenzeno (1,4 g, 30 %) como um óleo amarelo. RMN de 1H (400 MHz, CDCl3): δ 8,37 (s, 1H), 8,24 (s, 1H), 7,91 (s, 1H), 7,08 (s, 1H), 7,05 (s, 1H), 6,81 (s, 1H), 3,84 (s, 3H) (d) Síntese de 1-cloro-3-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)-5- nitrobenzeno[0142](3-Chloro-5-nitrophenyl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone (4.0 g, 10.65 mmol) was dissolved in 1,2-dibromoethane (106.0 mL) and PCl5 (11.1 g, 53.24 mmol) was added. The reaction mixture was stirred at 110°C for 24 hours and cooled to room temperature. The reaction mixture was poured into a solution of NaHCO3 in ice water, stirred vigorously and extracted with CH2Cl2. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel amine, n-Hex:EtOAc = 20:1) to obtain 1-chloro-3-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)- 5-nitrobenzene (1.4 g, 30%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H) (d) Synthesis of 1-chloro-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan -2-yl)-5-nitrobenzene

[0143]Solução 1 M de TiCl4 em CH2Cl2 (0,6 mL, 0,63 mmol) foi adicionada à solução 1,2 M de dimetilzinco em tolueno (7,8 mL, 9,41 mmols) a -40 °C e agitada durante 1 hora. 1-Cloro-3-(dicloro(3-metóxi-5-(trifluorometóxi)fenil)metil)-5- nitrobenzeno (1,4 g, 3,14 mmols) em CH2Cl2 (11,4 mL) foi lentamente adicionado às gotas a -40 °C e a mistura de reação foi aquecida a 0 °C e agitada durante 18 horas. H2O foi adicionada e a mistura de reação foi extraída com CH2Cl2. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n- Hex:EtOAc = 9:1) para obter 1-cloro-3-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2- il)-5-nitrobenzeno (750,0 mg, 61 %) como um sólido amarelo. RMN de 1H (400 MHz, CDCl3): δ 8,07 (s, 1H), 8,00 (s, 1H), 7,48 (s, 1H), 6,62 - 6,65 (m, 3H), 3,78 (s, 3H), 1,70 (s, 6H) (e) Síntese de 3-(2-(3-cloro-5-nitrofenil)propan-2-il)-5-(trifluorometóxi)fenol[0143] A 1 M solution of TiCl4 in CH2Cl2 (0.6 mL, 0.63 mmol) was added to a 1.2 M solution of dimethylzinc in toluene (7.8 mL, 9.41 mmol) at -40 °C and stirred for 1 hour. 1-Chloro-3-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)-5-nitrobenzene (1.4 g, 3.14 mmol) in CH2Cl2 (11.4 mL) was slowly added dropwise at -40°C and the reaction mixture was warmed to 0°C and stirred for 18 hours. H2O was added and the reaction mixture was extracted with CH2Cl2. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel amine, n-Hex:EtOAc = 9:1) to obtain 1-chloro-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan- 2-yl)-5-nitrobenzene (750.0 mg, 61%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 8.00 (s, 1H), 7.48 (s, 1H), 6.62 - 6.65 (m, 3H) , 3.78 (s, 3H), 1.70 (s, 6H) (e) Synthesis of 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol

[0144]1-Cloro-3-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)-5- nitrobenzeno (450,0 mg, 1,15 mmol) foi dissolvido em CH2Cl2 anidro (8,0 mL) e solução 1 M de BBr3 em CH2Cl2 (3,5 mL, 3,46 mmols) foi lentamente adicionada às gotas a 0 °C. A mistura de reação foi agitada na temperatura ambiente durante 8 horas, H2O foi adicionada a 0 °C e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n- Hex:EtOAc = 3:1) para obter 3-(2-(3-cloro-5-nitrofenil)propan-2-il)-5-(trifluorometóxi)fenol (380,0 mg, 88 %) como um óleo incolor.RMN de 1H (400 MHz, CDCl3): δ 8,07 (s, 1H), 8,00 (s, 1H), 7,48 (s, 1H), 6,64 (s, 1H), 6,61 (s, 1H), 6,55 (s, 1H), 5,00 (s, 1H), 1,69 (s, 6H) (f) Síntese de 1-cloro-3-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)-5- nitrobenzeno[0144] 1-Chloro-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (450.0 mg, 1.15 mmol) was dissolved in anhydrous CH2Cl2 HCl (8.0 mL) and 1M solution of BBr3 in CH2Cl2 (3.5 mL, 3.46 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 8 hours, H2O was added at 0 °C and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 3:1) to obtain 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-( trifluoromethoxy)phenol (380.0 mg, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 8.00 (s, 1H), 7.48 ( s, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 5.00 (s, 1H), 1.69 (s, 6H) ( f) Synthesis of 1-chloro-3-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene

[0145]3-(2-(3-Cloro-5-nitrofenil)propan-2-il)-5-(trifluorometóxi)fenol (370,0 mg, 0,98 mmol) foi dissolvido em DMF anidra (9,8 mL) e K2CO3 (406,0 mg, 2,94 mmols) e iodoetano (158,0 mL, 1,97 mmol) foram adicionados. A mistura de reação foi agitada a 40 °C durante 15 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 1-cloro-3-(2-(3-etóxi-5- (trifluorometóxi)fenil)propan-2-il)-5-nitrobenzeno (386,0 mg, 97 %) como um óleo incolor. RMN de 1H (400 MHz, CDCl3): δ 8,07 (s, 1H), 8,00 (s, 1H), 7,48 (s, 1H), 6,60 - 6,63 (m, 3H), 3,98 (q, 2H, J = 7,0 Hz), 1,69 (s, 6H), 1,40 (t, 3H, J = 7,0 Hz) (g) Síntese de 3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)anilina[0145] 3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol (370.0 mg, 0.98 mmol) was dissolved in anhydrous DMF (9.8 mL) and K2CO3 (406.0 mg, 2.94 mmol) and iodoethane (158.0 mL, 1.97 mmol) were added. The reaction mixture was stirred at 40°C for 15 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 1-chloro-3-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2 -yl)-5-nitrobenzene (386.0 mg, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 8.00 (s, 1H), 7.48 (s, 1H), 6.60 - 6.63 (m, 3H) , 3.98 (q, 2H, J = 7.0 Hz), 1.69 (s, 6H), 1.40 (t, 3H, J = 7.0 Hz) (g) Synthesis of 3-chloro- 5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline

[0146]1-Cloro-3-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)-5-nitrobenzeno (380,0 mg, 0,94 mmol) foi dissolvido em uma mistura de MeOH/H2O (10,0 mL, 9/1 v/v) e Zn (616,0 mg, 9,43 mmols) e NH4Cl (504,0 mg, 9,43 mmols) foram adicionados na temperatura ambiente. A mistura de reação foi ultrassonificada a 40 °C durante 40 minutos, esfriado até a temperatura ambiente, filtrada através de Celite e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:1) para obter 3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)anilina (350,0 mg, 98 %) como um sólido branco. LC/MS ESI (+): 374 (M+H1) (h) Síntese de N-(3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0146] 1-Chloro-3-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (380.0 mg, 0.94 mmol) was dissolved in a mixture of MeOH/H2O (10.0 mL, 9/1 v/v) and Zn (616.0 mg, 9.43 mmol) and NH4Cl (504.0 mg, 9.43 mmol) were added at room temperature. The reaction mixture was sonicated at 40 °C for 40 minutes, cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 1:1) to obtain 3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan- 2-yl)aniline (350.0 mg, 98%) as a white solid. LC/MS ESI (+): 374 (M+H1) (h) Synthesis of N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl )-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0147]Ácido 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (38,8 mg, 0,13 mmol), 3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)anilina (48,6 mg, 0,13 mmol) e HATU (53,0 mg, 0,14 mmol) foram dissolvidos em DMF anidra (1,3 mL) e DIPEA (44,0 μL, 0,24 mmol) foi adicionada. A mistura de reação foi agitada a 40 °C durante 3 horas, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico a 0,1 % em CH3CN:ácido fórmico a 0,1 % em H2O) para obter N-(3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (35,0 mg, 41 %) como um sólido branco. LC/MS ESI (+): 654 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,65 (s, 1H), 8,34 (s, 1H), 8,20 (s, 1H), 8,09 (d, 1H, J = 8,8 Hz), 7,88 (s, 1H), 7,74 (d, 1H, J = 8,8 Hz), 7,52 (s, 1H), 7,04 (s, 1H), 6,77 (s, 2H), 6,72 (s, 1H), 4,01 (q, 2H, J = 6,9 Hz), 2,73 (s, 3H), 1,84 (s, 6H), 1,64 (s, 6H), 1,29 (t, 3H, J = 6,9 Hz)[0147] 5-(2-(Methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (38.8 mg, 0.13 mmol), 3-chloro-5-(2-(3 -ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (48.6 mg, 0.13 mmol) and HATU (53.0 mg, 0.14 mmol) were dissolved in anhydrous DMF (1.3 mL) and DIPEA (44.0 µL, 0.24 mmol) was added. The reaction mixture was stirred at 40°C for 3 hours, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain N-(3-chloro-5-(2 -(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (35.0 mg , 41%) as a white solid. LC/MS ESI (+): 654 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.34 (s, 1H), 8.20 (s , 1H), 8.09 (d, 1H, J = 8.8 Hz), 7.88 (s, 1H), 7.74 (d, 1H, J = 8.8 Hz), 7.52 (s , 1H), 7.04 (s, 1H), 6.77 (s, 2H), 6.72 (s, 1H), 4.01 (q, 2H, J = 6.9 Hz), 2.73 (s, 3H), 1.84 (s, 6H), 1.64 (s, 6H), 1.29 (t, 3H, J = 6.9 Hz)

[0148]Os compostos a partir dos Exemplos 2 a 16 foram sintetizados através da via de síntese do Exemplo 1 e os dados destes compostos são listados, como segue.Tabela 2 Exemplo 17) Síntese de N-(3-cloro-5-(2-(4-metoxifenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 1-cloro-3-(2-(4-metoxifenil)propan-2-il)-5-nitrobenzeno[0148] The compounds from Examples 2 to 16 were synthesized through the synthesis route of Example 1 and the data of these compounds are listed, as follows.Table 2 Example 17) Synthesis of N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide (a) Synthesis of 1-chloro-3-(2-(4-methoxyphenyl)propan-2-yl)-5-nitrobenzene

[0149]1-(2-Bromopropan-2-il)-3-cloro-5-nitrobenzeno (30,0 mg, 0,11 mmol) e anisol (0,1 mL, 1,07 mmol) foram dissolvidos em 1,2-dicloroetano (1,1 mL) e AlCl3 (44,0 mg, 0,33 mmol) foi adicionado. A mistura de reação foi agitada na temperatura ambiente durante 12 horas, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 1-cloro-3-(2-(4-metoxifenil)propan-2-il)- 5-nitrobenzeno (40,0 mg, 90 %) como um sólido amarelo. RMN de 1H (400 MHz, CDCl3): δ 8,03 (s, 1H), 8,01 (s, 1H), 7,49 (s, 1H), 7,11 (d, 2H, J = 8,4 Hz), 6,84 (d, 2H, J = 8,6 Hz), 3,81 (s, 3H), 1,70 (s, 6H) (b) Síntese de 3-cloro-5-(2-(4-metoxifenil)propan-2-il)anilina[0149] 1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (30.0 mg, 0.11 mmol) and anisole (0.1 mL, 1.07 mmol) were dissolved in 1 ,2-Dichloroethane (1.1 mL) and AlCl 3 (44.0 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 1-chloro-3-(2-(4-methoxyphenyl)propan-2-yl)-5-nitrobenzene (40.0 mg, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.11 (d, 2H, J = 8, 4 Hz), 6.84 (d, 2H, J = 8.6 Hz), 3.81 (s, 3H), 1.70 (s, 6H) (b) Synthesis of 3-chloro-5-(2 -(4-methoxyphenyl)propan-2-yl)aniline

[0150]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de 1-cloro-3-(2-(4-metoxifenil)propan-2-il)-5-nitrobenzeno (84,2 mg, 0,24 mmol) como um material de partida para obter 3-cloro-5-(2-(4-metoxifenil)propan-2-il)anilina (20,0 mg, 56 %). LC/MS ESI (+): 276 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,14 (d, 2H, J = 8,4 Hz), 6,81 (d, 2H, J = 8,6 Hz), 6,64 (s, 1H), 6,49 (s, 1H), 6,36 (s, 1H), 3,79 (s, 3H), 3,62 (s, 2H), 1,59 (s, 6H) (c) Síntese de N-(3-cloro-5-(2-(4-metoxifenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0150] The synthesis procedure of Example 1-g was repeated, except for the use of 1-chloro-3-(2-(4-methoxyphenyl)propan-2-yl)-5-nitrobenzene (84.2 mg, 0.24 mmol) as a starting material to obtain 3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)aniline (20.0 mg, 56%). LC/MS ESI (+): 276 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.14 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.6 Hz), 6.64 (s, 1H), 6.49 (s, 1H), 6.36 (s, 1H), 3.79 (s, 3H), 3.62 (s, 2H ), 1.59 (s, 6H) (c) Synthesis of N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan -2-yl)benzo[b]thiophene-2-carboxamide

[0151]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 3-cloro-5-(2-(4-metoxifenil)propan-2-il)anilina (81,0 mg, 0,27 mmol) como um material de partida para obter N-(3-cloro-5-(2-(4-metoxifenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (40,0 mg, 27 %).LC/MS ESI (+): 556 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,64 (s, 1H), 8,36 (s, 1H), 8,20 (s, 1H), 8,10 (d, 1H, J = 8,4 Hz), 7,87 (s, 1H), 7,75 (dd, 1H, J = 8,4, 1,6 Hz), 7,54 (s, 1H), 7,17 (d, 2H, J = 8,8 Hz), 7,00 (s, 1H), 6,88 (d, 2H, J = 8,8 Hz), 3,74 (s, 3H), 2,74 (s, 3H), 1,86 (s, 6H), 1,64 (s, 6H)[0151] The synthesis procedure of Example 1-h was repeated, except for the use of 3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)aniline (81.0 mg, 0.27 mmol) as a starting material to obtain N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide (40.0 mg, 27 %).LC/MS ESI (+): 556 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s , 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H, J = 8.4 Hz), 7.87 (s, 1H), 7.75 (dd, 1H, J = 8.4, 1.6 Hz), 7.54 (s, 1H), 7.17 (d, 2H, J = 8.8 Hz), 7.00 (s, 1H) , 6.88 (d, 2H, J = 8.8 Hz), 3.74 (s, 3H), 2.74 (s, 3H), 1.86 (s, 6H), 1.64 (s, 6H)

[0152]Os compostos a partir do Exemplo 18 ao Exemplo 36 foram sintetizados através da via de síntese do Exemplo 17 e os dados destes compostos são listados, como segue.Tabela 3 Exemplo 37) Síntese de N-(3-cloro-5-(4-(trifluorometóxi)fenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 1-cloro-3-nitro-5-(4-(trifluorometóxi)fenóxi)benzeno[0152] The compounds from Example 18 to Example 36 were synthesized through the synthesis route of Example 17 and the data of these compounds are listed, as follows.Table 3 Example 37) Synthesis of N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a ) Synthesis of 1-chloro-3-nitro-5-(4-(trifluoromethoxy)phenoxy)benzene

[0153]1-Bromo-3-cloro-5-nitrobenzeno (200,0 mg, 0,84 mmol), 4- (trifluorometóxi)fenol (220,0 mg, 1,69 mmol), CuI (80,6 mg, 0,42 mmol), N,N- dimetilglicina (87,2 mg, 0,42 mmol) e Cs2CO3 (826,9 mg, 2,53 mmols) foram dissolvidos em 1,4-dioxano anidro (5,0 mL). A mistura de reação foi agitada a 120 °C durante 15 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex) para obter 1-cloro-3-nitro- 5-(4-(trifluorometóxi)fenóxi)benzeno (160,0 mg, 61 %) como um óleo amarelo. RMN de 1H (400 MHz, CDCl3): δ 7,95 (s, 1H), 7,65 (s, 1H), 7,26 - 7,30 (m, 3H), 7,09 (d, 2H, J = 8,8 Hz) (b) Síntese de 3-cloro-5-(4-(trifluorometóxi)fenóxi)anilina[0153] 1-Bromo-3-chloro-5-nitrobenzene (200.0 mg, 0.84 mmol), 4-(trifluoromethoxy)phenol (220.0 mg, 1.69 mmol), CuI (80.6 mg , 0.42 mmol), N,N-dimethylglycine (87.2 mg, 0.42 mmol) and Cs2CO3 (826.9 mg, 2.53 mmol) were dissolved in anhydrous 1,4-dioxane (5.0 mL ). The reaction mixture was stirred at 120°C for 15 hours, cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex) to obtain 1-chloro-3-nitro-5-(4-(trifluoromethoxy)phenoxy)benzene (160.0 mg, 61%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.65 (s, 1H), 7.26 - 7.30 (m, 3H), 7.09 (d, 2H, J = 8.8 Hz) (b) Synthesis of 3-chloro-5-(4-(trifluoromethoxy)phenoxy)aniline

[0154]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de 1-cloro-3-nitro-5-(4-(trifluorometóxi)fenóxi)benzeno (160,0 mg, 0,52 mmol) como um material de partida para obter 3-cloro-5-(4-(trifluorometóxi)fenóxi)anilina (130,0 mg, 79 %) como um óleo branco amarelado. LC/MS ESI (+): 304 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,31 (d, 2H, J = 8,7 Hz), 6,95 (d, 2H, J = 8,7 Hz), 6,41 (s, 1H), 6,34 (s, 1H), 6,16 (s, 1H), 3,76 (brs, 2H) (c) Síntese de N-(3-cloro-5-(4-(trifluorometóxi)fenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0154] The synthesis procedure of Example 1-g was repeated, except for the use of 1-chloro-3-nitro-5-(4-(trifluoromethoxy)phenoxy)benzene (160.0 mg, 0.52 mmol) as a starting material to obtain 3-chloro-5-(4-(trifluoromethoxy)phenoxy)aniline (130.0 mg, 79%) as an off-white oil. LC/MS ESI (+): 304 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.31 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.7 Hz), 6.41 (s, 1H), 6.34 (s, 1H), 6.16 (s, 1H), 3.76 (brs, 2H) (c) Synthesis of N-( 3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0155]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 3-cloro-5-(4-(trifluorometóxi)fenóxi)anilina (130,0 mg, 0,42 mmol) e ácido 5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (150,0 mg, 0,55 mmol) como materiais de partida para obter N-(3-cloro-5-(4-(trifluorometóxi)fenóxi)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (75,0 mg, 47 %) como um sólido branco.LC/MS ESI (+): 584 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,74 (brs, 1H), 8,34 (s, 1H), 8,21 (s, 1H), 8,09 (d, 1H, J = 8,7 Hz), 7,79 (s, 1H), 7,74 (d, 1H, J = 8,7 Hz), 7,46 (d, 2H, J = 8,7 Hz), 7,40 (t, 1H, J = 1,8 Hz), 7,26 (d, 2H, J = 8,9 Hz), 6,96 (t, 1H, J = 1,8 Hz), 2,73(s, 3H), 1,85 (s, 6H)[0155] The synthesis procedure of Example 1-h was repeated, except for the use of 3-chloro-5-(4-(trifluoromethoxy)phenoxy)aniline (130.0 mg, 0.42 mmol) and 5- (2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (150.0 mg, 0.55 mmol) as starting materials to obtain N-(3-chloro-5-(4- (trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (75.0 mg, 47%) as a white solid. LC/MS ESI ( +): 584 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.74 (brs, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 8 .09 (d, 1H, J = 8.7 Hz), 7.79 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.7 Hz), 7.40 (t, 1H, J = 1.8 Hz), 7.26 (d, 2H, J = 8.9 Hz), 6.96 (t, 1H, J = 1, 8 Hz), 2.73(s, 3H), 1.85(s, 6H)

[0156]Os compostos a partir do Exemplo 38 ao Exemplo 61 foram sintetizados através da via de síntese do Exemplo 37 e os dados destes compostos são listados, como segue.Tabela 4 Exemplo 62) Síntese de N-(2-cloro-6-(3,5-diclorofenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 2-cloro-6-(3,5-diclorofenóxi)piridino-4-amina[0156] The compounds from Example 38 to Example 61 were synthesized through the synthesis route of Example 37 and the data of these compounds are listed, as follows.Table 4 Example 62) Synthesis of N-(2-chloro-6-(3,5-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide (a) Synthesis of 2-chloro-6-(3,5-dichlorophenoxy)pyridine-4-amine

[0157]2,6-Dicloropiridino-4-amina (200,0 mg, 1,22 mmol) e 3,5-diclorofenol (400,0 mg, 2,45 mmols) foram dissolvidos em sulfolano (6,1 mL) e K2CO3 (339,0 mg, 2,45 mmols) foi adicionado. A mistura de reação foi agitada a 160 °C durante 16 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com solução aquosa de NaOH 1 N e salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter 2-cloro-6-(3,5- diclorofenóxi)piridino-4-amina (121,0 mg, 34 %) como um sólido branco. LC/MS ESI (+): 289 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 7,46 (s, 1H), 7,24 (d, 2H, J = 1,8 Hz), 6,63 (brs, 2H), 6,35 (d, 1H, J = 1,6 Hz), 6,00 (d, 1H, J = 1,6 Hz) (b) Síntese de N-(2-cloro-6-(3,5-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0157] 2,6-Dichloropyridine-4-amine (200.0 mg, 1.22 mmol) and 3,5-dichlorophenol (400.0 mg, 2.45 mmol) were dissolved in sulfolane (6.1 mL) and K2CO3 (339.0 mg, 2.45 mmol) was added. The reaction mixture was stirred at 160°C for 16 hours, cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with 1N aqueous NaOH solution and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain 2-chloro-6-(3,5-dichlorophenoxy) pyridin-4-amine (121.0 mg, 34%) as a white solid. LC/MS ESI (+): 289 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 7.24 (d, 2H, J = 1.8 Hz ), 6.63 (brs, 2H), 6.35 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 1.6 Hz) (b) Synthesis of N-( 2-chloro-6-(3,5-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0158]Ácido 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (50,0 mg, 0,16 mmol) foi dissolvido em CH2Cl2 (1,6 mL) e DMF (1,2 μL, 0,01 mmol) e (COCl)2 (16,1 μL, 0,18 mmol) foram adicionados. A mistura de reação foi agitada a 25 °C durante 2 horas e concentrada sob pressão reduzida para obter cloreto de 5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carbonila. Ao resíduo, 2-cloro-6-(3,5- diclorofenóxi)piridino-4-amina (50,9 mg, 0,17 mmol) e piridina (550,0 μL) foram adicionadas, agitadas a 30 °C durante 16 horas e concentradas sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter N-(2-cloro-6-(3,5-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (62,0 mg, 65 %) como um sólido branco. LC/MS ESI (+): 569 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 11,14 (brs, 1H), 8,42 (s, 1H), 8,26 (d, 1H, J = 2,8 Hz), 8,13 (d, 1H, J = 8,7 Hz), 7,77 (dd, 1H, J = 8,7, 1,8 Hz), 7,71 (d, 1H, J = 1,3 Hz), 7,56 (t, 1H, J = 1,8 Hz), 7,44 (d, 2H, J = 1,8 Hz), 7,39 (d, 1H, J = 1,4 Hz), 2,74 (s, 3H), 1,86 (s, 6H)[0158] 5-(2-(Methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (50.0 mg, 0.16 mmol) was dissolved in CH 2 Cl 2 (1.6 mL) and DMF (1.2 µL, 0.01 mmol) and (COCl)2 (16.1 µL, 0.18 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours and concentrated under reduced pressure to obtain 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carbonyl chloride. To the residue, 2-chloro-6-(3,5-dichlorophenoxy)pyridin-4-amine (50.9 mg, 0.17 mmol) and pyridine (550.0 µL) were added, stirred at 30 °C for 16 hours and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain N-(2-chloro-6-(3.5 -dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (62.0 mg, 65%) as a white solid. LC/MS ESI (+): 569 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 11.14 (brs, 1H), 8.42 (s, 1H), 8.26 (d , 1H, J = 2.8 Hz), 8.13 (d, 1H, J = 8.7 Hz), 7.77 (dd, 1H, J = 8.7, 1.8 Hz), 7.71 (d, 1H, J = 1.3 Hz), 7.56 (t, 1H, J = 1.8 Hz), 7.44 (d, 2H, J = 1.8 Hz), 7.39 (d , 1H, J = 1.4 Hz), 2.74 (s, 3H), 1.86 (s, 6H)

[0159]Os compostos a partir do Exemplo 63 ao Exemplo 86 foram sintetizados através da via de síntese do Exemplo 62 e os dados destes compostos são listados, como segue.Tabela 5 Exemplo 87) Síntese de N-(3-cloro-5-(2-(3-(prop-1-in-1-il)-5- (trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida (a) Síntese de trifluorometanossulfonato de 3-(2-(3-cloro-5-nitrofenil)propan- 2-il)-5-(trifluorometóxi)fenila[0159] The compounds from Example 63 to Example 86 were synthesized through the synthesis route of Example 62 and the data of these compounds are listed, as follows.Table 5 Example 87) Synthesis of N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5- (2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5 trifluoromethanesulfonate -(trifluoromethoxy)phenyl

[0160]3-(2-(3-Cloro-5-nitrofenil)propan-2-il)-5-(trifluorometóxi)fenol (100,0 mg, 0,27 mmol) foi dissolvido em CH2Cl2 (2,7 mL) e piridina (109,0 μL, 1,35 mmol) e Tf2O (45,0 μL, 0,27 mmol) foram lentamente adicionados às gotas a 0 °C. A mistura de reação foi agitada a 0 °C durante 2 horas, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter trifluorometanossulfonato de 3-(2-(3-cloro-5-nitrofenil)propan-2-il)-5-(trifluorometóxi)fenila (120,0 mg, 88 %) como um líquido incolor. RMN de 1H (400 MHz, CDCl3): δ 8,13 (t, 1H, J = 1,9 Hz), 7,99 (t, 1H, J = 1,9 Hz), 7,45 (t, 1H, J = 1,8 Hz), 7,08 - 7,10 (m, 2H), 7,04 (t, 1H, J = 1,9 Hz), 1,75 (s, 6H) (b) Síntese de 1-cloro-3-nitro-5-(2-(3-(prop-1-in-1-il)-5- (trifluorometóxi)fenil)propan-2-il)benzeno[0160] 3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol (100.0 mg, 0.27 mmol) was dissolved in CH 2 Cl 2 (2.7 mL ) and pyridine (109.0 μL, 1.35 mmol) and Tf2O (45.0 μL, 0.27 mmol) were slowly added dropwise at 0 °C. The reaction mixture was stirred at 0°C for 2 hours, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5 trifluoromethanesulfonate -(trifluoromethoxy)phenyl (120.0 mg, 88%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 8.13 (t, 1H, J = 1.9 Hz), 7.99 (t, 1H, J = 1.9 Hz), 7.45 (t, 1H , J = 1.8 Hz), 7.08 - 7.10 (m, 2H), 7.04 (t, 1H, J = 1.9 Hz), 1.75 (s, 6H) (b) Synthesis of 1-chloro-3-nitro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)benzene

[0161]Trifluorometanossulfonato de 3-(2-(3-cloro-5-nitrofenil)propan-2-il)-5- (trifluorometóxi)fenila (280,0 mg, 0,55 mmol) foi dissolvido em DMF anidra (5,5 mL), e 1-(trimetilsilil)-1-propino (123,0 μL, 0,83 mmol), Pd(PPh3)4 (64,0 mg, 0,06 mmol), CuI (21,0 mg, 0,11 mmol) e DIPEA (480,0 μL, 2,75 mmol) foram adicionados na temperatura ambiente. A mistura de reação foi agitada a 90 °C durante 15 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:CH2Cl2 = 4:1) para obter 1-cloro-3-nitro-5-(2-(3-(prop-1- in-1-il)-5-(trifluorometóxi)fenil)propan-2-il)benzeno (120,0 mg, 55 %) como um líquido incolor.RMN de 1H (400 MHz, CDCl3): δ 8,08 (t, 1H, J = 1,9 Hz), 7,99 (t, 1H, J = 1,9 Hz), 7,46 (t, 1H, J = 1,8 Hz), 7,11 - 7,13 (m, 2H), 6,94 (s, 1H), 2,04 (s, 3H), 1,70 (s, 6H) (c) Síntese de 3-cloro-5-(2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2- il)anilina[0161] 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate (280.0 mg, 0.55 mmol) was dissolved in anhydrous DMF (5 .5 mL), and 1-(trimethylsilyl)-1-propyne (123.0 µL, 0.83 mmol), Pd(PPh3)4 (64.0 mg, 0.06 mmol), CuI (21.0 mg , 0.11 mmol) and DIPEA (480.0 µL, 2.75 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 15 hours, cooled to room temperature, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH2Cl2 = 4:1) to obtain 1-chloro-3-nitro-5-(2-(3-(prop-1-in-1 -yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)benzene (120.0 mg, 55%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 8.08 (t, 1H , J = 1.9 Hz), 7.99 (t, 1H, J = 1.9 Hz), 7.46 (t, 1H, J = 1.8 Hz), 7.11 - 7.13 (m , 2H), 6.94 (s, 1H), 2.04 (s, 3H), 1.70 (s, 6H) (c) Synthesis of 3-chloro-5-(2-(3-(prop- 1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline

[0162]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de 1-cloro-3-nitro-5-(2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2- il)benzeno (120,0 mg, 0,32 mmol) como um material de partida para obter 3-cloro-5- (2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2-il)anilina (93,0 mg, 84 %).LC/MS ESI (+): 368 (M+1) (d) Síntese de N-(3-cloro-5-(2-(3-(prop-1-in-1-il)-5- (trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida[0162] The synthesis procedure of Example 1-g was repeated, except for the use of 1-chloro-3-nitro-5-(2-(3-(prop-1-yn-1-yl)-5- (trifluoromethoxy)phenyl)propan-2-yl)benzene (120.0 mg, 0.32 mmol) as a starting material to obtain 3-chloro-5-(2-(3-(prop-1-yn-1 -yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (93.0 mg, 84%). LC/MS ESI (+): 368 (M+1) (d) Synthesis of N-( 3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan- 2-yl)benzo[b]thiophene-2-carboxamide

[0163]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 3-cloro-5-(2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2-il)anilina (55,0 mg, 0,15 mmol) como um material de partida para obter N-(3-cloro-5-(2-(3-(prop-1-in- 1-il)-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (23,5 mg, 33 %). LC/MS ESI (+): 648 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,65 (s, 1H), 8,34 (s, 1H), 8,20 (s, 1H), 8,10 (d, 1H, J = 8,8 Hz), 7,90 (s, 1H), 7,74 (d, 1H, J = 8,8 Hz), 7,50 (s, 1H), 7,19 - 7,22 (m, 3H), 7,07 (s, 1H), 2,73 (s, 3H), 2,03 (s, 3H), 1,85 (s, 6H), 1,65 (s, 6H) Exemplo 88) Síntese de N-(1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H- pirazol-5-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 4-(4-clorofenil)-4-metil-3-oxopentanonitrila[0163] The synthesis procedure of Example 1-h was repeated, except for the use of 3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl )propan-2-yl)aniline (55.0 mg, 0.15 mmol) as a starting material to obtain N-(3-chloro-5-(2-(3-(prop-1-yn-1- yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (23.5 mg, 33% ). LC/MS ESI (+): 648 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.34 (s, 1H), 8.20 (s , 1H), 8.10 (d, 1H, J = 8.8 Hz), 7.90 (s, 1H), 7.74 (d, 1H, J = 8.8 Hz), 7.50 (s , 1H), 7.19 - 7.22 (m, 3H), 7.07 (s, 1H), 2.73 (s, 3H), 2.03 (s, 3H), 1.85 (s, 6H), 1.65 (s, 6H) Example 88) Synthesis of N-(1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5- yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 4-(4-chlorophenyl)-4-methyl-3-oxopentanenitrile

[0164]Ácido 2-(4-clorofenil)-2-metilpropanoico (500,0 mg, 2,52 mmols) foi dissolvido em THF (10,0 mL), carbonildi-imidazol (490,0 mg, 3,02 mmols) foi adicionado e agitado durante 2 horas. À mistura de reação foi adicionada uma solução preparada por meio da dissolução de CH3CN (0,2 mL, 8,31 mmols) em THF (10,0 mL), adição de solução 1,6 M de n-BuLi em THF (4,7 mL, 7,56 mmols) lentamente às gotas a -78 °C e agitação durante 1 hora. A mistura resultante foi agitada a -78 °C durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:CH2Cl2 = 1:2) para obter 4-(4-clorofenil)-4-metil-3- oxopentanonitrila (333,0 mg, 59 %) como um óleo branco amarelado. LC/MS ESI (-): 220 (M-1) RMN de 1H (400 MHz, CDCl3): δ 7,38 (d, 2H, J = 8,4 Hz), 7,19 (d, 2H, J = 8,8 Hz), 3,30 (s, 2H), 1,53 (s, 6H) (b) Síntese de 1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-amina[0164] 2-(4-Chlorophenyl)-2-methylpropanoic acid (500.0 mg, 2.52 mmol) was dissolved in THF (10.0 mL), carbonyldiimidazole (490.0 mg, 3.02 mmol ) was added and stirred for 2 hours. To the reaction mixture was added a solution prepared by dissolving CH3CN (0.2 mL, 8.31 mmol) in THF (10.0 mL), adding 1.6 M solution of n-BuLi in THF (4 .7 mL, 7.56 mmol) slowly dropwise at -78 °C and stirred for 1 hour. The resulting mixture was stirred at -78°C for 2 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH 2 Cl 2 = 1:2) to obtain 4-(4-chlorophenyl)-4-methyl-3-oxopentanenitrile (333.0 mg, 59%) like a yellowish white oil. LC/MS ESI (-): 220 (M-1) 1H NMR (400 MHz, CDCl3): δ 7.38 (d, 2H, J = 8.4 Hz), 7.19 (d, 2H, J = 8.8 Hz), 3.30 (s, 2H), 1.53 (s, 6H) (b) Synthesis of 1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2 -yl)-1H-pyrazol-5-amine

[0165]Cloreto de terc-butil-hidrazina (463,0 mg, 3,72 mmols) foi dissolvido em EtOH (1,9 mL) e NaOH (119,0 g, 2,97 mmols) foi adicionado. 4-(4-Clorofenil)-4- metil-3-oxopentanonitrila (330,0 mg, 1,49 mmol) em EtOH (1,0 mL) foi adicionado à mistura de reação às gotas. A mistura de reação foi agitada a 80 °C durante 12 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi seco em Na2SO4 e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:1) para obter 1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-amina (130,0 mg, 30 %) como um sólido branco. LC/MS ESI (+): 292 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,25 (d, 2H, J = 9,2 Hz), 7,19 (d, 2H, J = 8,8 Hz), 5,24 (s, 1H), 3,41 (s, 2H), 1,62 (s, 9H), 1,59 (s, 6H) (c) Síntese de N-(1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)- 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0165]Tert-butylhydrazine chloride (463.0 mg, 3.72 mmol) was dissolved in EtOH (1.9 mL) and NaOH (119.0 g, 2.97 mmol) was added. 4-(4-Chlorophenyl)-4-methyl-3-oxopentanenitrile (330.0 mg, 1.49 mmol) in EtOH (1.0 mL) was added to the reaction mixture dropwise. The reaction mixture was stirred at 80°C for 12 hours, H2O was added and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 1:1) to obtain 1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl )-1H-pyrazol-5-amine (130.0 mg, 30%) as a white solid. LC/MS ESI (+): 292 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.25 (d, 2H, J = 9.2 Hz), 7.19 (d, 2H, J = 8.8 Hz), 5.24 (s, 1H), 3.41 (s, 2H), 1.62 (s, 9H), 1.59 (s, 6H) (c) Synthesis of N-( 1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide

[0166]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-amina (100,0 mg, 0,34 mmol) como um material de partida para obter N-(1-(terc-butil)-3-(2-(4- clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida (78,0 mg, 40 %). LC/MS ESI (+): 572 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,35 (s, 1H), 8,27 (s, 1H), 8,26 (s, 1H), 8,10 (d, 1H, J = 8,8 Hz), 7,76 (d, 1H, J = 8,8 Hz), 7,30 - 7,35 (m, 4H), 6,08 (s, 1H), 2,74 (s, 3H), 1,85 (s, 6H), 1,63 (s, 6H), 1,57 (s, 9H). Exemplo 89) Síntese de N-(3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0166] The synthesis procedure of Example 1-h was repeated, except for the use of 1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5 -amine (100.0 mg, 0.34 mmol) as a starting material to obtain N-(1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H- pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (78.0 mg, 40%). LC/MS ESI (+): 572 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.27 (s, 1H), 8.26 (s , 1H), 8.10 (d, 1H, J = 8.8 Hz), 7.76 (d, 1H, J = 8.8 Hz), 7.30 - 7.35 (m, 4H), 6 .08 (s, 1H), 2.74 (s, 3H), 1.85 (s, 6H), 1.63 (s, 6H), 1.57 (s, 9H). Example 89) Synthesis of N-(3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide

[0167]N-(1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (30,0 mg, 0,05 mmol) foi dissolvida em ácido fórmico (4,0 mL). A mistura de reação foi agitada a 80 °C durante 12 horas e concentrada sob pressão reduzida, basificada com solução aquosa de NaHCO3 sat. (pH = 9) e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter N-(3- (2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (17,0 mg, 67 %) como um sólido branco. LC/MS ESI (+): 516 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 12,30 (s, 1H), 11,23 (s, 1H), 8,44 (s, 1H), 8,13 (s, 1H), 8,09 (d, 1H, J = 8,8 Hz), 7,74 (d, 1H, J = 8,8 Hz), 7,38 (d, 2H, J = 8,4 Hz), 7,29 (d, 2H, J = 8,4 Hz), 6,50 (s, 1H), 2,74 (s, 3H), 1,86 (s, 6H), 1,67 (s, 6H) Exemplo 90 e Exemplo 91) Síntese de N-(2-cloro-6-(2-(3-metóxi-5- (trifluorometóxi)fenil)propan-2-il)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida e N-(4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 4,6-dicloro-N-metóxi-N-metilisonicotinamida[0167] N-(1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan- 2-yl)benzo[b]thiophene-2-carboxamide (30.0 mg, 0.05 mmol) was dissolved in formic acid (4.0 mL). The reaction mixture was stirred at 80°C for 12 hours and concentrated under reduced pressure, basified with sat. (pH = 9) and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain N-(3-(2-(4-chlorophenyl) propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (17.0 mg, 67%) as a white solid. LC/MS ESI (+): 516 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 11.23 (s, 1H), 8.44 (s , 1H), 8.13 (s, 1H), 8.09 (d, 1H, J = 8.8 Hz), 7.74 (d, 1H, J = 8.8 Hz), 7.38 (d , 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4 Hz), 6.50 (s, 1H), 2.74 (s, 3H), 1.86 (s , 6H), 1.67 (s, 6H) Example 90 and Example 91) Synthesis of N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl) pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide and N-(4-chloro-6-(2-(3-methoxy-5- (trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 4,6- dichloro-N-methoxy-N-methylisonicotinamide

[0168]Ácido 4,6-dicloroisonicotínico (3,0 g, 15,6 mmols) foi dissolvido em CH2Cl2 anidro (100,0 mL) e (COCl)2 (2,1 mL, 23,40 mmols) e DMF anidra foram adicionados às gotas em uma quantidade catalítica, seguido por agitação a 0 °C durante 1 hora. A mistura de reação foi seca sob pressão reduzida durante 1 hora, o resíduo foi dissolvido em CH2Cl2 anidro (100,0 mL) e N,O-dimetil-hidroxiamina (4,6 g, 46,80 mmols) e piridina (7,5 mL, 93,60 mmols) foram adicionadas a 0 °C. A mistura de reação foi agitada a 0 °C durante 1 hora, H2O foi adicionada e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 1:4) para obter 4,6- dicloro-N-metóxi-N-metilisonicotinamida (3,5 g, 83 %) como um sólido branco.LC/MS ESI (+): 235 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,56 (brs, 1H), 7,44 (s, 1H), 3,80 (s, 3H), 3,36 (s, 3H) (b) Síntese de (4,6-dicloropiridin-2-il)(3-metóxi-5-(trifluorometóxi)fenil)metanona[0168] 4,6-Dichloroisonicotinic acid (3.0 g, 15.6 mmol) was dissolved in anhydrous CH2Cl2 (100.0 mL) and (COCl)2 (2.1 mL, 23.40 mmol) and anhydrous DMF were added dropwise in a catalytic amount, followed by stirring at 0 °C for 1 hour. The reaction mixture was dried under reduced pressure for 1 hour, the residue was dissolved in anhydrous CH2Cl2 (100.0 mL) and N,O-dimethylhydroxyamine (4.6 g, 46.80 mmol) and pyridine (7. 5 mL, 93.60 mmol) was added at 0 °C. The reaction mixture was stirred at 0°C for 1 hour, H2O was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 1:4) to obtain 4,6-dichloro-N-methoxy-N-methylisonicotinamide (3.5 g, 83%) as a white solid. LC/MS ESI (+): 235 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.56 (brs, 1H), 7.44 (s, 1H), 3.80 (s, 3H), 3.36 (s, 3H) (b) Synthesis of (4,6-dichloropyridin-2-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone

[0169]1-Bromo-3-metóxi-5-(trifluorometóxi)benzeno (5,0 g, 18,45 mmols) foi dissolvido em THF (90,0 mL), solução 1,7 M de terc-BuLi em pentano (11,4 mL, 19,30 mmols) foi adicionada às gotas a -78 °C e agitada durante 1 hora. 4,6-Dicloro- N-metóxi-N-metilisonicotinamida (3,5 g, 14,88 mmols) em THF (10,0 mL) foi lentamente adicionada e a mistura de reação foi agitada a 0 °C durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:CH2Cl2 = 1:10) para obter (4,6-dicloropiridin-2-il)(3-metóxi-5-(trifluorometóxi)fenil)metanona (2,4 g, 44 %) como um sólido amarelo. LC/MS ESI (+): 366 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,00 (s, 1H), 7,63 (s, 1H), 7,61 (s, 1H), 7,59 (s, 1H), 7,01 (s, 1H), 3,89 (s, 3H) (c) Síntese de 2,4-dicloro-6-(dicloro(3-metóxi-5- (trifluorometóxi)fenil)metil)piridina[0169] 1-Bromo-3-methoxy-5-(trifluoromethoxy)benzene (5.0 g, 18.45 mmol) was dissolved in THF (90.0 mL), 1.7 M solution of tert-BuLi in pentane (11.4 mL, 19.30 mmol) was added dropwise at -78°C and stirred for 1 hour. 4,6-Dichloro-N-methoxy-N-methylisonicotinamide (3.5 g, 14.88 mmol) in THF (10.0 mL) was added slowly and the reaction mixture was stirred at 0 °C for 2 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH 2 Cl 2 = 1:10) to obtain (4,6-dichloropyridin-2-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone (2.4 g, 44%) as a yellow solid. LC/MS ESI (+): 366 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H) ), 7.59 (s, 1H), 7.01 (s, 1H), 3.89 (s, 3H) (c) Synthesis of 2,4-dichloro-6-(dichloro(3-methoxy-5- (trifluoromethoxy)phenyl)methyl)pyridine

[0170]O procedimento de síntese do Exemplo 1-c foi repetido, exceto para o uso de (4,6-dicloropiridin-2-il)(3-metóxi-5-(trifluorometóxi)fenil)metanona (2,4 g, 6,55 mmols) como um material de partida para obter 2,4-dicloro-6-(dicloro(3-metóxi-5- (trifluorometóxi)fenil)metil)piridina (2,1 g, 76 %). LC/MS ESI (+): 420 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,76 (s, 1H), 7,37 (s, 1H), 7,13 (s, 1H), 7,06 (s, 1H), 6,77 (s, 1H), 3,84 (s, 3H) (d) Síntese de 2,4-dicloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2- il)piridina[0170] The synthesis procedure of Example 1-c was repeated, except for the use of (4,6-dichloropyridin-2-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone (2.4 g, 6.55 mmol) as a starting material to obtain 2,4-dichloro-6-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)pyridine (2.1 g, 76%). LC/MS ESI (+): 420 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.37 (s, 1H), 7.13 (s, 1H ), 7.06 (s, 1H), 6.77 (s, 1H), 3.84 (s, 3H) (d) Synthesis of 2,4-dichloro-6-(2-(3-methoxy-5 -(trifluoromethoxy)phenyl)propan-2-yl)pyridine

[0171]O procedimento de síntese do Exemplo 1-d foi repetido, exceto para o uso de 2,4-dicloro-6-(dicloro(3-metóxi-5-(trifluorometóxi)fenil)metil)piridina (2,1 g, 4,98 mmols) como um material de partida para obter 2,4-dicloro-6-(2-(3-metóxi-5- (trifluorometóxi)fenil)propan-2-il)piridina (1,3 g, 69 %) como um óleo branco amarelado. LC/MS ESI (+): 380 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,19 (s, 1H), 6,94 (s, 1H), 6,73 (s, 1H), 6,70 (s, 1H), 6,62 (s, 1H), 3,79 (s, 3H), 1,69 (s, 6H) (e) Síntese de 2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2- il)piridino-4-amina e (f) síntese de 4-cloro-6-(2-(3-metóxi-5- (trifluorometóxi)fenil)propan-2-il)piridino-2-amina[0171] The synthesis procedure of Example 1-d was repeated, except for the use of 2,4-dichloro-6-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)pyridine (2.1 g , 4.98 mmol) as a starting material to obtain 2,4-dichloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine (1.3 g, 69 %) as a yellowish white oil. LC/MS ESI (+): 380 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.19 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H ), 6.70 (s, 1H), 6.62 (s, 1H), 3.79 (s, 3H), 1.69 (s, 6H) (e) Synthesis of 2-chloro-6-(2 -(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-amine and (f) synthesis of 4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl) )propan-2-yl)pyridin-2-amine

[0172]2,4-Dicloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridina (50,0 mg, 0,13 mmol), NaN3 (17,0 mg, 0,26 mmol), Cu2O (18,7 mg, 0,131 mmol) e L- prolina (19,5 mg, 0,17 mmol) foram dissolvidos em DMSO anidro (1,0 mL). A mistura de reação foi agitada a 100 °C durante 12 horas, esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n-Hex:EtOAc = 9:1) para obter 2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridino-4-amina (14,0 mg, 30 %) e 4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridino-2- amina (4,0 mg, 8 %) como um óleo branco amarelado. (f) LC/MS ESI (+): 361 (M+1) RMN de 1H (400 MHz, CDCl3): δ 6,74 (s, 1H), 6,72 (s, 1H), 6,96 (s, 1H), 6,37 (d, 1H, J = 1,2 Hz), 6,14 (d, 1H, J = 1,2 Hz), 4,13 (brs, 2H), 3,76 (s, 3H), 1,64 (s, 6H) LC/MS ESI (+): 361 (M+1) RMN de 1H (400 MHz, CDCl3): δ 6,72 (s, 1H), 6,71 (s, 1H), 6,59 (s, 1H), 6,48 (s, 1H), 6,32 (s, 1H), 4,43 (brs, 2H), 3,77 (s, 3H), 1,62 (s, 6H) (g) Síntese de N-(2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2- il)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0172] 2,4-Dichloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine (50.0 mg, 0.13 mmol), NaN3 (17.0 mg, 0.26 mmol), Cu2O (18.7 mg, 0.131 mmol) and L-proline (19.5 mg, 0.17 mmol) were dissolved in anhydrous DMSO (1.0 mL). The reaction mixture was stirred at 100°C for 12 hours, cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, n-Hex:EtOAc = 9:1) to obtain 2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan- 2-yl)pyridin-4-amine (14.0 mg, 30%) and 4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2- amine (4.0 mg, 8%) as an off-white oil. (f) LC/MS ESI (+): 361 (M+1) 1H NMR (400 MHz, CDCl3): δ 6.74 (s, 1H), 6.72 (s, 1H), 6.96 ( s, 1H), 6.37 (d, 1H, J = 1.2 Hz), 6.14 (d, 1H, J = 1.2 Hz), 4.13 (brs, 2H), 3.76 ( s, 3H), 1.64 (s, 6H) LC/MS ESI (+): 361 (M+1) 1H NMR (400 MHz, CDCl3): δ 6.72 (s, 1H), 6.71 (s, 1H), 6.59 (s, 1H), 6.48 (s, 1H), 6.32 (s, 1H), 4.43 (brs, 2H), 3.77 (s, 3H) , 1.62 (s, 6H) (g) Synthesis of N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl) -5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0173]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridino-4-amina (38,0 mg, 0,11 mmol) como um material de partida para obter N-(2-cloro-6-(2-(3- metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (20,0 mg, 30 %) como um sólido branco. LC/MS ESI (+): 641 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,99 (s, 1H), 8,39 (s, 1H), 8,24 (s, 1H), 8,13 (d, 1H, J = 8,8 Hz), 7,89 (s, 1H), 7,77 (d, 1H, J = 8,8 Hz), 7,56 (s, 1H), 6,84 (s, 1H), 6,83 (s, 1H), 6,77 (s, 1H), 3,79 (s, 3H), 2,75 (s, 3H), 1,86 (s, 6H), 1,68 (s, 6H) (h) Síntese de N-(4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2- il)piridin-2-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0173] The synthesis procedure of Example 1-h was repeated, except for the use of 2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine-4 -amine (38.0 mg, 0.11 mmol) as a starting material to obtain N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl) pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (20.0 mg, 30%) as a white solid. LC/MS ESI (+): 641 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.39 (s, 1H), 8.24 (s , 1H), 8.13 (d, 1H, J = 8.8 Hz), 7.89 (s, 1H), 7.77 (d, 1H, J = 8.8 Hz), 7.56 (s , 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 3.79 (s, 3H), 2.75 (s, 3H), 1 .86 (s, 6H), 1.68 (s, 6H) (h) Synthesis of N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl )pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0174]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridino-2-amina (20,0 mg, 0,06 mmol) como um material de partida para obter N-(4-cloro-6-(2-(3- metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (12,0 mg, 34 %) como um sólido branco. LC/MS ESI (+): 641 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 11,16 (s, 1H), 8,64 (s, 1H), 8,19 (s, 1H), 8,11 (d, 1H, J = 8,8 Hz), 8,09 (d, 1H, J = 2,0 Hz), 7,77 (dd, 1H, J = 8,8, 2,0 Hz), 7,20 (s, 1H), 6,86 (s, 1H), 6,79 - 6,81 (m, 2H), 3,78 (s, 3H), 2,76 (s, 3H), 1,86 (s, 6H), 1,74 (s, 6H) Exemplo 92) Síntese de N-(3-cloro-5-((2,2,6,6-tetrametilpiperidin-4- il)óxi)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 4-(3-bromo-5-clorofenóxi)-2,2,6,6-tetrametilpiperidina[0174] The synthesis procedure of Example 1-h was repeated, except for the use of 4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine-2 -amine (20.0 mg, 0.06 mmol) as a starting material to obtain N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl) pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (12.0 mg, 34%) as a white solid. LC/MS ESI (+): 641 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 8.64 (s, 1H), 8.19 (s , 1H), 8.11 (d, 1H, J = 8.8 Hz), 8.09 (d, 1H, J = 2.0 Hz), 7.77 (dd, 1H, J = 8.8, 2.0 Hz), 7.20 (s, 1H), 6.86 (s, 1H), 6.79 - 6.81 (m, 2H), 3.78 (s, 3H), 2.76 ( s, 3H), 1.86 (s, 6H), 1.74 (s, 6H) Example 92) Synthesis of N-(3-chloro-5-((2,2,6,6-tetramethylpiperidin-4- yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 4-(3-bromo-5-chlorophenoxy)-2,2 ,6,6-tetramethylpiperidine

[0175]1-Bromo-3-cloro-5-nitrobenzeno (200,0 mg, 0,42 mmol) foi dissolvido em DMF anidra (2,1 mL) e 2,2,6,6-tetrametilpiperidin-4-ol (66,0 mg, 0,42 mmol) e NaH 60 % em peso (50,4 mg, 1,26 mmol) foram adicionados. A mistura de reação foi agitada na temperatura ambiente durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 4-(3-bromo-5- clorofenóxi)-2,2,6,6-tetrametilpiperidina (160,0 mg, 54 %) como um óleo branco amarelado. LC/MS ESI (+): 346 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,09 (s, 1H), 6,93 (s, 1H), 6,81 (s, 1H), 4,60 (m, 1H), 2,02 - 2,06 (m, 2H), 1,20 - 1,30 (m, 14H) (b) Síntese de 3-cloro-5-((2,2,6,6-tetrametilpiperidin-4-il)óxi)anilina[0175] 1-Bromo-3-chloro-5-nitrobenzene (200.0 mg, 0.42 mmol) was dissolved in anhydrous DMF (2.1 mL) and 2,2,6,6-tetramethylpiperidin-4-ol (66.0 mg, 0.42 mmol) and 60 wt% NaH (50.4 mg, 1.26 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 4-(3-bromo-5-chlorophenoxy)-2,2,6,6-tetramethylpiperidine (160, 0 mg, 54%) as an off-white oil. LC/MS ESI (+): 346 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.09 (s, 1H), 6.93 (s, 1H), 6.81 (s, 1H ), 4.60 (m, 1H), 2.02 - 2.06 (m, 2H), 1.20 - 1.30 (m, 14H) (b) Synthesis of 3-chloro-5-((2 ,2,6,6-tetramethylpiperidin-4-yl)oxy)aniline

[0176]O procedimento de síntese do Exemplo 91-e foi repetido, exceto para o uso de 4-(3-bromo-5-clorofenóxi)-2,2,6,6-tetrametilpiperidina (34,0 mg, 0,10 mmol) como um material de partida para obter 3-cloro-5-((2,2,6,6-tetrametilpiperidin-4- il)óxi)anilina (16,0 mg, 58 %).LC/MS ESI (+): 283 (M+1) RMN de 1H (400 MHz, CDCl3): δ 6,31 (s, 1H), 6,29 (s, 1H), 6,10 (s, 1H), 4,58 (m, 1H), 3,70 (brs, 2H), 2,03 - 2,05 (m, 2H), 1,18 - 1,23 (m, 14H) (c) Síntese de N-(3-cloro-5-((2,2,6,6-tetrametilpiperidin-4-il)óxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0176] The synthesis procedure of Example 91-e was repeated, except for the use of 4-(3-bromo-5-chlorophenoxy)-2,2,6,6-tetramethylpiperidine (34.0 mg, 0.10 mmol) as a starting material to obtain 3-chloro-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)aniline (16.0 mg, 58%).LC/MS ESI (+ ): 283 (M+1) 1H NMR (400 MHz, CDCl3): δ 6.31 (s, 1H), 6.29 (s, 1H), 6.10 (s, 1H), 4.58 ( m, 1H), 3.70 (brs, 2H), 2.03 - 2.05 (m, 2H), 1.18 - 1.23 (m, 14H) (c) Synthesis of N-(3-chloro -5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0177]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 3-cloro-5-((2,2,6,6-tetrametilpiperidin-4-il)óxi)anilina (16,0 mg, 0,06 mmol) como um material de partida para obter N-(3-cloro-5-((2,2,6,6-tetrametilpiperidin-4- il)óxi)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (9,0 mg, 28 %) como um sólido branco. LC/MS ESI (+): 563 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,53 (s, 1H), 8,28 (s, 1H), 8,16 (s, 1H), 8,03 (d, 1H, J = 8,8 Hz), 7,68 (dd, 1H, J = 8,8, 2,0 Hz), 7,41 (s, 1H), 7,33 (s, 1H), 6,73 (s, 1H), 4,66 - 4,71 (m, 1H), 1,88 (dd, 2H, J = 12,4, 4,0 Hz), 1,79 (s, 6H), 1,14 (s, 6H), 1,07 - 1,10 (m, 2H), 1,02 (s, 6H) Exemplo 93) Síntese de (2-(3-(4-clorofenóxi)-5-(5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamido)fenóxi)etil)carbamato de terc-butila (a) Síntese de 1-(4-clorofenóxi)-3-metóxi-5-nitrobenzeno[0177] The synthesis procedure of Example 1-h was repeated, except for the use of 3-chloro-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)aniline (16.0 mg , 0.06 mmol) as a starting material to obtain N-(3-chloro-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)phenyl)-5-(2-(methylsulfonyl )propan-2-yl)benzo[b]thiophene-2-carboxamide (9.0 mg, 28%) as a white solid. LC/MS ESI (+): 563 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.28 (s, 1H), 8.16 (s , 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.68 (dd, 1H, J = 8.8, 2.0 Hz), 7.41 (s, 1H), 7 .33 (s, 1H), 6.73 (s, 1H), 4.66 - 4.71 (m, 1H), 1.88 (dd, 2H, J = 12.4, 4.0 Hz), 1.79 (s, 6H), 1.14 (s, 6H), 1.07 - 1.10 (m, 2H), 1.02 (s, 6H) Example 93) Synthesis of (2-(3- tert-Butyl (4-chlorophenoxy)-5-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)phenoxy)ethyl)carbamate (a) Synthesis of 1-( 4-chlorophenoxy)-3-methoxy-5-nitrobenzene

[0178]O procedimento de síntese do Exemplo 40-a foi repetido, exceto para o uso de 1-bromo-3-metóxi-5-nitrobenzeno (500,0 mg 1,71 mmol) como um material de partida para obter 1-(4-clorofenóxi)-3-metóxi-5-nitrobenzeno (400,0 mg, 66 %).LC/MS ESI (+): 280 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,48 (t, 1H, J = 2,2 Hz), 7,37 (t, 1H, J = 2,1 Hz), 7,36 (d, 2H, J = 8,8 Hz), 7,00 (d, 2H, J = 8,9 Hz), 6,83 (t, 1H, J = 2,1 Hz), 3,87 (s, 3H) (b) Síntese de 3-(4-clorofenóxi)-5-nitrofenol[0178] The synthesis procedure of Example 40-a was repeated, except for the use of 1-bromo-3-methoxy-5-nitrobenzene (500.0 mg 1.71 mmol) as a starting material to obtain 1- (4-chlorophenoxy)-3-methoxy-5-nitrobenzene (400.0 mg, 66%). LC/MS ESI (+): 280 (M+1) 1H NMR (400 MHz, CDCl3): δ 7, 48 (t, 1H, J = 2.2 Hz), 7.37 (t, 1H, J = 2.1 Hz), 7.36 (d, 2H, J = 8.8 Hz), 7.00 ( d, 2H, J = 8.9 Hz), 6.83 (t, 1H, J = 2.1 Hz), 3.87 (s, 3H) (b) Synthesis of 3-(4-chlorophenoxy)-5 -nitrophenol

[0179]O procedimento de síntese do Exemplo 1-e foi repetido, exceto para o uso de 1-(4-clorofenóxi)-3-metóxi-5-nitrobenzeno (396,0 mg, 1,42 mmol) como um material de partida para obter 3-(4-clorofenóxi)-5-nitrofenol (307,0 mg, 82 %).LC/MS ESI (+): 266 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,39 (t, 1H, J = 2,2 Hz), 7,35 (d, 2H, J = 8,9 Hz), 7,33 (t, 1H, J = 2,1 Hz), 6,98 (d, 2H, J = 8,9 Hz), 6,74 (t, 1H, J = 2,2 Hz) (c) Síntese de (2-(3-(4-clorofenóxi)-5-nitrofenóxi)etil)carbamato de terc-butila[0179] The synthesis procedure of Example 1-e was repeated, except for the use of 1-(4-chlorophenoxy)-3-methoxy-5-nitrobenzene (396.0 mg, 1.42 mmol) as a starting material Starting to give 3-(4-chlorophenoxy)-5-nitrophenol (307.0 mg, 82%). LC/MS ESI (+): 266 (M+1) 1H NMR (400 MHz, CDCl3): δ 7 .39 (t, 1H, J = 2.2 Hz), 7.35 (d, 2H, J = 8.9 Hz), 7.33 (t, 1H, J = 2.1 Hz), 6.98 (d, 2H, J = 8.9 Hz), 6.74 (t, 1H, J = 2.2 Hz) (c) Synthesis of (2-(3-(4-chlorophenoxy)-5-nitrophenoxy)ethyl ) tert-butyl carbamate

[0180]3-(4-Clorofenóxi)-5-nitrofenol (297,0 mg, 1,11 mmol) foi dissolvido em DMF anidra (10,0 mL), K2CO3 (231,0 mg, 1,68 mmol) foi adicionado, agitado na temperatura ambiente durante 10 minutos e (2-bromoetil)carbamato de terc-butila (300,0 mg, 1,34 mmol) foi adicionado. A mistura de reação foi agitada na temperatura ambiente durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 6:1) para obter (2-(3-(4-clorofenóxi)-5- nitrofenóxi)etil)carbamato de terc-butila (435,0 mg, 95 %). LC/MS ESI (+): 409 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,44 (t, 1H, J = 2,1 Hz), 7,37 (t, 1H, J = 2,1 Hz), 7,36 (d, 2H, J = 8,9 Hz), 6,98 (d, 2H, J = 8,9 Hz), 6,79 (t, 1H, J = 2,2 Hz), 4,90 (brs, 1H), 4,04 (t, 2H, J = 5,1 Hz), 3,51 - 3,55 (m, 2H), 1,43 (s, 9H) (d) Síntese de (2-(3-amino-5-(4-clorofenóxi)fenóxi)etil)carbamato de terc- butila[0180]3-(4-Chlorophenoxy)-5-nitrophenol (297.0 mg, 1.11 mmol) was dissolved in anhydrous DMF (10.0 mL), K2CO3 (231.0 mg, 1.68 mmol) was added, stirred at room temperature for 10 minutes and tert-butyl (2-bromoethyl)carbamate (300.0 mg, 1.34 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 6:1) to obtain tert-butyl (2-(3-(4-chlorophenoxy)-5-nitrophenoxy)ethyl)carbamate ( 435.0 mg, 95%). LC/MS ESI (+): 409 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.44 (t, 1H, J = 2.1 Hz), 7.37 (t, 1H, J = 2.1 Hz), 7.36 (d, 2H, J = 8.9 Hz), 6.98 (d, 2H, J = 8.9 Hz), 6.79 (t, 1H, J = 2 .2 Hz), 4.90 (brs, 1H), 4.04 (t, 2H, J = 5.1 Hz), 3.51 - 3.55 (m, 2H), 1.43 (s, 9H ) (d) Synthesis of tert-butyl (2-(3-amino-5-(4-chlorophenoxy)phenoxy)ethyl)carbamate

[0181]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de (2-(3-(4-clorofenóxi)-5-nitrofenóxi)etil)carbamato de terc-butila (425,0 mg, 1,04 mmol) como um material de partida para obter (2-(3-amino-5-(4- clorofenóxi)fenóxi)etil)carbamato de terc-butila (360,0 mg, 92 %). LC/MS ESI (+): 379 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,28 (d, 2H, J = 8,9 Hz), 6,96 (d, 2H, J = 8,9 Hz), 5,98 (t, 1H, J = 2,0 Hz), 5,91 - 5,94 (m, 2H), 3,92 (t, 2H, J = 5,0 Hz), 3,73 (brs, 2H), 3,46 - 3,50 (m, 2H), 1,44 (s, 9H) (e) Síntese de (2-(3-(4-clorofenóxi)-5-(5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamido)fenóxi)etil)carbamato de terc-butila[0181] The synthesis procedure of Example 1-g was repeated, except for the use of tert-butyl (2-(3-(4-chlorophenoxy)-5-nitrophenoxy)ethyl)carbamate (425.0 mg, 1 .04 mmol) as a starting material to obtain tert-butyl (2-(3-amino-5-(4-chlorophenoxy)phenoxy)ethyl)carbamate (360.0 mg, 92%). LC/MS ESI (+): 379 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.28 (d, 2H, J = 8.9 Hz), 6.96 (d, 2H, J = 8.9 Hz), 5.98 (t, 1H, J = 2.0 Hz), 5.91 - 5.94 (m, 2H), 3.92 (t, 2H, J = 5.0 Hz ), 3.73 (brs, 2H), 3.46 - 3.50 (m, 2H), 1.44 (s, 9H) (e) Synthesis of (2-(3-(4-chlorophenoxy)-5 tert-butyl-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)phenoxy)ethyl)carbamate

[0182]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de (2-(3-amino-5-(4-clorofenóxi)fenóxi)etil)carbamato de terc-butila (211,0 mg, 0,56 mmol) como um material de partida para obter (2-(3-(4-clorofenóxi)-5-(5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamido)fenóxi)etil)carbamato de terc-butila (360,0 mg, 98 %) como um sólido branco. LC/MS ESI (+): 682 (M+Na) RMN de 1H (400 MHz, DMSO-d6): δ 10,53 (brs, 1H), 8,33 (s, 1H), 8,19 (s, 1H), 8,08 (d, 1H, J = 8,7 Hz), 7,73 (d, 1H, J = 8,7 Hz), 7,47 (d, 2H, J = 8,7 Hz), 7,29 (s, 1H), 7,12 (d, 2H, J = 8,9 Hz), 7,02 - 7,04 (m, 2H), 6,44 (s, 1H), 3,94 - 3,97 (m, 2H), 3,28 - 3,32 (m, 2H), 2,73 (s, 3H), 1,85 (s, 6H), 1,38 (s, 9H) Exemplo 94) Síntese de N-(3-(2-aminoetóxi)-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0182] The synthesis procedure of Example 1-h was repeated, except for the use of tert-butyl (2-(3-amino-5-(4-chlorophenoxy)phenoxy)ethyl)carbamate (211.0 mg, 0.56 mmol) as a starting material to obtain (2-(3-(4-chlorophenoxy)-5-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido tert-butyl)phenoxy)ethyl)carbamate (360.0 mg, 98%) as a white solid. LC/MS ESI (+): 682 (M+Na) 1H NMR (400 MHz, DMSO-d6): δ 10.53 (brs, 1H), 8.33 (s, 1H), 8.19 (s , 1H), 8.08 (d, 1H, J = 8.7 Hz), 7.73 (d, 1H, J = 8.7 Hz), 7.47 (d, 2H, J = 8.7 Hz ), 7.29 (s, 1H), 7.12 (d, 2H, J = 8.9 Hz), 7.02 - 7.04 (m, 2H), 6.44 (s, 1H), 3 .94 - 3.97 (m, 2H), 3.28 - 3.32 (m, 2H), 2.73 (s, 3H), 1.85 (s, 6H), 1.38 (s, 9H ) Example 94) Synthesis of N-(3-(2-aminoethoxy)-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0183](2-(3-(4-Clorofenóxi)-5-(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamido)fenóxi)etil)carbamato de terc-butila (187,0 mg, 0,28 mmol) foram dissolvidos em CH2Cl2 anidro (3,0 mL) e TFA (220,0 μL, 2,84 mmol) foi adicionado a 0 °C. A mistura de reação foi agitada na temperatura ambiente durante 5 horas, NaHCO3 sat. foi adicionado e extraído com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, CH2Cl2:MeOH = 20:1) para obter N-(3-(2-aminoetóxi)-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (81,0 mg, 51 %) como um sólido branco. LC/MS ESI (+): 559 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,54 (brs, 1H), 8,35 (s, 1H), 8,20 (s, 1H), 8,09 (d, 1H, J = 8,7 Hz), 7,74 (d, 1H, J = 8,7 Hz), 7,50 (d, 2H, J = 8,7 Hz), 7,32 (s, 1H), 7,12 (d, 2H, J = 8,9 Hz), 7,04 (s, 1H), 6,42 (s, 1H), 3,90 - 3,94(t, 2H, J = 5,6 Hz), 2,87 - 2,90 (t, 2H, J = 5,6 Hz), 2,51 (s, 3H), 2,00 (brs, 2H), 1,85 (s, 6H) Exemplo 95) Síntese de N-(5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-il)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida (a) Síntese de 3’-cloro-2,4-difluoro-5’-nitro-1,1’-bifenilatert-(2-(3-(4-Chlorophenoxy)-5-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)phenoxy)ethyl)carbamate butyl (187.0 mg, 0.28 mmol) was dissolved in anhydrous CH2Cl2 (3.0 mL) and TFA (220.0 µL, 2.84 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 hours, sat. was added and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, CH 2 Cl 2 :MeOH = 20:1) to obtain N-(3-(2-aminoethoxy)-5-(4-chlorophenoxy)phenyl)-5-(2 - (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (81.0 mg, 51%) as a white solid. LC/MS ESI (+): 559 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.54 (brs, 1H), 8.35 (s, 1H), 8.20 (s , 1H), 8.09 (d, 1H, J = 8.7 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.50 (d, 2H, J = 8.7 Hz ), 7.32 (s, 1H), 7.12 (d, 2H, J = 8.9 Hz), 7.04 (s, 1H), 6.42 (s, 1H), 3.90 - 3 .94(t, 2H, J = 5.6 Hz), 2.87 - 2.90 (t, 2H, J = 5.6 Hz), 2.51 (s, 3H), 2.00 (brs, 2H), 1.85 (s, 6H) Example 95) Synthesis of N-(5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-yl)-5-((methylsulfonyl )methyl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3'-chloro-2,4-difluoro-5'-nitro-1,1'-biphenyl

[0184]1-Bromo-3-cloro-5-nitrobenzeno (1,0 g, 4,23 mmols), ácido (2,4- difluorofenil)borônico (0,7 g, 4,23 mmols), Pd(PPh3)4 (490,0 mg, 0,42 mmol) e Na2CO3 (1,4 g, 12,70 mmol) foram adicionados a uma mistura de DME/H2O (42,0 mL, 4/1 v/v). A mistura de reação foi agitada a 90 °C durante 3 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter 3’-cloro-2,4-difluoro-5’-nitro-1,1’-bifenila (1,1 g, 96 %) como um sólido branco.RMN de 1H (400 MHz, CDCl3): δ 8,27 (s, 1H), 8,23 (s, 1H), 7,83 (s, 1H), 7,26 - 7,46 (m, 1H), 6,98 - 7,03 (m, 2H) (b) Síntese de 5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-amina[0184] 1-Bromo-3-chloro-5-nitrobenzene (1.0 g, 4.23 mmol), (2,4-difluorophenyl)boronic acid (0.7 g, 4.23 mmol), Pd(PPh3 )4 (490.0 mg, 0.42 mmol) and Na2CO3 (1.4 g, 12.70 mmol) were added to a mixture of DME/H2O (42.0 mL, 4/1 v/v). The reaction mixture was stirred at 90°C for 3 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain 3'-chloro-2,4-difluoro-5'-nitro-1,1'-biphenyl (1 .1 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 7.26 - 7.46 (m, 1H), 6.98 - 7.03 (m, 2H) (b) Synthesis of 5-chloro-2',4'-difluoro-[1,1'-biphenyl] -3-amine

[0185]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de 3’-cloro-2,4-difluoro-5’-nitro-1,1’-bifenila (1,1 g, 4,08 mmols) como um material de partida para obter 5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-amina (830,0 mg, 85 %).RMN de 1H (400 MHz, CDCl3): δ 7,33 - 7,37 (m, 1H), 6,85 - 6,93 (m, 3H), 6,68 (m, 2H), 3,81 (brs, 2H) (c) Síntese de N-(5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-il)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida[0185] The synthesis procedure of Example 1-g was repeated, except for the use of 3'-chloro-2,4-difluoro-5'-nitro-1,1'-biphenyl (1.1 g, 4, 08 mmol) as a starting material to obtain 5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-amine (830.0 mg, 85%). 1H NMR (400 MHz , CDCl3): δ 7.33 - 7.37 (m, 1H), 6.85 - 6.93 (m, 3H), 6.68 (m, 2H), 3.81 (brs, 2H) (c ) Synthesis of N-(5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-yl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide

[0186]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-amina (40,0 mg, 0,17 mmol) como um material de partida para obter N-(5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-il)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida (30,8 mg, 41 %). LC/MS ESI (+): 492 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,76 (s, 1H), 8,40 (s, 1H), 8,11 (d, 1H, J = 8,4 Hz), 8,06 (s, 1H), 8,00 (m, 1H), 7,91 (m, 1H), 7,66 (m, 1H), 7,54 (d, 1H, J = 8,4 Hz), 7,43 (m, 1H), 7,37 (m, 1H), 7,25 (m, 1H), 4,65 (s, 2H), 2,94 (s, 3H) Exemplo 96) Síntese de (8-cloro-6-(4-clorofenóxi)-2,3-di-hidro-4H-benzo[b][1,4]oxazin-4-il)(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofen-2-il)metanona (a) Síntese de 6-bromo-8-cloro-3,4-di-hidro-2H-benzo[b][1,4]oxazina[0186] The synthesis procedure of Example 1-h was repeated, except for the use of 5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-amine (40.0 mg, 0.17 mmol) as a starting material to obtain N-(5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-yl)-5-((methylsulfonyl)methyl)benzoic [b]thiophene-2-carboxamide (30.8 mg, 41%). LC/MS ESI (+): 492 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.40 (s, 1H), 8.11 (d , 1H, J = 8.4 Hz), 8.06 (s, 1H), 8.00 (m, 1H), 7.91 (m, 1H), 7.66 (m, 1H), 7.54 (d, 1H, J = 8.4 Hz), 7.43 (m, 1H), 7.37 (m, 1H), 7.25 (m, 1H), 4.65 (s, 2H), 2 .94 (s, 3H) Example 96) Synthesis of (8-chloro-6-(4-chlorophenoxy)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) (5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophen-2-yl)methanone (a) Synthesis of 6-bromo-8-chloro-3,4-dihydro-2H-benzoyl [b][1,4]oxazine

[0187]2-Amino-4-bromo-6-clorofenol (100,0 mg, 0,45 mmol), dibromoetano (0,1 mL, 1,12 mmol) e K2CO3 (186,0 mg, 1,35 mmol) foram dissolvidos em DMF anidra (1,5 mL). A mistura de reação foi agitada a 125 °C durante 15 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 3:1) para obter 6- bromo-8-cloro-3,4-di-hidro-2H-benzo[b][1,4]oxazina (70,0 mg, 63 %) como um sólido branco. LC/MS ESI (+): 248 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 6,84 (s, 1H), 6,61 (s, 1H), 4,31 - 4,33 (m, 2H), 3,42 - 3,45 (m, 2H), 3,97 (brs, 1H) (b) Síntese de 8-cloro-6-(4-clorofenóxi)-3,4-di-hidro-2H-benzo[b][1,4]oxazina[0187] 2-Amino-4-bromo-6-chlorophenol (100.0 mg, 0.45 mmol), dibromoethane (0.1 mL, 1.12 mmol) and K2CO3 (186.0 mg, 1.35 mmol ) were dissolved in anhydrous DMF (1.5 ml). The reaction mixture was stirred at 125°C for 15 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 3:1) to obtain 6-bromo-8-chloro-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (70.0 mg, 63%) as a white solid. LC/MS ESI (+): 248 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 6.84 (s, 1H), 6.61 (s, 1H), 4.31 - 4 .33 (m, 2H), 3.42 - 3.45 (m, 2H), 3.97 (brs, 1H) (b) Synthesis of 8-chloro-6-(4-chlorophenoxy)-3,4- dihydro-2H-benzo[b][1,4]oxazine

[0188]6-Bromo-8-cloro-3,4-di-hidro-2H-benzo[b][1,4]oxazina (60,0 mg, 0,24 mmol), 4-clorofenol (62 mg, 0,48 mmol), CuI (23,0 mg, 0,12 mmol), N,N-dimetilglicina (24,9 mg, 0,24 mmol) e Cs2CO3 (236,0 mg, 0,72 mmol) foram adicionados ao 1,4- dioxano anidro (2,4 mL). A mistura de reação foi agitada a 120 °C durante 15 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, n- Hex:EtOAc = 9:1) para obter 8-cloro-6-(4-clorofenóxi)-3,4-di-hidro-2H- benzo[b][1,4]oxazina (42,0 mg, 42 %). LC/MS ESI (+): 296 (M+1) (c) Síntese de (8-cloro-6-(4-clorofenóxi)-2,3-di-hidro-4H-benzo[b][1,4]oxazin- 4-il)(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofen-2-il)metanona[0188]6-Bromo-8-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazine (60.0 mg, 0.24 mmol), 4-chlorophenol (62 mg, 0.48 mmol), CuI (23.0 mg, 0.12 mmol), N,N-dimethylglycine (24.9 mg, 0.24 mmol) and Cs2CO3 (236.0 mg, 0.72 mmol) were added to anhydrous 1,4-dioxane (2.4 mL). The reaction mixture was stirred at 120°C for 15 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel amine, n-Hex:EtOAc = 9:1) to obtain 8-chloro-6-(4-chlorophenoxy)-3,4-dihydro-2H-benzoyl [b][1,4]oxazine (42.0 mg, 42%). LC/MS ESI (+): 296 (M+1) (c) Synthesis of (8-chloro-6-(4-chlorophenoxy)-2,3-dihydro-4H-benzo[b][1,4 ]oxazin-4-yl)(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophen-2-yl)methanone

[0189]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 8-cloro-6-(4-clorofenóxi)-3,4-di-hidro-2H-benzo[b][1,4]oxazina (20,0 mg, 0,07 mmol) como um material de partida para obter (8-cloro-6-(4-clorofenóxi)-2,3-di-hidro- 4H-benzo[b][1,4]oxazin-4-il)(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofen-2- il)metanona (13,0 mg, 33 %) como um sólido branco. LC/MS ESI (+): 576 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 8,20 (s, 1H), 8,07 (d, 1H, J = 8,6 Hz), 7,88 (s, 1H), 7,75 (d, 1H, J = 8,7 Hz), 7,02 - 7,09 (m, 4H), 6,79 (d, 2H, J = 8,3 Hz), 4,46 - 4,51 (m, 2H), 4,10 - 4,16 (m, 2H), 2,74 (s, 3H), 1,84 (s, 6H) Exemplo 97) Síntese de N-(3-cloro-5-(1-(4-clorofenil)ciclopropil)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de (3-cloro-5-nitrofenil)(4-clorofenil)metanona[0189] The synthesis procedure of Example 1-h was repeated, except for the use of 8-chloro-6-(4-chlorophenoxy)-3,4-dihydro-2H-benzo[b][1,4 ]oxazine (20.0 mg, 0.07 mmol) as a starting material to obtain (8-chloro-6-(4-chlorophenoxy)-2,3-dihydro-4H-benzo[b][1, 4]oxazin-4-yl)(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophen-2-yl)methanone (13.0 mg, 33%) as a white solid. LC/MS ESI (+): 576 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.07 (d, 1H, J = 8.6 Hz ), 7.88 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.02 - 7.09 (m, 4H), 6.79 (d, 2H, J = 8.3 Hz), 4.46 - 4.51 (m, 2H), 4.10 - 4.16 (m, 2H), 2.74 (s, 3H), 1.84 (s, 6H) Example 97) Synthesis of N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ( a) Synthesis of (3-chloro-5-nitrophenyl)(4-chlorophenyl)methanone

[0190]Ácido 3-cloro-5-nitrobenzoico (2,0 g, 9,92 mmols) e DMF (0,1 mL, 0,99 mmol) foram dissolvidos em SOCl2 (3,6 mL, 49,60 mmols). A mistura de reação foi agitada a 80 °C durante 3 horas e concentrada sob pressão reduzida para obter cloreto de 3-cloro-5-nitrobenzoila. O resíduo foi dissolvido em clorobenzeno (20,0 mL), AlCl3 (4,0 g, 29,80 mmols) foi adicionado a 0 °C e agitado a 50 °C durante 5 horas. H2O foi adicionada a 0 °C e a mistura de reação foi extraída com EtOAc. O extrato orgânico foi lavado com solução aquosa de NaHCO3 sat. e salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:DCM = 4:1) para obter (3- cloro-5-nitrofenil)(4-clorofenil)metanona (2,8 g, 96 %) como um sólido amarelo.RMN de 1H (400 MHz, CDCl3): δ 8,46 (m, 1H), 8,44 (m, 1H), 8,08 (m, 1H), 7,75 (d, 2H, J = 8,5 Hz), 7,54 (d, 2H, J = 8,5 Hz) (b) Síntese de 1-cloro-3-(1-(4-clorofenil)vinil)-5-nitrobenzeno[0190] 3-Chloro-5-nitrobenzoic acid (2.0 g, 9.92 mmol) and DMF (0.1 mL, 0.99 mmol) were dissolved in SOCl2 (3.6 mL, 49.60 mmol) . The reaction mixture was stirred at 80°C for 3 hours and concentrated under reduced pressure to obtain 3-chloro-5-nitrobenzoyl chloride. The residue was dissolved in chlorobenzene (20.0 mL), AlCl 3 (4.0 g, 29.80 mmol) was added at 0 °C and stirred at 50 °C for 5 hours. H2O was added at 0 °C and the reaction mixture was extracted with EtOAc. The organic extract was washed with sat. NaHCO 3 aqueous solution. and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:DCM = 4:1) to obtain (3-chloro-5-nitrophenyl)(4-chlorophenyl)methanone (2.8 g, 96%) as a yellow solid.1H NMR (400 MHz, CDCl3): δ 8.46 (m, 1H), 8.44 (m, 1H), 8.08 (m, 1H), 7.75 (d, 2H , J = 8.5 Hz), 7.54 (d, 2H, J = 8.5 Hz) (b) Synthesis of 1-chloro-3-(1-(4-chlorophenyl)vinyl)-5-nitrobenzene

[0191]Bromo(metil)trifenilfosforano (5,3 g, 19,10 mmols) foi dissolvido em THF (25,0 mL), solução 1,6 M de n-BuLi em n-Hex (12,0 mL, 19,10 mmols) foi adicionada às gotas a 0 °C e agitada durante 30 minutos. A mistura de reação foi lentamente adicionada a uma solução de (3-cloro-5-nitrofenil)(4-clorofenil)metanona (2,8 g, 9,56 mmols) em THF (8,0 mL) a 0 °C. A mistura de reação foi agitada na temperatura ambiente durante 12 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:DCM = 4:1) para obter 1-cloro-3-(1-(4-clorofenil)vinil)-5- nitrobenzeno (1,8 g, 65 %) como um sólido colorido. RMN de 1H (400 MHz, CDCl3): δ 8,18 (m, 1H), 8,07 (m, 1H), 7,61 (m, 1H), 7,36 (d, 2H, J = 8,4 Hz), 7,22 (d, 2H, J = 8,4 Hz), 5,63 (s, 1H), 5,60 (s, 1H) (c) Síntese de 1-cloro-3-(2,2-dibromo-1-(4-clorofenil)ciclopropil)-5- nitrobenzeno[0191]Bromo(methyl)triphenylphosphorane (5.3 g, 19.10 mmol) was dissolved in THF (25.0 mL), 1.6 M solution of n-BuLi in n-Hex (12.0 mL, 19 .10 mmol) was added dropwise at 0 °C and stirred for 30 minutes. The reaction mixture was slowly added to a solution of (3-chloro-5-nitrophenyl)(4-chlorophenyl)methanone (2.8 g, 9.56 mmol) in THF (8.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:DCM = 4:1) to obtain 1-chloro-3-(1-(4-chlorophenyl)vinyl)-5-nitrobenzene (1.8 g, 65%) as a colored solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 8.07 (m, 1H), 7.61 (m, 1H), 7.36 (d, 2H, J = 8, 4 Hz), 7.22 (d, 2H, J = 8.4 Hz), 5.63 (s, 1H), 5.60 (s, 1H) (c) Synthesis of 1-chloro-3-(2 ,2-dibromo-1-(4-chlorophenyl)cyclopropyl)-5-nitrobenzene

[0192]1-Cloro-3-(1-(4-clorofenil)vinil)-5-nitrobenzeno (1,8 g, 6,19 mmols), CHBr3 (735,0 μL, 8,42 mmols) e cloreto de benzil trietil amônio (254,0 mg, 1,11 mmol) foram dissolvidos em 1,2-dicloroetano (6,2 mL) e NaOH (9,4 g, 235,0 mmols) em H2O (9,4 mL) foi adicionado. A mistura de reação foi agitada a 40 °C durante 16 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:DCM = 4:1) para obter 1-cloro-3-(2,2-dibromo-1-(4-clorofenil)ciclopropil)-5-nitrobenzeno (2,2 g, 75 %) como um óleo amarelo. RMN de 1H (400 MHz, CDCl3): δ 8,22 (s, 1H), 8,11 (s, 1H), 7,79 (s, 1H), 7,44 (d, 2H, J = 8,4 Hz), 7,35 (d, 2H, J = 8,4 Hz), 2,50 - 2,55 (m, 2H) (d) Síntese de 3-cloro-5-(1-(4-clorofenil)ciclopropil)anilina[0192] 1-Chloro-3-(1-(4-chlorophenyl)vinyl)-5-nitrobenzene (1.8 g, 6.19 mmol), CHBr3 (735.0 μL, 8.42 mmol) and sodium chloride benzyl triethyl ammonium (254.0 mg, 1.11 mmol) was dissolved in 1,2-dichloroethane (6.2 mL) and NaOH (9.4 g, 235.0 mmol) in H2O (9.4 mL) was added. The reaction mixture was stirred at 40°C for 16 hours, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:DCM = 4:1) to obtain 1-chloro-3-(2,2-dibromo-1-(4-chlorophenyl)cyclopropyl)-5 -nitrobenzene (2.2 g, 75%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.44 (d, 2H, J = 8, 4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 2.50 - 2.55 (m, 2H) (d) Synthesis of 3-chloro-5-(1-(4-chlorophenyl) )cyclopropyl)aniline

[0193]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de 1-cloro-3-(2,2-dibromo-1-(4-clorofenil)ciclopropil)-5-nitrobenzeno (2,2 g, 4,61 mmols) como um material de partida para obter 3-cloro-5-(1-(4- clorofenil)ciclopropil)anilina (1,2 g, 95 %) como um óleo amarelo. LC/MS ESI (+): 278 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,24 (d, 2H, J = 8,4 Hz), 7,15 (d, 2H, J = 8,4 Hz), 6,56 (s, 1H), 6,50 (s, 1H), 6,35 (s, 1H), 3,66 (brs, 2H), 1,20 - 1,28 (m, 4H) (e) Síntese de N-(3-cloro-5-(1-(4-clorofenil)ciclopropil)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0193] The synthesis procedure of Example 1-g was repeated, except for the use of 1-chloro-3-(2,2-dibromo-1-(4-chlorophenyl)cyclopropyl)-5-nitrobenzene (2,2 g, 4.61 mmol) as a starting material to obtain 3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)aniline (1.2 g, 95%) as a yellow oil. LC/MS ESI (+): 278 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.24 (d, 2H, J = 8.4 Hz), 7.15 (d, 2H, J = 8.4 Hz), 6.56 (s, 1H), 6.50 (s, 1H), 6.35 (s, 1H), 3.66 (brs, 2H), 1.20 - 1.28 (m, 4H) (e) Synthesis of N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide

[0194]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 3-cloro-5-(1-(4-clorofenil)ciclopropil)anilina (46,7 mg, 0,17 mmol) como um material de partida para obter N-(3-cloro-5-(1-(4-clorofenil)ciclopropil)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (44,1 mg, 47 %).LC/MS ESI (+): 558 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,64 (s, 1H), 8,34 (s, 1H), 8,20 (s, 1H), 8,10 (d, 1H, J = 8,7 Hz), 7,84 (m, 1H), 7,74 (dd, 1H, J = 8,7, 1,8 Hz), 7,54 (m, 1H), 7,38 (d, 2H, J = 8,6 Hz), 7,29 (d, 2H, J = 8,6 Hz), 7,02 (m, 1H), 2,73 (s, 3H), 1,85 (s, 6H), 1,30 - 1,32 (m, 4H) Exemplo 98) Síntese de N-(3-cloro-5-((2,4-difluorofenil)(metil)amino)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de N-(3-cloro-5-nitrofenil)-2,4-difluoroanilina[0194] The synthesis procedure of Example 1-h was repeated, except for the use of 3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)aniline (46.7 mg, 0.17 mmol) as a starting material to obtain N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (44.1 mg, 47%).LC/MS ESI (+): 558 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.34 ( s, 1H), 8.20 (s, 1H), 8.10 (d, 1H, J = 8.7 Hz), 7.84 (m, 1H), 7.74 (dd, 1H, J = 8 .7, 1.8 Hz), 7.54 (m, 1H), 7.38 (d, 2H, J = 8.6 Hz), 7.29 (d, 2H, J = 8.6 Hz), 7.02 (m, 1H), 2.73 (s, 3H), 1.85 (s, 6H), 1.30 - 1.32 (m, 4H) Example 98) Synthesis of N-(3-chloro -5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of N-( 3-chloro-5-nitrophenyl)-2,4-difluoroaniline

[0195]1-Bromo-3-cloro-5-nitrobenzeno (100,0 mg, 0,42 mmol), 2,4- difluoroanilina (35,6 μL, 0,35 mmol), Pd2(dba)3-CHCl3 (18,3 mg, 0,02 mmol), BINAP (21,9 mg, 0,04 mmol) e NaOt-Bu (47,5 mg, 0,49 mmol) foram adicionados ao tolueno anidro (3,5 mL). A mistura de reação foi reagida a 110 °C durante 30 minutos em um micro-ondas em 150 W. A mistura de reação foi esfriada até a temperatura ambiente, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n- Hex:EtOAc = 9:1) para obter N-(3-cloro-5-nitrofenil)-2,4-difluoroanilina (76,6 mg, 76 %) como um sólido amarelo. LC/MS ESI (+): 285 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,68 (s, 1H), 7,58 (s, 1H), 7,31 (m, 1H), 7,11 (s, 1H), 6,91 - 7,00 (m, 2H), 5,79 (s, 1H) (b) Síntese de N-(3-cloro-5-nitrofenil)-2,4-difluoro-N-metilanilina[0195] 1-Bromo-3-chloro-5-nitrobenzene (100.0 mg, 0.42 mmol), 2,4-difluoroaniline (35.6 μL, 0.35 mmol), Pd2(dba)3-CHCl3 (18.3 mg, 0.02 mmol), BINAP (21.9 mg, 0.04 mmol) and NaOt-Bu (47.5 mg, 0.49 mmol) were added to anhydrous toluene (3.5 mL) . The reaction mixture was reacted at 110 °C for 30 minutes in a microwave at 150 W. The reaction mixture was cooled to room temperature, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain N-(3-chloro-5-nitrophenyl)-2,4-difluoroaniline (76.6 mg, 76 %) as a yellow solid. LC/MS ESI (+): 285 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.58 (s, 1H), 7.31 (m, 1H ), 7.11 (s, 1H), 6.91 - 7.00 (m, 2H), 5.79 (s, 1H) (b) Synthesis of N-(3-chloro-5-nitrophenyl)-2 ,4-difluoro-N-methylaniline

[0196]N-(3-cloro-5-nitrofenil)-2,4-difluoroanilina (167,1 mg, 0,59 mmol) foi dissolvida em DMF (6,0 mL) e NaH 60 % em peso (35,2 mg, 0,88 mmol) e CH3I (73,1 μL, 1,17 mmol) foram adicionados a 0 °C. A mistura de reação foi agitada na temperatura ambiente durante 1 hora, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 9:1) para obter N-(3-cloro-5-nitrofenil)-2,4- difluoro-N-metilanilina (172,4 mg, 98 %) como um sólido amarelo. RMN de 1H (400 MHz, CDCl3): δ 7,58 (s, 1H), 7,34 (s, 1H), 7,27 (m, 1H), 6,97 - 7,02 (m, 2H), 6,82 (s, 1H), 3,31 (s, 3H) (c) Síntese de 5-cloro-N1-(2,4-difluorofenil)-N1-metilbenzeno-1,3-diamina[0196]N-(3-chloro-5-nitrophenyl)-2,4-difluoroaniline (167.1 mg, 0.59 mmol) was dissolved in DMF (6.0 mL) and 60 wt% NaH (35, 2 mg, 0.88 mmol) and CH3I (73.1 µL, 1.17 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, H2O was added and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 9:1) to obtain N-(3-chloro-5-nitrophenyl)-2,4-difluoro-N-methylaniline (172. 4 mg, 98%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 7.34 (s, 1H), 7.27 (m, 1H), 6.97 - 7.02 (m, 2H) , 6.82 (s, 1H), 3.31 (s, 3H) (c) Synthesis of 5-chloro-N1-(2,4-difluorophenyl)-N1-methylbenzene-1,3-diamine

[0197]O procedimento de síntese do Exemplo 1-g foi repetido, exceto para o uso de N-(3-cloro-5-nitrofenil)-2,4-difluoro-N-metilanilina (172,4 mg, 0,58 mmol) como um material de partida para obter 5-cloro-N1-(2,4-difluorofenil)-N1- metilbenzeno-1,3-diamina (148,4 mg, 96 %) como um óleo vermelho. RMN de 1H (400 MHz, CDCl3): δ 7,22 (m, 1H), 6,87 - 6,94 (m, 2H), 6,14 (s, 1H), 6,06 (s, 1H), 5,79 (s, 1H), 3,60 (brs, 2H), 3,18 (s, 3H) (d) Síntese de N-(3-cloro-5-((2,4-difluorofenil)(metil)amino)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0197] The synthesis procedure of Example 1-g was repeated, except for the use of N-(3-chloro-5-nitrophenyl)-2,4-difluoro-N-methylaniline (172.4 mg, 0.58 mmol) as a starting material to obtain 5-chloro-N1-(2,4-difluorophenyl)-N1-methylbenzene-1,3-diamine (148.4 mg, 96%) as a red oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (m, 1H), 6.87 - 6.94 (m, 2H), 6.14 (s, 1H), 6.06 (s, 1H) , 5.79 (s, 1H), 3.60 (brs, 2H), 3.18 (s, 3H) (d) Synthesis of N-(3-chloro-5-((2,4-difluorophenyl)( methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0198]O procedimento de síntese do Exemplo 1-h foi repetido, exceto para o uso de 5-cloro-N1-(2,4-difluorofenil)-N1-metilbenzeno-1,3-diamina (35,6 mg, 0,13 mmol) como um material de partida para obter N-(3-cloro-5-((2,4- difluorofenil)(metil)amino)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxamida (57,2 mg, 79 %) como um sólido branco. LC/MS ESI (+): 549 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,45 (s, 1H), 8,31 (s, 1H), 8,19 (s, 1H), 8,08 (d, 1H, J = 8,7 Hz), 7,73 (m, 1H), 7,41 - 7,53 (m, 3H), 7,21 (m, 1H), 6,93 (s, 1H), 6,48 (s, 1H), 3,23 (s, 3H), 2,72 (s, 3H), 1,84 (s, 6H)[0198] The synthesis procedure of Example 1-h was repeated, except for the use of 5-chloro-N1-(2,4-difluorophenyl)-N1-methylbenzene-1,3-diamine (35.6 mg, 0 .13 mmol) as a starting material to obtain N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide (57.2 mg, 79%) as a white solid. LC/MS ESI (+): 549 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.31 (s, 1H), 8.19 (s , 1H), 8.08 (d, 1H, J = 8.7 Hz), 7.73 (m, 1H), 7.41 - 7.53 (m, 3H), 7.21 (m, 1H) , 6.93 (s, 1H), 6.48 (s, 1H), 3.23 (s, 3H), 2.72 (s, 3H), 1.84 (s, 6H)

[0199]Os compostos a partir do Exemplo 99 e Exemplo 100 foram sintetizados através da via de síntese do Exemplo 98, dados destes compostos são listados, como segue.Tabela 6 Exemplo 101) Síntese de N-(2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridin- 4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 4-amino-6-cloropiridin-2-ol[0199] The compounds from Example 99 and Example 100 were synthesized through the synthesis route of Example 98, data of these compounds are listed, as follows.Table 6 Example 101) Synthesis of N-(2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 4-amino-6-chloropyridin-2-ol

[0200]2,6-Dicloropiridino-4-amina (1,0 g, 6,13 mmols) foi dissolvida em terc- BuOH (30,7 mL) e KOH (516,0 mg, 9,20 mmols) foi adicionado. A mistura de reação foi agitada a 150 °C durante 15 horas, H2O foi adicionada e extraída com EtOAc. A camada aquosa foi acidificada com solução aquosa de HCl 1 N e depois extraída com EtOAc. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, MeOH:EtOAc = 1:10) para obter 4-amino-6-cloropiridin-2-ol (120,0 mg, 14 %) como um sólido branco amarelado. LC/MS ESI (+): 145 (M+1) (b) Síntese de benzoato de 4-clorociclo-hex-3-en-1-ila[0200] 2,6-Dichloropyridin-4-amine (1.0 g, 6.13 mmol) was dissolved in tert-BuOH (30.7 mL) and KOH (516.0 mg, 9.20 mmol) was added . The reaction mixture was stirred at 150°C for 15 hours, H2O was added and extracted with EtOAc. The aqueous layer was acidified with 1N aqueous HCl solution and then extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, MeOH:EtOAc = 1:10) to obtain 4-amino-6-chloropyridin-2-ol (120.0 mg, 14%) as an off-white solid. LC/MS ESI (+): 145 (M+1) (b) Synthesis of 4-chlorocyclohex-3-en-1-yl benzoate

[0201]Benzoato de 4-oxociclo-hexila (1,1 g, 4,76 mmols) foi dissolvido em tolueno (55,0 mL) e PCl5 (1,3 g, 6,05 mmols) foi adicionado a -40 °C. A mistura de reação foi agitada na temperatura ambiente durante 2 horas, H2O foi adicionada e extraída com EtOAc. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:4) para obter benzoato de 4-clorociclo-hex-3- en-1-ila (850,0 mg, 65 %) como um óleo branco amarelado. RMN de 1H (400 MHz, CDCl3): δ 8,03 (d, 2H, J = 8,0 Hz), 7,57 (t, 1H, J = 7,6 Hz), 7,44 (t, 2H, J = 7,6 Hz), 5,76 (m, 1H), 5,31 (m, 1H), 2,34 - 2,61 (m, 4H), 2,05 - 2,10 (m, 2H) (c) Síntese de 4-clorociclo-hex-3-en-1-ol[0201] 4-Oxocyclohexyl benzoate (1.1 g, 4.76 mmol) was dissolved in toluene (55.0 mL) and PCl5 (1.3 g, 6.05 mmol) was added at -40 ° W. The reaction mixture was stirred at room temperature for 2 hours, H2O was added and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:4) to obtain 4-chlorocyclohex-3-en-1-yl benzoate (850.0 mg, 65%) like a yellowish white oil. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 2H, J = 8.0 Hz), 7.57 (t, 1H, J = 7.6 Hz), 7.44 (t, 2H , J = 7.6 Hz), 5.76 (m, 1H), 5.31 (m, 1H), 2.34 - 2.61 (m, 4H), 2.05 - 2.10 (m, 2H) (c) Synthesis of 4-chlorocyclohex-3-en-1-ol

[0202]Benzoato de 4-clorociclo-hex-3-en-1-ila (400,0 mg, 1,69 mmol) foi dissolvido em MeOH (8,4 mL) e solução 0,5 M de NaOMe em MeOH (3,8 mL, 1,86 mmol) foi adicionada a 0 °C. A mistura de reação foi agitada durante 2 horas, NaHSO4 e solução tampão NaH2PO4 foram adicionados e extraídos com CH2Cl2. O extrato orgânico foi seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n- Hex:EtOAc = 1:1) para obter 4-clorociclo-hex-3-en-1-ol (90,0 mg, 40 %) como um óleo branco amarelado. RMN de 1H (400 MHz, CDCl3): δ 5,69 (m, 1H), 4,01 (m, 1H), 2,41 - 2,45 (m, 3H), 2,14 (m, 1H), 1,82 - 1,92 (m, 2H) (d) Síntese de 2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridino-4-amina[0202] 4-Chlorocyclohex-3-en-1-yl benzoate (400.0 mg, 1.69 mmol) was dissolved in MeOH (8.4 mL) and 0.5 M solution of NaOMe in MeOH ( 3.8 mL, 1.86 mmol) was added at 0 °C. The reaction mixture was stirred for 2 hours, NaHSO4 and NaH2PO4 buffer were added and extracted with CH2Cl2. The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:1) to obtain 4-chlorocyclohex-3-en-1-ol (90.0 mg, 40%) as a yellowish white oil. 1H NMR (400 MHz, CDCl3): δ 5.69 (m, 1H), 4.01 (m, 1H), 2.41 - 2.45 (m, 3H), 2.14 (m, 1H) , 1.82 - 1.92 (m, 2H) (d) Synthesis of 2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-amine

[0203]4-Amino-6-cloropiridin-2-ol (80,0 mg, 0,55mmol) foi dissolvido em THF (2,0 mL) e 2-4-clorociclo-hex-3-en-1-ol (81,0 mg, 0,61 mmol), Solução 2,2 M de DEAD em tolueno (377,0 μL, 0,83 mmol) e PPh3 (189,0 mg, 0,72 mmol) foram adicionados. A mistura de reação foi agitada na temperatura ambiente durante 15 horas e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, n-Hex:EtOAc = 1:2) para obter 2- cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridino-4-amina (51,0 mg, 36 %) como um óleo amarelo. LC/MS ESI (+): 259 (M+1) RMN de 1H (400 MHz, CDCl3): δ 6,21 (s, 1H), 5,82 (s, 1H), 5,72 (m, 1H), 5,27 (m, 1H), 4,14 (s, 2H), 2,43 - 2,51 (m, 4H), 1,98 - 2,02 (m, 2H) (e) Síntese de N-(2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0203] 4-Amino-6-chloropyridin-2-ol (80.0 mg, 0.55mmol) was dissolved in THF (2.0 mL) and 2-4-chlorocyclohex-3-en-1-ol (81.0 mg, 0.61 mmol), 2.2 M DEAD solution in toluene (377.0 µL, 0.83 mmol) and PPh3 (189.0 mg, 0.72 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc = 1:2) to obtain 2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy) pyridine-4-amine (51.0 mg, 36%) as a yellow oil. LC/MS ESI (+): 259 (M+1) 1H NMR (400 MHz, CDCl3): δ 6.21 (s, 1H), 5.82 (s, 1H), 5.72 (m, 1H ), 5.27 (m, 1H), 4.14 (s, 2H), 2.43 - 2.51 (m, 4H), 1.98 - 2.02 (m, 2H) (e) Synthesis of N-(2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide

[0204]O procedimento de síntese do Exemplo 67-b foi repetido, exceto para o uso de 2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridino-4-amina (40,0 mg, 0,15 mmol) como um material de partida para obter N-(2-cloro-6-((4-clorociclo-hex-3-en-1- il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (35,0 mg, 42 %).LC/MS ESI (+): 539 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,96 (s, 1H), 8,40 (s, 1H), 8,26 (s, 1H), 8,13 (d, 1H, J = 8,8 Hz), 7,78 (d, 1H, J = 8,8 Hz), 7,46 (s, 1H), 7,24 (s, 1H), 5,81 (m, 1H), 5,21 (m, 1H), 2,75 (s, 3H), 2,43 - 2,68 (m, 4H), 2,01 - 2,03 (m, 2H) Exemplo 102) Síntese de N-(2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4- il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de octa-hidroindolizin-7-ol[0204] The synthesis procedure of Example 67-b was repeated, except for the use of 2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-amine ( 40.0 mg, 0.15 mmol) as a starting material to obtain N-(2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-yl) -5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (35.0 mg, 42%). LC/MS ESI (+): 539 (M+1) 1H (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.13 (d, 1H, J = 8, 8 Hz), 7.78 (d, 1H, J = 8.8 Hz), 7.46 (s, 1H), 7.24 (s, 1H), 5.81 (m, 1H), 5.21 (m, 1H), 2.75 (s, 3H), 2.43 - 2.68 (m, 4H), 2.01 - 2.03 (m, 2H) Example 102) Synthesis of N-(2- chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of octahydroindolizin-7-ol

[0205]Hexa-hidroindolizin-7(1H)-ona (220,0 mg, 1,58 mmol) foi dissolvida em THF (12,5 ml) e LiAlH4 1,0 M em THF (3,95 ml, 3,95 mmols) foi adicionado à mesma na temperatura ambiente. A mistura foi agitada a 80 °C durante 30 min. e água foi adicionada a 0 °C. A mistura de reação resultante foi filtrada através de Celite e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro, filtrado e evaporado para obter octa-hidroindolizin-7-ol (220,0 mg, 99 %) como um líquido incolor.LC/MS ESI (+): 142 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 4,63 - 4,64 (m, 1H), 2,86 - 2,93 (m, 2H), 1,86 - 1,97 (m, 3H), 1,56 - 1,79 (m, 5H), 1,25 - 1,40 (m, 2H), 0,98 - 1,07 (m, 1H) (b) Síntese de 2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4-amina[0205] Hexahydroindolizin-7(1H)-one (220.0 mg, 1.58 mmol) was dissolved in THF (12.5 mL) and 1.0 M LiAlH4 in THF (3.95 mL, 3. 95 mmol) was added thereto at room temperature. The mixture was stirred at 80 °C for 30 min. and water was added at 0 °C. The resulting reaction mixture was filtered through Celite and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and evaporated to give octahydroindolizin-7-ol (220.0 mg, 99%) as a colorless liquid. LC/MS ESI (+): 142 (M +1) 1H NMR (400 MHz, DMSO-d6): δ 4.63 - 4.64 (m, 1H), 2.86 - 2.93 (m, 2H), 1.86 - 1.97 ( m, 3H), 1.56 - 1.79 (m, 5H), 1.25 - 1.40 (m, 2H), 0.98 - 1.07 (m, 1H) (b) Synthesis of 2- chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-amine

[0206]Octa-hidroindolizin-7-ol (200,0 mg, 1,42 mmol) e 2,6-dicloropiridin-4- amina (462,0 mg, 2,83 mmols) foram dissolvidos em sulfolano (7,0 ml) e NaH 60 % em peso (113,0 mg, 2,83 mmols) foi adicionado aos mesmos na temperatura ambiente. A mistura foi agitada a 160 °C durante 1 hora e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro, filtrado e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter 2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4- amina (200,0 mg, 52 %) como um líquido incolor. LC/MS ESI (+): 268 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 6,28 (s, 2H), 6,18 (d, 1H, J = 1,6 Hz), 5,74 - 5,76 (m, 1H), 4,72 - 4,80 (m, 1H), 2,89 - 3,01 (m, 2H), 2,12 - 2,16 (m, 1H), 1,86 - 2,06 (m, 4H), 1,62 - 1,83 (m, 3H), 1,47 - 1,56 (m, 1H), 1,27 - 1,37 (m, 1H), 1,15 - 1,27 (m, 1H) (c) Síntese de N-(2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0206] Octahydroindolizin-7-ol (200.0 mg, 1.42 mmol) and 2,6-dichloropyridin-4-amine (462.0 mg, 2.83 mmol) were dissolved in sulfolane (7.0 ml) and 60 wt% NaH (113.0 mg, 2.83 mmol) was added thereto at room temperature. The mixture was stirred at 160 °C for 1 hour and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain 2-chloro-6-((octahydroindolizin-7 -yl)oxy)pyridin-4-amine (200.0 mg, 52%) as a colorless liquid. LC/MS ESI (+): 268 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 6.28 (s, 2H), 6.18 (d, 1H, J = 1.6 Hz ), 5.74 - 5.76 (m, 1H), 4.72 - 4.80 (m, 1H), 2.89 - 3.01 (m, 2H), 2.12 - 2.16 (m , 1H), 1.86 - 2.06 (m, 4H), 1.62 - 1.83 (m, 3H), 1.47 - 1.56 (m, 1H), 1.27 - 1.37 (m, 1H), 1.15 - 1.27 (m, 1H) (c) Synthesis of N-(2-chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-yl) -5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0207]O procedimento de síntese do Exemplo 62-b foi repetido, exceto para o uso de 2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4-amina (50,0 mg, 0,19 mmol) como um material de partida para obter N-(2-cloro-6-((octa-hidroindolizin-7- il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (11,1 mg, 10 %) LC/MS ESI (+): 548 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,95 (s, 1H), 8,40 (s, 1H), 8,26 (d, 1H, J = 1,6 Hz), 8,12 - 8,16 (m, 1H), 7,78 (dd, 1H, J = 8,8, 1,6 Hz), 7,45 (d, 1H, J = 1,6 Hz), 7,20 (d, 1H, J = 1,2 Hz), 4,88 - 4,94 (m, 1H), 2,94 - 3,08 (m, 2H), 2,75 (s, 3H), 2,22 - 2,26 (m, 1H), 1,95 - 1,96 (m, 4H), 1,79 - 1,90 (m, 6H), 1,60 - 1,76 (m, 3H), 1,23 - 1,42 (m, 3H) Exemplo 103) Síntese de 2,2,2-trifluoroacetato de N-(3-cloro-5-(4- clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboximidamida (a) Síntese de 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0207] The synthesis procedure of Example 62-b was repeated, except for the use of 2-chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-amine (50.0 mg, 0 .19 mmol) as a starting material to obtain N-(2-chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide (11.1 mg, 10%) LC/MS ESI (+): 548 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10, 95 (s, 1H), 8.40 (s, 1H), 8.26 (d, 1H, J = 1.6 Hz), 8.12 - 8.16 (m, 1H), 7.78 (dd , 1H, J = 8.8, 1.6 Hz), 7.45 (d, 1H, J = 1.6 Hz), 7.20 (d, 1H, J = 1.2 Hz), 4.88 - 4.94 (m, 1H), 2.94 - 3.08 (m, 2H), 2.75 (s, 3H), 2.22 - 2.26 (m, 1H), 1.95 - 1 .96 (m, 4H), 1.79 - 1.90 (m, 6H), 1.60 - 1.76 (m, 3H), 1.23 - 1.42 (m, 3H) Example 103) Synthesis of N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboximidamide 2,2,2-trifluoroacetate ( a) Synthesis of 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0208]Ácido 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxílico (111,0 mg, 0,37 mmol) foi dissolvido em CH2Cl2 (3,6 mL) e (COCl)2 (50,8 mg, 0,40 mmol) e DMF (cat.) foram adicionados às gotas. A mistura de reação foi agitada na temperatura ambiente durante 1 hora e concentrada sob pressão reduzida para obter cloreto de 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carbonila. O resíduo foi dissolvido em 1,4-dioxano (3,7 mL) e solução 2 N de NH3 em MeOH (1,8 mL) foi adicionada às gotas. A mistura de reação foi agitada na temperatura ambiente durante 40 minutos e concentrada sob pressão reduzida. O resíduo foi purificado por cromatografia em fase reversa (gel de sílica C18, CH3CN:H2O) para obter 5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (110,0 mg, quant). LC/MS ESI (+): 298 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 8,26 (brs, 1H), 8,11 (d, 1H, J = 1,7 Hz), 8,08 (s, 1H), 8,04 (d, 1H, J = 8,7 Hz), 7,70 (dd, 1H, J = 8,7, 2,0 Hz), 7,66 (brs, 1H), 2,71 (s, 3H), 1,83 (s, 6H) (b) Síntese de 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carbimidato de etila[0208] 5-(2-(Methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid (111.0 mg, 0.37 mmol) was dissolved in CH 2 Cl 2 (3.6 mL) and ( COCl) 2 (50.8 mg, 0.40 mmol) and DMF (cat.) were added dropwise. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carbonyl chloride. The residue was dissolved in 1,4-dioxane (3.7 mL) and 2N solution of NH 3 in MeOH (1.8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 40 minutes and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18 silica gel, CH3CN:H2O) to obtain 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (110.0 mg, amount). LC/MS ESI (+): 298 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 8.26 (brs, 1H), 8.11 (d, 1H, J = 1.7 Hz ), 8.08 (s, 1H), 8.04 (d, 1H, J = 8.7 Hz), 7.70 (dd, 1H, J = 8.7, 2.0 Hz), 7.66 (brs, 1H), 2.71 (s, 3H), 1.83 (s, 6H) (b) Synthesis of 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- ethyl carbimidate

[0209]5-(2-(Metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (85,0 mg, 0,29 mmol) foi dissolvida em CH2Cl2 (6,0 mL) e solução 1,0 M de tetrafluoroborato de trietiloxônio em CH2Cl2 (109,0 mL, 0,57 mmol) foi adicionada às gotas. A mistura de reação foi agitada na temperatura ambiente durante 16 horas e extraída com CH2Cl2. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica amina, CH2Cl2:MeOH = 9:1) para obter 5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carbimidato de etila (63,9 mg, 69 %).LC/MS ESI (+): 326 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 9,15 (s, 1H), 8,17 (s, 1H), 8,12 (d, 1H, J = 1,5 Hz), 8,03 (d, 1H, J = 8,7 Hz), 7,70 (dd, 1H, J = 8,9, 1,8 Hz), 4,27 (q, 2H, J = 7,1 Hz), 2,72 (s, 3H), 1,83 (s, 6H), 1,33 (t, 3H, J = 7,1 Hz) (c) Síntese de2,2,2-trifluoroacetato de N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboximidamida[0209] 5-(2-(Methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (85.0 mg, 0.29 mmol) was dissolved in CH 2 Cl 2 (6.0 mL) and solution 1 .0 M triethyloxonium tetrafluoroborate in CH 2 Cl 2 (109.0 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica amine gel, CH 2 Cl 2 :MeOH = 9:1) to obtain ethyl 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carbimidate (63.9 mg, 69 %).LC/MS ESI (+): 326 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.17 ( s, 1H), 8.12 (d, 1H, J = 1.5 Hz), 8.03 (d, 1H, J = 8.7 Hz), 7.70 (dd, 1H, J = 8.9 , 1.8 Hz), 4.27 (q, 2H, J = 7.1 Hz), 2.72 (s, 3H), 1.83 (s, 6H), 1.33 (t, 3H, J = 7.1 Hz) (c) Synthesis of N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic acid 2,2,2-trifluoroacetate [b]thiophene-2-carboximidamide

[0210]5-(2-(Metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carbimidato de etila (63,9 mg, 0,20 mmol) e 3-cloro-5-(4-clorofenóxi)anilina (59,9 mg, 0,24 mmol) foram dissolvidos em DMF (0,4 mL) e trietilamina (19,9 mg, 0,20 mmol) foi adicionada às gotas. A mistura de reação foi agitada a 60 °C durante 16 horas e depois a 100 °C durante 16 horas. A mistura de reação foi purificada por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter2,2,2-trifluoroacetato de N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboximidamida (2,4 mg, 2 %) como sólido branco.LC/MS ESI (+): 533 (M+1), Forma livre RMN de 1H (400 MHz, DMSO-d6): δ 11,79 (brs, 2H), 8,31 (s, 1H), 8,26 (s, 1H), 8,18 (d, 1H, J = 7,3 Hz), 7,80 (d, 1H, J = 8,6 Hz), 7,49 (d, 2H, J = 7,7 Hz), 7,26 (brs, 1H), 7,18 (d, 2H, J = 8,4 Hz), 7,14 (brs, 1H), 6,96 (brs, 1H), 2,75 (s, 3H), 1,86 (s, 6H) Exemplo 104) Síntese de N-(2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)- il)piridin-4-il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4- aminaEthyl 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carbimidate (63.9 mg, 0.20 mmol) and 3-chloro-5-(4-chlorophenoxy) )aniline (59.9 mg, 0.24 mmol) was dissolved in DMF (0.4 mL) and triethylamine (19.9 mg, 0.20 mmol) was added dropwise. The reaction mixture was stirred at 60°C for 16 hours and then at 100°C for 16 hours. The reaction mixture was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain N-(3 -chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboximidamide (2.4 mg, 2%) as white solid.LC /MS ESI (+): 533 (M+1), Free form 1H NMR (400 MHz, DMSO-d6): δ 11.79 (brs, 2H), 8.31 (s, 1H), 8.26 (s, 1H), 8.18 (d, 1H, J = 7.3 Hz), 7.80 (d, 1H, J = 8.6 Hz), 7.49 (d, 2H, J = 7, 7 Hz), 7.26 (brs, 1H), 7.18 (d, 2H, J = 8.4 Hz), 7.14 (brs, 1H), 6.96 (brs, 1H), 2.75 (s, 3H), 1.86 (s, 6H) Example 104) Synthesis of N-(2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin- 4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-chloro-6-(hexahydropyrrolo[1,2-a] pyrazin-2(1H)-yl)pyridin-4-amine

[0211]2,6-dicloropiridin-4-amina (50,0 mg, 0,31 mmol) e octa-hidropirrolo[1,2- a]pirazina (77,6 mg, 0,61 mmol) foram dissolvidas em sulfolano (0,5 mL), seguido por aquecimento a 150 °C durante a noite. Octa-hidropirrolo[1,2-a]pirazina (100,0 mg, 0,80 mmol) foi adicionada. A mistura de reação foi agitada a 150 °C durante 1 dia, adicionalmente, e depois esfriada até a temperatura ambiente e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro, concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia instantânea em coluna (gel de sílica, CH2Cl2:MeOH = 7:1) para obter 2-cloro-6- (hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4-amina (66,0 mg, 85 %) como um amorfo amarelo claro. RMN de 1H (400 MHz, CDCl3): δ 6,00 (s, 1H), 5,71 (s, 1H) 4,31 (d, 1H, J = 11,9 Hz), 4,07 (d, 1H, J = 12,2 Hz), 4,02 (s, 2H), 3,11 - 3,15 (m, 2H), 2,94 - 3,01 (m, 1H), 2,57 - 2,63 (m, 1H), 2,28 - 2,31 (m, 1H), 2,15 - 2,19 (m, 1H), 2,03 - 2,08 (m, 2H), 1,77 - 1,83 (m, 2H), 1,47 - 1,50 (m, 1H) (b) Síntese de N-(2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4- il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0211]2,6-dichloropyridin-4-amine (50.0 mg, 0.31 mmol) and octahydropyrrolo[1,2-a]pyrazine (77.6 mg, 0.61 mmol) were dissolved in sulfolane HCl (0.5 mL), followed by heating at 150 °C overnight. Octahydropyrrolo[1,2-a]pyrazine (100.0 mg, 0.80 mmol) was added. The reaction mixture was stirred at 150°C for 1 day further and then cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH 2 Cl 2 :MeOH = 7:1) to obtain 2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl) pyridin-4-amine (66.0 mg, 85%) as a light yellow amorphous. 1H NMR (400 MHz, CDCl3): δ 6.00 (s, 1H), 5.71 (s, 1H) 4.31 (d, 1H, J = 11.9 Hz), 4.07 (d, 1H, J = 12.2 Hz), 4.02 (s, 2H), 3.11 - 3.15 (m, 2H), 2.94 - 3.01 (m, 1H), 2.57 - 2 .63 (m, 1H), 2.28 - 2.31 (m, 1H), 2.15 - 2.19 (m, 1H), 2.03 - 2.08 (m, 2H), 1.77 - 1.83 (m, 2H), 1.47 - 1.50 (m, 1H) (b) Synthesis of N-(2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2) (1H)-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0212]O procedimento de síntese do Exemplo 62-b foi repetido, exceto para o uso de 2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4-amina (62,0 mg, 0,25 mmol) para obter N-(2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4- il)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (28,4 mg, 22 %).LC/MS ESI (+): 533 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 10,73 (s, 1H), 8,39 (s, 1H), 8,22 (m, 1H), 8,12 (d, 1H, J = 8,7 Hz), 7,76 (dd, 1H, J = 8,7, 1,8 Hz), 7,22 (s, 1H), 7,13 (s, 1H), 4,23 (d, 1H, J = 11,1 Hz), 4,08 (d, 1H, J = 12,4 Hz), 3,00 - 3,09 (m, 2H), 2,87 - 2,94 (m, 1H), 2,74 (s, 3H), 2,55 - 2,60 (m, 1H), 2,03 - 2,16 (m, 2H), 1,86 - 1,97 (m, 8H), 1,66 - 1,76 (m, 2H), 1,33 - 1,43 (m, 1H)[0212] The synthesis procedure of Example 62-b was repeated, except for the use of 2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-4- amine (62.0 mg, 0.25 mmol) to obtain N-(2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-4-yl)- 5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide (28.4 mg, 22%). LC/MS ESI (+): 533 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.39 (s, 1H), 8.22 (m, 1H), 8.12 (d, 1H, J = 8.7 Hz), 7.76 (dd, 1H, J = 8.7, 1.8 Hz), 7.22 (s, 1H), 7.13 (s, 1H), 4.23 (d, 1H, J = 11.1 Hz), 4.08 (d, 1H, J = 12.4 Hz), 3.00 - 3.09 (m, 2H), 2.87 - 2.94 (m, 1H), 2 .74 (s, 3H), 2.55 - 2.60 (m, 1H), 2.03 - 2.16 (m, 2H), 1.86 - 1.97 (m, 8H), 1.66 - 1.76 (m, 2H), 1.33 - 1.43 (m, 1H)

[0213]Os compostos a partir do Exemplo 105 e Exemplo 108 foram sintetizados através da via de síntese do Exemplo 104, dados destes compostos são listados, como segue.Tabela 7 Exemplo 109) Síntese de N-(2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida (a) Síntese de 1-óxido de 4-bromo-2,6-dicloropiridina[0213] The compounds from Example 105 and Example 108 were synthesized through the synthesis route of Example 104, data of these compounds are listed, as follows.Table 7 Example 109) Synthesis of N-(2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b ]thiophene-2-carboxamide (a) Synthesis of 4-bromo-2,6-dichloropyridine 1-oxide

[0214]4-Bromo-2,6-dicloropiridina (5,0 g, 22,04 mmols) foi dissolvida em TFA (23,8 ml, 309,00 mmols) e H2O2 (4,8 ml, 55,10 mmols) foi adicionada na temperatura ambiente. A mistura foi submetida ao refluxo com agitação a 100 °C durante 14 horas, seguido por esfriamento até a temperatura ambiente e filtrada. O filtrado foi extraído com EtOAc. O extrato orgânico foi lavado com NaOH 1 N, seco com Na2SO4 anidro, filtrado e evaporado para obter 1-óxido de 4-bromo-2,6- dicloropiridina (2,7 g, 49 %) como um sólido amarelo. LC/MS ESI (+): 244 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,61 (s, 2H) (b) Síntese de 1-óxido de 4-bromo-2-cloro-6-((5-metiltiazol-2-il)óxi)piridina[0214]4-Bromo-2,6-dichloropyridine (5.0 g, 22.04 mmol) was dissolved in TFA (23.8 ml, 309.00 mmol) and H2O2 (4.8 ml, 55.10 mmol ) was added at room temperature. The mixture was refluxed with stirring at 100°C for 14 hours, followed by cooling to room temperature and filtered. The filtrate was extracted with EtOAc. The organic extract was washed with 1N NaOH, dried with anhydrous Na 2 SO 4 , filtered and evaporated to give 4-bromo-2,6-dichloropyridine 1-oxide (2.7 g, 49%) as a yellow solid. LC/MS ESI (+): 244 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.61 (s, 2H) (b) Synthesis of 4-bromo-2-chloro-1-oxide 6-((5-methylthiazol-2-yl)oxy)pyridine

[0215]1-Óxido de 4-bromo-2,6-dicloropiridina (112,0 mg, 0,46 mmol) foi dissolvido em DMF (4,0 ml) e 5-metiltiazol-2-ol (53,0 mg, 0,46 mmol), Cs2CO3 (300,0 mg, 0,92 mmol) foram adicionados na temperatura ambiente. A mistura foi agitada a 40 °C durante 2 horas. A mistura de reação foi purificada por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter 1-óxido de 4-bromo-2-cloro-6-((5-metiltiazol-2- il)óxi)piridina (50,0 mg, 33 %) como um sólido amarelo. LC/MS ESI (+): 321 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,72 (d, 1H, J = 2,8 Hz), 7,67 (d, 1H, J = 2,8 Hz), 6,77 - 6,78 (m, 1H), 2,02 (d, 3H, J = 1,6 Hz) (c) Síntese de 2-((4-bromo-6-cloropiridin-2-il)óxi)-5-metiltiazol[0215] 4-Bromo-2,6-dichloropyridine 1-oxide (112.0 mg, 0.46 mmol) was dissolved in DMF (4.0 mL) and 5-methylthiazol-2-ol (53.0 mg , 0.46 mmol), Cs2CO3 (300.0 mg, 0.92 mmol) were added at room temperature. The mixture was stirred at 40°C for 2 hours. The reaction mixture was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain 4-bromo-2-chloro 1-oxide -6-((5-methylthiazol-2-yl)oxy)pyridine (50.0 mg, 33%) as a yellow solid. LC/MS ESI (+): 321 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.72 (d, 1H, J = 2.8 Hz), 7.67 (d, 1H, J = 2.8 Hz), 6.77 - 6.78 (m, 1H), 2.02 (d, 3H, J = 1.6 Hz) (c) Synthesis of 2-((4-bromo-6- chloropyridin-2-yl)oxy)-5-methylthiazole

[0216]1-Óxido de 4-bromo-2-cloro-6-((5-metiltiazol-2-il)óxi)piridina (40,0 mg, 0,12 mmol) foi dissolvido em CHCl3 (1,2 ml) e PCl3 (33,0 μl, 0,37 mmol) foi adicionado ao mesmo a 0 °C. A mistura foi agitada na temperatura ambiente durante 6 horas e extraída com EtOAc. O extrato orgânico foi lavado com NaOH 1 N e salmoura, seco em Na2SO4 anidro, filtrado e evaporado para obter 2-((4-bromo-6- cloropiridin-2-il)óxi)-5-metiltiazol (35,0 mg, 92 %) como um sólido marfim. LC/MS ESI (+): 305 (M+1) RMN de 1H (400 MHz, CDCl3): δ 8,48 (s, 1H), 7,40 (s, 1H), 7,37 (s, 1H), 2,21 (s, 3H) (d) Síntese de 2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-amina[0216] 4-Bromo-2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridine 1-oxide (40.0 mg, 0.12 mmol) was dissolved in CHCl3 (1.2 ml ) and PCl3 (33.0 µl, 0.37 mmol) was added thereto at 0 °C. The mixture was stirred at room temperature for 6 hours and extracted with EtOAc. The organic extract was washed with 1N NaOH and brine, dried over anhydrous Na2SO4, filtered and evaporated to give 2-((4-bromo-6-chloropyridin-2-yl)oxy)-5-methylthiazole (35.0 mg, 92%) as an ivory solid. LC/MS ESI (+): 305 (M+1) 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.40 (s, 1H), 7.37 (s, 1H ), 2,21 (s, 3H) (d) Synthesis of 2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-amine

[0217]2-((4-Bromo-6-cloropiridin-2-il)óxi)-5-metiltiazol (30,0 mg, 0,10 mmol) foi dissolvido em DMSO (1,0 ml) e Cu2O (16,9 mg, 0,12 mmol), azida sódica (12,8 mg, 0,20 mmol) foram adicionados na temperatura ambiente. A mistura foi agitada a 100 °C durante 1 hora e extraída com EtOAc. O extrato orgânico foi lavado com salmoura, seco em Na2SO4 anidro, filtrado e concentrado sob pressão reduzida. O resíduo foi purificado por cromatografia em coluna em fase reversa (gel de sílica C18, ácido fórmico em CH3CN 0,1 %:ácido fórmico em H2O 0,1 %) para obter 2- cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-amina (4,0 mg, 16 %) como um sólido branco amarelado.LC/MS ESI (+): 242 (M+1) RMN de 1H (400 MHz, CDCl3): δ 7,48 (d, 1H, J = 1,6 Hz), 7,38 (d, 1H, J = 1,2 Hz), 6,42 (d, 1H, J = 1,6 Hz), 6,44 (brs, 2H), 2,18 (d, 3H, J = 1,2 Hz) (e) Síntese de N-(2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida[0217] 2-((4-Bromo-6-chloropyridin-2-yl)oxy)-5-methylthiazole (30.0 mg, 0.10 mmol) was dissolved in DMSO (1.0 ml) and Cu2O (16 .9 mg, 0.12 mmol), sodium azide (12.8 mg, 0.20 mmol) were added at room temperature. The mixture was stirred at 100°C for 1 hour and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 0.1% formic acid in CH3CN:0.1% formic acid in H2O) to obtain 2-chloro-6-((5-methylthiazole-2 -yl)oxy)pyridin-4-amine (4.0 mg, 16%) as an off-white solid. LC/MS ESI (+): 242 (M+1) 1H NMR (400 MHz, CDCl3): δ 7.48 (d, 1H, J = 1.6 Hz), 7.38 (d, 1H, J = 1.2 Hz), 6.42 (d, 1H, J = 1.6 Hz), 6, 44 (brs, 2H), 2.18 (d, 3H, J = 1.2 Hz) (e) Synthesis of N-(2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin- 4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide

[0218]O procedimento de síntese do Exemplo 62-b foi repetido, exceto para o uso de 2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-amina (4,0 mg, 0,02 mmol) para obter N-(2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida (1,1 mg, 13 %) como um sólido branco.LC/MS ESI (+): 522 (M+1) RMN de 1H (400 MHz, DMSO-d6): δ 11,33 (brs, 1H), 8,49 (s, 2H), 8,24 (s, 1H), 8,12 (d, 1H, J = 8,8 Hz), 8,00 (d, 1H, J = 1,2 Hz), 7,77 (dd, 1H, J = 8,8, 1,6 Hz), 7,48 (d, 1H, J = 1,2 Hz), 2,74 (s, 3H), 2,22 (d, 3H, J = 0,8 Hz), 1,86 (s, 6H)[0218] The synthesis procedure of Example 62-b was repeated, except for the use of 2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-amine (4.0 mg, 0 .02 mmol) to obtain N-(2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide (1.1 mg, 13%) as a white solid. LC/MS ESI (+): 522 (M+1) 1H NMR (400 MHz, DMSO-d6): δ 11, 33 (brs, 1H), 8.49 (s, 2H), 8.24 (s, 1H), 8.12 (d, 1H, J = 8.8 Hz), 8.00 (d, 1H, J = 1.2 Hz), 7.77 (dd, 1H, J = 8.8, 1.6 Hz), 7.48 (d, 1H, J = 1.2 Hz), 2.74 (s, 3H ), 2.22 (d, 3H, J = 0.8 Hz), 1.86 (s, 6H)

[0219]Os compostos a partir do Exemplo 110 e Exemplo 121 foram sintetizados através da via de síntese do Exemplo 109, dados destes compostos são listados, como segue.Tabela 8 [0219] The compounds from Example 110 and Example 121 were synthesized through the synthesis route of Example 109, data of these compounds are listed, as follows.Table 8

EXEMPLOS EXPERIMENTAISEXPERIMENTAL EXAMPLES

[0220]Os experimentos foram realizados, conforme mostrado abaixo, para os compostos preparados nos Exemplos acima.Exemplo Experimental 1) Experimento sobre a inibição das atividades de STAT3 e STAT1 por intermédio do ensaio de gene reporter 1-1) Experimento sobre a inibição da atividade de STAT3[0220] The experiments were performed, as shown below, for the compounds prepared in the Examples above. Experimental Example 1) Experiment on the inhibition of STAT3 and STAT1 activities through the reporter gene assay 1-1) Experiment on the inhibition of STAT3 activity

[0221]Uma linhagem celular de câncer de próstata humano (linhagem celular estável LNCaP; plasmídeo pSTAT3-TA-luc), que contém um promotor de STAT3 que opera de forma estável, foi cultivada em meio RPMI1640 (Cat No 11875, Life Technologies) contendo soro fetal bovino a 10 % (FBS) (Cat No SH30396, Thermo Scientific) e solução de G-418 150 μg/mL (Cat No 04 727 894 001, Roche). O ensaio de gene repórter usando linhagem celular estável LNCaP foi realizado em meio RPMI1640 contendo DCC-FBS a 3 % sem solução de G-418. Células estáveis LNCaP foram plaqueadas em duas (2) placas de 96 poços brancas com 30.000 células/50 μL em cada poço. As células foram cultivadas a 37 °C, sob CO2 a 5 % durante 24 horas e depois tratadas com os compostos listados nos Exemplos que foram diluídos em várias concentrações. Subsequentemente, IL-6 foi adicionada a cada poço com uma concentração final de 10 ng/mL. Após a conclusão do tratamento com os compostos e IL-6, as células foram cultivadas a 37 °C, sob CO2 a 5 % durante 24 horas. As placas foram observadas sob microscópio e precipitação do fármaco e descobertas particulares foram investigadas e registradas.[0221] A human prostate cancer cell line (LNCaP stable cell line; plasmid pSTAT3-TA-luc), which contains a stably operating STAT3 promoter, was grown in RPMI1640 medium (Cat No 11875, Life Technologies) containing 10% Fetal Bovine Serum (FBS) (Cat No SH30396, Thermo Scientific) and 150 μg/mL G-418 Solution (Cat No 04 727 894 001, Roche). Reporter gene assay using LNCaP stable cell line was performed in RPMI1640 medium containing 3% DCC-FBS without G-418 solution. Stable LNCaP cells were plated into two (2) white 96-well plates with 30,000 cells/50 µL in each well. Cells were grown at 37°C, under 5% CO 2 for 24 hours and then treated with the compounds listed in the Examples which were diluted to various concentrations. Subsequently, IL-6 was added to each well with a final concentration of 10 ng/ml. After completion of treatment with compounds and IL-6, cells were cultured at 37°C under 5% CO 2 for 24 hours. Plaques were observed under a microscope and drug precipitation and particular findings were investigated and recorded.

[0222]O ensaio de luciferase e o ensaio de viabilidade celular foram realizados, respectivamente, com uma entre as duas placas. Para o ensaio de luciferase, o meio líquido na placa de 96 poços foi removido e, depois, 20 μL de tampão de lise celular passivo foram adicionados a cada poço. Depois de agitar a placa durante 30 minutos, as atividades de luciferase de cada poço foram medidas em um leitor de microplaca PHERAstarTM (BMG LABTECH) usando um sistema de ensaio de luciferase (Cat No E1501, Promega). Para o ensaio de viabilidade celular, a placa de 96 poços foi colocada na temperatura ambiente durante 30 minutos, adicionada com 20 μL/poço de solução CellTiter-Glo (Cat No G7573, Promega) e agitada durante 10 minutos, de modo a medir a citotoxicidade causada pelos compostos listados nos Exemplos com um leitor de microplaca PHERAstarTM (BMG LABTECH). Os poços sem DMSO a 0,1 % e estímulo foram usados como um controle negativo e os poços com DMSO a 0,1 % e estímulo foram usados como um controle positivo. 1-2) Experimento sobre a inibição da atividade de STAT1[0222] The luciferase assay and the cell viability assay were performed, respectively, with one of the two plates. For the luciferase assay, the liquid medium in the 96-well plate was removed and then 20 µL of passive cell lysis buffer was added to each well. After shaking the plate for 30 minutes, the luciferase activities of each well were measured in a PHERAstarTM microplate reader (BMG LABTECH) using a luciferase assay system (Cat No E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 µL/well of CellTiter-Glo solution (Cat No G7573, Promega) and shaken for 10 minutes in order to measure the cell viability assay. cytotoxicity caused by the compounds listed in the Examples with a PHERAstarTM microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulus were used as a negative control and wells with 0.1% DMSO and stimulus were used as a positive control. 1-2) Experiment on the inhibition of STAT1 activity

[0223]Uma linhagem celular de osteossarcoma humano (linhagem celular estável U2OS; pGL4-STAT1-TA-luc), que contém um promotor de STAT1 que opera de forma estável, foi cultivada em meio McCoy 5’A (Cat No 16600, Life Technologies) contendo FBS a 10 % (Cat No SH30396, Thermo Scientific) e solução de G418 1000 μg/mL (Cat No 04 727 894 001, Roche). O ensaio de gene repórter usando linhagem celular estável U2OS foi realizado em meio McCoy 5’A contendo FBS a 10 % sem solução de G-418. Células estáveis U2OS foram plaqueadas em duas (2) placas de 96 poços brancas com 25.000 células/50 μL em cada poço. As células foram cultivadas a 37 °C, sob CO2 a 5 % durante 24 horas e depois tratadas com os compostos listados nos Exemplos que foram diluídos em várias concentrações. Subsequentemente, IFN-Y foi adicionado a cada poço com uma concentração final de 50 ng/mL. Após a conclusão do tratamento com os compostos e IFN-Y, as células foram cultivadas a 37 °C, sob CO2 a 5 % durante 8 horas. As placas foram observadas sob microscópio e precipitação de fármaco e descobertas particulares foram investigadas e registradas.[0223] A human osteosarcoma cell line (U2OS stable cell line; pGL4-STAT1-TA-luc), which contains a stably operating STAT1 promoter, was grown in McCoy 5'A medium (Cat No 16600, Life Technologies) containing 10% FBS (Cat No SH30396, Thermo Scientific) and 1000 µg/mL G418 solution (Cat No 04 727 894 001, Roche). Reporter gene assay using U2OS stable cell line was performed in McCoy 5'A medium containing 10% FBS without G-418 solution. Stable U2OS cells were plated into two (2) white 96-well plates with 25,000 cells/50 µL in each well. Cells were grown at 37°C, under 5% CO 2 for 24 hours and then treated with the compounds listed in the Examples which were diluted to various concentrations. Subsequently, IFN-Y was added to each well with a final concentration of 50 ng/ml. After completion of treatment with compounds and IFN-Y, cells were cultured at 37°C under 5% CO 2 for 8 hours. Plaques were observed under a microscope and drug precipitation and particular findings were investigated and recorded.

[0224]O ensaio de luciferase e o ensaio de viabilidade celular foram realizados, respectivamente, com uma entre as duas placas. Para o ensaio de luciferase, o meio líquido na placa de 96 poços foi removido e, depois, 20 μL de tampão de lise celular passivo foram adicionados a cada poço. Depois de agitar a placa durante 30 minutos, as atividades de luciferase de cada poço foram medidas em um leitor de microplaca PHERAstarTM (BMG LABTECH) usando um sistema de ensaio de luciferase (Cat No E1501, Promega). Para o ensaio de viabilidade celular, a placa de 96 poços foi colocada na temperatura ambiente durante 30 minutos, adicionada com 20 μL/poço da solução CellTiter-Glo (Cat No G7573, Promega) e agitada durante 10 minutos, de modo a medir a citotoxicidade causada pelos compostos listados nos Exemplos com um leitor de microplaca PHERAstarTM (BMG LABTECH). Os poços sem DMSO a 0,1 % e estímulo foram usados como um controle negativo e os poços com DMSO a 0,1 % e estímulo foram usados como um controle positivo.[0224] The luciferase assay and the cell viability assay were performed, respectively, with one of the two plates. For the luciferase assay, the liquid medium in the 96-well plate was removed and then 20 µL of passive cell lysis buffer was added to each well. After shaking the plate for 30 minutes, the luciferase activities of each well were measured in a PHERAstarTM microplate reader (BMG LABTECH) using a luciferase assay system (Cat No E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 µl/well of CellTiter-Glo solution (Cat No G7573, Promega) and shaken for 10 minutes in order to measure the cell viability assay. cytotoxicity caused by the compounds listed in the Examples with a PHERAstarTM microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulus were used as a negative control and wells with 0.1% DMSO and stimulus were used as a positive control.

[0225]Os resultados da avaliação sobre o efeito inibitório dos compostos listados nos Exemplos sobre a dimerização de STAT3 e STAT1 obtidas por intermédio dos ensaios de gene repórter de STAT3 e STAT1 são mostrados na Tabela 9 abaixo.Tabela 9 [0225] The results of the evaluation on the inhibitory effect of the compounds listed in the Examples on the dimerization of STAT3 and STAT1 obtained through the STAT3 and STAT1 reporter gene assays are shown in Table 9 below.Table 9

[0226]Conforme mostrado na Tabela 9, os compostos, de acordo com a presente invenção, exibiram efeitos inibitórios excelentes contra a atividade da proteína STAT3, mas quase não mostraram efeito inibitório contra a atividade da proteína STAT1.Exemplo Experimental 2) Ensaio de inibição de crescimento celular[0226] As shown in Table 9, the compounds according to the present invention exhibited excellent inhibitory effects against STAT3 protein activity, but showed almost no inhibitory effect against STAT1 protein activity.Experimental Example 2) Inhibition Assay of cell growth

[0227]Os efeitos inibitórios dos compostos da presente invenção contra o crescimento de células de câncer foram avaliados, conforme mostrado abaixo. As linhagens celulares de câncer, incluindo linhagens celulares de câncer de próstata (LNCaP, DU-145), linhagem celular de câncer de estômago (NCI-N87) e linhagens celulares de câncer de mama (MDA-MB-468) foram cultivadas sob o protocolo fornecido por cada fornecedor. Um meio suplementado com 10 ng/mL de IL-6 foi usado para LNCaP, uma linhagem celular de câncer de próstata, quando tratado com um fármaco. Cada tipo de células usadas nos experimentos foi subcultivado em uma placa de 96 poços por meio da contagem do número exato de células usando Citômetro com base na Imagem TaliTM (Life Technologies). Em uma placa de 96 poços, DU-145 foi utilizada com 3.000 células/poço; NCI-N87 foi utilizada com 5.000 células/poço; e LNCaP e MDA-MB-468 foram utilizadas com 10.000 células/poço. As células foram tratadas com os compostos listados nos Exemplos que foram diluídos em várias concentrações. Após a conclusão do tratamento com os compostos, as células LNCaP, DU-145, NCI-N87 foram cultivadas a 37 °C sob CO2 a 5 % durante 96 horas e as células MDA-MB-468 foram cultivadas a 37 °C no ar durante 96 horas. Subsequentemente, as células foram observadas sob microscópio e precipitação de fármaco e descobertas particulares foram investigadas e registradas. Em seguida, a placa de 96 poços foi colocada na temperatura ambiente durante 30 minutos, adicionada com 20 μL/poço de solução CellTiter-Glo (Cat No G7573, Promega) e agitada durante 10 minutos, em seguida sendo submetida à medição usando leitor de microplaca PHERAstarTM (BMG LABTECH), de acordo com o protocolo de luminômetro geral do fornecedor. Os poços onde apenas o líquido de cultura adicionado sem plaqueamento celular foram usados como um controle negativo, ao passo que os poços onde o líquido de cultura contendo DMSO a 0,1 % ao invés dos compostos listados nos Exemplos foram usados como um controle positivo.[0227] The inhibitory effects of the compounds of the present invention against the growth of cancer cells were evaluated, as shown below. Cancer cell lines, including prostate cancer cell lines (LNCaP, DU-145), stomach cancer cell lines (NCI-N87) and breast cancer cell lines (MDA-MB-468) were cultured under the protocol provided by each vendor. A medium supplemented with 10 ng/ml IL-6 was used for LNCaP, a prostate cancer cell line, when treated with a drug. Each cell type used in the experiments was subcultured into a 96-well plate by counting the exact number of cells using a Tali™ Image-based Cytometer (Life Technologies). In a 96-well plate, DU-145 was used at 3,000 cells/well; NCI-N87 was used at 5,000 cells/well; and LNCaP and MDA-MB-468 were used at 10,000 cells/well. Cells were treated with the compounds listed in the Examples which were diluted to various concentrations. After completion of compound treatment, LNCaP, DU-145, NCI-N87 cells were grown at 37°C under 5% CO 2 for 96 hours and MDA-MB-468 cells were grown at 37°C in air for 96 hours. Subsequently, cells were observed under a microscope and drug precipitation and particular findings were investigated and recorded. Then, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No G7573, Promega) and stirred for 10 minutes, after which it was subjected to measurement using a PHERAstarTM microplate (BMG LABTECH), according to the supplier's general luminometer protocol. Wells where only culture liquid was added without cell plating were used as a negative control, whereas wells where culture liquid containing 0.1% DMSO instead of the compounds listed in the Examples were used as a positive control.

[0228]Os resultados dos efeitos inibitórios dos compostos preparados nos Exemplos contra o crescimento de células de câncer são mostrados na Tabelas 10 a 13 abaixo.Tabela 10Tabela 11 Tabela 12 Tabela 13 [0228] The results of the inhibitory effects of the compounds prepared in the Examples against the growth of cancer cells are shown in Tables 10 to 13 below. Table 10 Table 11 Table 12 Table 13

[0229]Conforme mostrado nas Tabelas 10 a 13, os compostos, de acordo com a presente invenção, exibiram efeitos inibitórios excelentes contra o crescimento de vários tipos de células de câncer.[0229] As shown in Tables 10 to 13, the compounds according to the present invention exhibited excellent inhibitory effects against the growth of various types of cancer cells.

Claims (11)

1. Composto CARACTERIZADO pelo fato de que é selecionado a partir do grupo que consiste em um heterocíclico representado pela fórmula (I) e um sal farmaceuticamente aceitável e um estereoisômero do mesmo: em que: um entre X1, X2, X3 e X4 é -C(-Rx)=, e os outros são, independentemente, - C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH= ou -N=; Rx é Xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6, alquilcarbonila C1-6- alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou heterociclila de 5 a 10 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio, alquila C1-6, carbamoil-alquila C1-6, alquilamino C1-6-alquila C1-6 ou dialquilamino C1-6-alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, cada um, independentemente, hidrogênio, halogênio, nitro, amino, alcóxi C1-6, haloalcóxi C1-6 ou alquilsulfonila C1-6; A e B são, cada um, independentemente, um carbociclo C3-10 monocíclico ou bicíclico, saturado ou insaturado ou heterociclo de 5 a 12 membros; Rc é =O, =NH, =N(-alquila C1-6) ou =N(-OH); RN é hidrogênio ou alquila C1-6, ou RN é ligado a RA para formar uma cadeia; LB é -[C(-RL)(-RL’)]m-, -[C(-RL)(-RL’)]n-O-, -O-, -NH-, -N(alquila C1-6)-, -S(=O)2-, -C(=O)-, ou -C(=CH2)-, em que m é um número inteiro de 0 a 3, n é um número inteiro de 1 a 3, RL e RL’ são, cada um, independentemente, hidrogênio, hidróxi, halogênio ou alquila C1-6, ou RL e RL’ são ligados para formar uma cadeia; RA é hidrogênio, halogênio, ciano, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alquilcarbonila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, alquilamino C16, dialquilamino C1-6, alquiltio C1-6, alquilaminocarbonila C1-6, dialquilaminocarbonila C1-6, alquinila C2-8, alcóxi-carbonilamino C1-6-alcóxi C1-6, aminoalcóxi C1-6 ou heterociclila de 3 a 6 membros, ou RA é ligado a RN para formar uma cadeia; RB é hidrogênio, halogênio, hidróxi, ciano, nitro, amino, oxo, aminossulfonila, sulfonilamido, alquilamino C1-6, alquila C1-6, haloalquila C1-6, cianoalquila C1-6, alcóxi C1-6, haloalcóxi C1-6, cianoalcóxi C1-6, cicloalquilóxi C3-8, alquenila C2-8, alquenilóxi C28, alquinila C2-8, alquinilóxi C2-8, alquilamino C1-6-alcóxi C1-6, dialquilamino C1-6-alcóxi C1-6, alcóxi-carbonila C1-6, carbamoila, carbamoila-alcóxi C1-6, alquiltio C1-6, alquilsulfinila C1-6, alquilsulfonila C1-6, heterociclila de 5 a 10 membros, heterociclila de 5 a 10 membros-alquila C1-6, heterociclila de 5 a 10 membros-alcóxi C1-6 ou heterociclila-óxi de 5 a 10 membros; p é um número inteiro de 0 a 4 e, quando p é 2 ou maior, porções de RA são as mesmas ou diferentes; q é um número inteiro de 0 a 4 e, quando q é 2 ou maior, porções de RB são as mesmas ou diferentes; e cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo ou contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste em -O-, -NH-, -N=, -S-, - S(=O)- e -S(=O)2- na cadeia, e não substituída ou substituída com pelo menos um selecionado a partir do grupo que consiste em halogênio, alquila C1-6 e alcóxi C1-6; e cada um entre o dito heterociclo e porções de heterociclila contém, independentemente, pelo menos um heterogrupo selecionado a partir do grupo que consiste em -O-, -NH-, -N=, -S-, -S(=O)- e -S(=O)2-.1. Compound CHARACTERIZED by the fact that it is selected from the group consisting of a heterocyclic represented by formula (I) and a pharmaceutically acceptable salt and a stereoisomer thereof: wherein: one of X1, X2, X3 and X4 is -C(-Rx)=, and the others are independently -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH= or -N=; Rx is Xs is =O or =NH; Ls is -C(-Rs')(-Rs'')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, C1-6 aminoalkyl, or 5- to 10-membered heterocyclyl , or Rs is joined to Rs' to form a chain; Rs' and Rs'' are independently hydrogen, halogen, C1-6 alkyl, carbamoyl-C1-6 alkyl, C1-6 alkylamino-C1-6 alkyl or diC1-6 alkylamino-C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is each independently hydrogen, halogen, nitro, amino, C1-6 alkoxy, C1-6 haloalkoxy, or C1-6 alkylsulfonyl; A and B are each independently a saturated or unsaturated C3-10 monocyclic or bicyclic carbocycle or 5- to 12-membered heterocycle; Rc is =O, =NH, =N(-C1-6 alkyl) or =N(-OH); RN is hydrogen or C1-6 alkyl, or RN is linked to RA to form a chain; LB is -[C(-RL)(-RL')]m-, -[C(-RL)(-RL')]nO-, -O-, -NH-, -N(C1-6 alkyl) -, -S(=O)2-, -C(=O)-, or -C(=CH2)-, where m is an integer from 0 to 3, n is an integer from 1 to 3, RL and RL' are each independently hydrogen, hydroxy, halogen or C1-6 alkyl, or RL and RL' are joined to form a chain; RA is hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C16 alkylamino, C1-6 dialkylamino , C1-6 alkylthio, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C2-8 alkynyl, C1-6 alkoxycarbonylamino-C1-6 alkoxy, C1-6 aminoalkoxy or 3- to 6-membered heterocyclyl, or RA is attached to RN to form a chain; RB is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6 alkylamino, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C3-8 cycloalkyloxy, C2-8 alkenyl, C28 alkenyloxy, C2-8 alkynyl, C2-8 alkynyloxy, C1-6 alkylamino-C1-6 alkoxy, C1-6 dialkylamino-C1-6 alkoxy, alkoxy- C1-6 carbonyl, carbamoyl, carbamoyl-C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C1-6 alkyl, 5 to 10 membered-C 1-6 alkoxy or 5 to 10 membered heterocyclyl-oxy; p is an integer from 0 to 4 and, when p is 2 or greater, RA portions are the same or different; q is an integer from 0 to 4 and, when q is 2 or greater, portions of RB are the same or different; and each of said chains is independently a saturated or unsaturated C2-10 hydrocarbon chain not containing or containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, - S-, -S(=O)- and -S(=O)2- in the chain, and unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1-6 alkoxy ; and each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-. 2. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que: um entre X2 e X3 é -C(-Rx)= e o outro é -C(-Rx’)= ou -N=; X1 e X4 são, independentemente, -C(-Rx’)= ou -N=; um entre Y e Z é -S- ou -NH- e o outro é -CH=; e Rx e Rx’ são os mesmos definidos na reivindicação 1.2. Compound, according to claim 1, CHARACTERIZED by the fact that: one of X2 and X3 is -C(-Rx)= and the other is -C(-Rx')= or -N=; X1 and X4 are independently -C(-Rx')= or -N=; one of Y and Z is -S- or -NH- and the other is -CH=; and Rx and Rx' are the same as defined in claim 1. 3. Composto, de acordo com a reivindicação 2, CARACTERIZADO pelo fato de que: Rx é Xs é =O ou =NH; Ls é -C(-Rs’)(-Rs’’)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6 ou heterociclila de 5 a 6 membros, ou Rs é ligado a Rs’ para formar uma cadeia; Rs’ e Rs’’ são, cada um, independentemente, hidrogênio, halogênio ou alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, ou Rs’ é ligado a Rs para formar uma cadeia; Rx’ é, cada um, independentemente, hidrogênio ou halogênio; e cada uma entre as ditas cadeias é, independentemente, uma cadeia de hidrocarboneto C2-7 saturada ou insaturada não contendo ou contendo pelo menos um heteroátomo selecionado a partir do grupo que consiste em O, N e S.3. Compound, according to claim 2, CHARACTERIZED by the fact that: Rx is Xs is =O or =NH; Ls is -C(-Rs')(-Rs'')-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, or 5- to 6-membered heterocyclyl, or Rs is joined to Rs' to form a chain; Rs' and Rs'' are each independently hydrogen, halogen or C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, or Rs' is linked to Rs to form a chain; Rx' is each independently hydrogen or halogen; and each of said chains is independently a saturated or unsaturated C2-7 hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of O, N and S. 4. Composto, de acordo com a reivindicação 3, CARACTERIZADO pelo fato de que: A é benzeno ou uma heteroarila de 5 a 10 membros contendo 1 a 3 átomos de nitrogênio; B é um carbociclo C6-10 monocíclico ou bicíclico, saturado ou insaturado ou heterociclo de 5 a 10 membros; LB é -[C(-RL)(-RL’)]m-, -O-, -NH- ou -N(alquila C1-6)-, em que m é 0 ou 1, RL e RL’ são, cada um, independentemente, hidrogênio, hidróxi, halogênio ou alquila C1-6, ou RL e RL’ são ligados em conjunto para formar alquileno C2-5; RA é halogênio, alcóxi-carbonilamino C1-6-alcóxi C1-6, aminoalcóxi C1-6 ou heterociclila de 3 a 6 membros; RB é halogênio, alquila C1-6, alcóxi C1-6, haloalquilóxi C1-6, alquenilóxi C2-6, alquinilóxi C2-6, alcóxi-carbonila C1-6, carbociclila C3-10-óxi ou heterociclila-alcóxi de 3 a 10 membros C1-3; e cada uma entre as ditas porções heteroarila, heterociclo e heterociclila contêm, cada uma, independentemente, 1 a 3 heteroátomos selecionados a partir do grupo que consiste em O, N e S.4. Compound, according to claim 3, CHARACTERIZED by the fact that: A is benzene or a 5- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; B is a C6-10 monocyclic or bicyclic, saturated or unsaturated carbocycle or 5- to 10-membered heterocycle; LB is -[C(-RL)(-RL')]m-, -O-, -NH- or -N(C1-6 alkyl)-, where m is 0 or 1, RL and RL' are, each independently hydrogen, hydroxy, halogen or C1-6 alkyl, or RL and RL' are bonded together to form C2-5 alkylene; RA is halogen, C1-6alkoxycarbonylamino-C1-6alkoxy, C1-6aminoalkoxy, or 3- to 6-membered heterocyclyl; RB is halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkoxycarbonyl, C3-10 carbocyclyl-oxy, or 3- to 10-alkoxy heterocyclyl members C1-3; and each of said heteroaryl, heterocycle and heterocyclyl moieties each independently contains 1 to 3 heteroatoms selected from the group consisting of O, N and S. 5. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que: X1 e X4 são -CH=; X2 é -C(-Rx)=; X3 é -N= ou -C(-Rx’)-; Y é -C=; Z é -S-; Rx é Ls é -C(-CH3)(-CH3)-; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6alquila C1-6, alquilcarbonila C1- 6alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou uma heterociclila de 5 a 10 membros contendo 1 a 3 heteroátomos selecionados a partir do grupo que consiste em O, N e S; Rx’ é hidrogênio, halogênio, nitro, amino, alcóxi C1-6, haloalcóxi C1-6 ou alquilsulfonila C1-6; Rc é =O; e RN é hidrogênio.5. Compound, according to claim 1, CHARACTERIZED by the fact that: X1 and X4 are -CH=; X2 is -C(-Rx)=; X3 is -N= or -C(-Rx')-; Y is -C=; Z is -S-; Rx is Ls is -C(-CH3)(-CH3)-; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C1-6 alkylcarbonylC1-6 alkyl, C2-7 alkenyl, amino, C1-6 aminoalkyl, or a 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, N and S; Rx' is hydrogen, halogen, nitro, amino, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 alkylsulfonyl; Rc is =O; and RN is hydrogen. 6. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que: X1, X3 e X4 são -CH=; X2 é -C(-Rx)=; Y é -C=; Z é -S-; Rx é Ls é -C(-Rs’)(-Rs’’)-; Xs é =O ou =NH; Rs é alquila C1-6, haloalquila C1-6, alcóxi C1-6-alquila C1-6, alquilcarbonila C1-6- alquila C1-6, alquenila C2-7, amino, aminoalquila C1-6 ou um heterociclila de 5 a 10 membros contendo 1 a 3 heteroátomos selecionados a partir do grupo que consiste em O, N e S; Rs’ e Rs’’ são, independentemente, hidrogênio, halogênio, alquila C1-6, carbamoilalquila C1-6, alquilamino C1-6-alquila C1-6 ou dialquilamino C1-6-alquila C1-6, ou Rs’ e Rs’’ são ligados para formar uma cadeia, em que a cadeia é uma cadeia de hidrocarboneto C2-10 saturada ou insaturada não contendo ou contendo pelo menos um heterogrupo selecionado a partir do grupo que consiste em -O-, -NH-, -N=, -S-, - S(=O)- e -S(=O)2- na cadeia, e não substituída ou substituída com pelo menos um selecionado a partir do grupo que consiste em halogênio, alquila C1-6 e alcóxi C1-6; Rc é =O; e RN é hidrogênio.6. Compound, according to claim 1, CHARACTERIZED by the fact that: X1, X3 and X4 are -CH=; X2 is -C(-Rx)=; Y is -C=; Z is -S-; Rx is Ls is -C(-Rs')(-Rs'')-; Xs is =O or =NH; Rs is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, aminoC1-6 alkyl or a 5 to 10 heterocyclyl members containing 1 to 3 heteroatoms selected from the group consisting of O, N and S; Rs' and Rs'' are independently hydrogen, halogen, C1-6 alkyl, carbamoylC1-6 alkyl, C1-6 alkylamino-C1-6 alkyl, or diC1-6 alkylamino-C1-6 alkyl, or Rs' and Rs'' are linked to form a chain, wherein the chain is a saturated or unsaturated C2-10 hydrocarbon chain containing no or containing at least one heterogroup selected from the group consisting of -O-, -NH-, -N= , -S-, -S(=O)- and -S(=O)2- in the chain, and unsubstituted or substituted with at least one selected from the group consisting of halogen, C1-6 alkyl and C1 alkoxy -6; Rc is =O; and RN is hydrogen. 7. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que: X1, X3 e X4 são -CH=; X2 é -C(-Rx)=; Y é -C=; Z é -S-; Rx é o mesmo conforme definido na reivindicação 1; Rc é =O; e RN é hidrogênio.7. Compound, according to claim 1, CHARACTERIZED by the fact that: X1, X3 and X4 are -CH=; X2 is -C(-Rx)=; Y is -C=; Z is -S-; Rx is the same as defined in claim 1; Rc is =O; and RN is hydrogen. 8. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que: X1, X2 e X4 são -CH=; X3 é -C(-Rx)=; Y é -C=; Z é -S- ou -NH-; Rx é Xs é =O; Ls é -C(-CH3)(-CH3)-; Rs é metila; Rc é =O; e RN é hidrogênio.8. Compound, according to claim 1, CHARACTERIZED by the fact that: X1, X2 and X4 are -CH=; X3 is -C(-Rx)=; Y is -C=; Z is -S- or -NH-; Rx is Xs is =O; Ls is -C(-CH3)(-CH3)-; Rs is methyl; Rc is =O; and RN is hydrogen. 9. Composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que é selecionado a partir do grupo que consiste em: 1) N-(3-cloro-5-(2-(3-etóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 2) N-(3-cloro-5-(2-(3-propóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 3) N-(3-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 4) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroetóxi)-5- (trifluorometóxi)fenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno- 2-carboxamida; 5) N-(3-cloro-5-(2-(3-(1,1,2,2-tetrafluoroetóxi)-5-(trifluorometóxi)fenil)propan- 2-il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 6) N-(3-metóxi-5-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 7) N-(3-cloro-5-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 8) N-(3-cloro-5-(2-(3-(2-morfolinoetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 9) N-(3-bromo-5-(2-(3-isopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 10) N-(3-(2-(3-(but-2-in-1-ilóxi)-5-(trifluorometóxi)fenil)propan-2-il)-5- clorofenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 11) N-(3-cloro-5-(2-(3-isobutóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 12) N-(3-cloro-5-(2-(3-(2,2,2-trifluoroetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 13) N-(3-cloro-5-(2-(3-(2,2-difluoroetóxi)-5-(trifluorometóxi)fenil)propan-2- il)fenil)-5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 14) N-(3-(2-(3-(alilóxi)-5-(trifluorometóxi)fenil)propan-2-il)-5-clorofenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 15) N-(3-cloro-5-(2-(3-ciclopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 16) N-(3-cloro-5-(2-(3-isopropóxi-5-(trifluorometóxi)fenil)propan-2-il)fenil)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 17) N-(3-cloro-5-(2-(4-metoxifenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 18) N-(3-cloro-5-(2-(4-fluorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 19) N-(3-cloro-5-(2-(4-fluorofenil)propan-2-il)fenil)-6-fluoro-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 20) N-(3-bromo-5-(2-(4-fluorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 21) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 22) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 23) 6-cloro-N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 24) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxamida; 25) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5- (fluoro(metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 26) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(2-(metilsulfonil)propan-2- il)tieno[2,3-c]piridino-2-carboxamida; 27) N-(3-cloro-5-(2-(5-clorotiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 28) N-(3-cloro-5-(2-(5-isopropiltiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 29) N-(3-cloro-5-(2-(5-metoxitiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 30) N-(3-cloro-5-(2-(2-metoxitiofen-3-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 31) N-(3-cloro-5-(2-(1-metil-1H-pirrol-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 32) N-(3-cloro-5-(2-(4-metiltiofen-2-il)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 33) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(1- (metilsulfonil)ciclopropil)benzo[b]tiofeno-2-carboxamida; 34) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-(4-(metilsulfonil)tetra- hidro-2H-piran-4-il)benzo[b]tiofeno-2-carboxamida; 35) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-6-(2-(metilsulfonil)propan-2- il)-1H-indol-2-carboxamida; 36) N-(3-cloro-5-(2-(4-clorofenil)propan-2-il)fenil)-5-((S- metilsulfonimidoil)metil)benzo[b]tiofeno-2-carboxamida; 37) N-(3-cloro-5-(4-(trifluorometóxi)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 38) N-(3-cloro-5-(4-(trifluorometil)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 39) N-(3-bromo-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 40) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-(2-(metilsulfonil)propan-2-il)-1H-indol- 2-carboxamida; 41) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-((metilsulfonil)metil)benzo[b]tiofeno-2- carboxamida; 42) N-(3-cloro-5-(4-clorofenóxi)fenil)-5- (((trifluorometil)sulfonil)metil)benzo[b]tiofeno-2-carboxamida; 43) N-(3-cloro-5-(4-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 44) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-fluoro-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 45) 6-cloro-N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 46) N-(3-(4-clorofenóxi)-5-metoxifenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 47) N-(3-cloro-5-(3-cloro-5-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 48) N-(3-cloro-5-(3-(trifluorometóxi)fenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 49) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 50) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2-il)tieno[2,3- c]piridino-2-carboxamida; 51) N-(3-cloro-5-(3-cloro-4-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 52) N-(3-cloro-5-(3,4-difluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 53) N-(3-cloro-5-(3-fluoro-5-metoxifenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 54) N-(3-cloro-5-(4-cloro-3-fluorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 55) N-(3-cloro-5-(2-(3-cloro-5-metoxifenil)propan-2-il)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 56) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(4-(metilsulfonil)tetra-hidro-2H-piran-4- il)benzo[b]tiofeno-2-carboxamida; 57) N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2-((2-metoxietil)sulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 58) N-(3-cloro-5-(4-clorofenóxi)fenil)-6-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 59) N-(3-(azetidin-1-il)-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 60) N-(3-cloro-5-((6-cloropiridin-3-il)óxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 61) N-(3-cloro-5-((5-cloropiridin-2-il)óxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 62) N-(2-cloro-6-(3,5-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 63) N-(6-cloro-4-(4-clorofenóxi)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 64) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 65) N-(2-cloro-6-((6-cloropiridin-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 66) N-(4-cloro-6-(4-clorofenóxi)piridin-2-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 67) N-(2-cloro-6-(4-(trifluorometil)fenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 68) N-(2-cloro-6-(4-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 69) N-(2-bromo-6-(4-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 70) N-(2-cloro-6-(3-cloro-5-metoxifenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 71) N-(2-cloro-6-(3-cloro-4-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 72) N-(2-cloro-6-(4-cloro-3-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 73) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(1,1-dioxidotetra-hidrotiofen-2- il)benzo[b]tiofeno-2-carboxamida; 74) N-(2-cloro-6-(4-clorofenóxi)piridin-4-il)-5-(1,1-dioxidotetra-hidro-2H- tiopiran-2-il)benzo[b]tiofeno-2-carboxamida; 75) N-(2-cloro-6-(4-clorofenóxi)pirimidin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 76) N-(6-cloro-2-(4-clorofenóxi)pirimidin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 77) N-(2-(4-clorofenóxi)-6-fluoropiridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 78) N-(2-(biciclo[2,2,1]hept-5-en-2-ilóxi)-6-cloropiridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 79) N-(2-cloro-6-(3,4-difluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 80) N-(2-cloro-6-(3-clorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 81) N-(2-cloro-6-(3-(trifluorometóxi)fenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 82) N-(2-cloro-6-(3,4-diclorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 83) N-(2-cloro-6-(4-cloro-2-fluorofenóxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 84) N-(2-cloro-6-(4-(trifluorometóxi)fenóxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 85) N-(2-cloro-6-((5-cloropiridin-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 86) N-(2-cloro-6-((4-clorobenzil)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 87) N-(3-cloro-5-(2-(3-(prop-1-in-1-il)-5-(trifluorometóxi)fenil)propan-2-il)fenil)- 5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 88) N-(1-(terc-butil)-3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 89) N-(3-(2-(4-clorofenil)propan-2-il)-1H-pirazol-5-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 90) N-(2-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-4-il)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 91) N-(4-cloro-6-(2-(3-metóxi-5-(trifluorometóxi)fenil)propan-2-il)piridin-2-il)-5- (2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 92) N-(3-cloro-5-((2,2,6,6-tetrametilpiperidin-4-il)óxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 93) (2-(3-(4-clorofenóxi)-5-(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxamido)fenóxi)etil)carbamato de terc-butila; 94) N-(3-(2-aminoetóxi)-5-(4-clorofenóxi)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 95) N-(5-cloro-2’,4’-difluoro-[1,1’-bifenil]-3-il)-5- ((metilsulfonil)metil)benzo[b]tiofeno-2-carboxamida; 96) (8-cloro-6-(4-clorofenóxi)-2,3-di-hidro-4H-benzo[b][1,4]oxazin-4-il)(5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofen-2-il)metanona; 97) N-(3-cloro-5-(1-(4-clorofenil)ciclopropil)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 98) N-(3-cloro-5-((2,4-difluorofenil)(metil)amino)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 99) N-(3-cloro-5-((4-clorofenil)(metil)amino)fenil)-5-(2-(metilsulfonil)propan-2- il)benzo[b]tiofeno-2-carboxamida; 100) N-(2-cloro-6-((4-clorofenil)(metil)amino)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 101) N-(2-cloro-6-((4-clorociclo-hex-3-en-1-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 102) N-(2-cloro-6-((octa-hidroindolizin-7-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 103) 2,2,2-trifluoroacetato de N-(3-cloro-5-(4-clorofenóxi)fenil)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboximidamida; 104) N-(2-cloro-6-(hexa-hidropirrolo[1,2-a]pirazin-2(1H)-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 105) N-(2-(4-(terc-butil)piperidin-1-il)-6-cloropiridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 106) N-(2-cloro-6-(octa-hidro-2H-pirido[1,2-a]pirazin-2-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 107) N-(2-cloro-6-(7-etil-2,7-diazaespiro[4,4]nonan-2-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 108) N-(2-cloro-6-(octa-hidroisoquinolin-2(1H)-il)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 109) N-(2-cloro-6-((5-metiltiazol-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 110) N-(2-cloro-6-((1-metil-1H-pirazol-5-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 111) N-(2-cloro-6-((1,3,5-trimetil-1H-pirazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 112) N-(2-cloro-6-((1-metil-1H-pirazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 113) N-(2-cloro-6-((3,5-dimetilisoxazol-4-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 114) N-(2-cloro-6-((5-metiltiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 115) N-(2-cloro-6-((2-metiltiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 116) N-(2-cloro-6-((4,5-dimetilisoxazol-3-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 117) N-(2-cloro-6-((5-(trifluorometil)tiofen-3-il)óxi)piridin-4-il)-5-(2- (metilsulfonil)propan-2-il)benzo[b]tiofeno-2-carboxamida; 118) 3-((6-cloro-4-(5-(2-(metilsulfonil)propan-2-il)benzo[b]tiofeno-2- carboxamido)piridin-2-il)óxi)isoxazol-5-carboxilato de metila; 119) N-(2-cloro-6-((4-metiltiazol-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; 120) N-(2-cloro-6-((5-metiltiofen-2-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida; e 121) N-(2-cloro-6-((2-clorotiofen-3-il)óxi)piridin-4-il)-5-(2-(metilsulfonil)propan- 2-il)benzo[b]tiofeno-2-carboxamida.9. Compound, according to claim 1, CHARACTERIZED by the fact that it is selected from the group consisting of: 1) N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy) phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 2) N-(3-chloro-5-(2-(3-propoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 3) N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 4) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 5) N-(3-chloro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 6) N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 7) N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 8) N-(3-chloro-5-(2-(3-(2-morpholinoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 9) N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 10) N-(3-(2-(3-(but-2-yn-1-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(2-( methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 11) N-(3-chloro-5-(2-(3-isobutoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 12) N-(3-chloro-5-(2-(3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl) )propan-2-yl)benzo[b]thiophene-2-carboxamide; 13) N-(3-chloro-5-(2-(3-(2,2-difluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan -2-yl)benzo[b]thiophene-2-carboxamide; 14) N-(3-(2-(3-(allyloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 15) N-(3-chloro-5-(2-(3-cyclopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzoic [b]thiophene-2-carboxamide; 16) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2 -carboxamide; 17) N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 18) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 19) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 20) N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 21) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 22) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2- carboxamide; 23) 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 24) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 25) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(fluoro(methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 26) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c] pyridine-2-carboxamide; 27) N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 28) N-(3-chloro-5-(2-(5-isopropylthiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 29) N-(3-chloro-5-(2-(5-methoxythiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 30) N-(3-chloro-5-(2-(2-methoxythiophen-3-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 31) N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 32) N-(3-chloro-5-(2-(4-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 33) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(1-(methylsulfonyl)cyclopropyl)benzo[b]thiophene-2-carboxamide; 34) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[ b]thiophene-2-carboxamide; 35) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxamide ; 36) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((S-methylsulfonimidoyl)methyl)benzo[b]thiophene-2-carboxamide; 37) N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 38) N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 39) N-(3-bromo-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 40) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)-1H-indole-2-carboxamide; 41) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 42) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(((trifluoromethyl)sulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 43) N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 44) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-fluoro-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 45) 6-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 46) N-(3-(4-chlorophenoxy)-5-methoxyphenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 47) N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 48) N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 49) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 50) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)thieno[2,3-c]pyridine-2-carboxamide; 51) N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 52) N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 53) N-(3-chloro-5-(3-fluoro-5-methoxyphenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 54) N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 55) N-(3-chloro-5-(2-(3-chloro-5-methoxyphenyl)propan-2-yl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 56) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxamide; 57) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-((2-methoxyethyl)sulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 58) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 59) N-(3-(azetidin-1-yl)-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 60) N-(3-chloro-5-((6-chloropyridin-3-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 61) N-(3-chloro-5-((5-chloropyridin-2-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 62) N-(2-chloro-6-(3,5-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 63) N-(6-chloro-4-(4-chlorophenoxy)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 64) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 65) N-(2-chloro-6-((6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 66) N-(4-chloro-6-(4-chlorophenoxy)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 67) N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 68) N-(2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 69) N-(2-bromo-6-(4-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 70) N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 71) N-(2-chloro-6-(3-chloro-4-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 72) N-(2-chloro-6-(4-chloro-3-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 73) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(1,1-dioxidotetrahydrothiophen-2-yl)benzo[b]thiophene-2-carboxamide; 74) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(1,1-dioxidotetrahydro-2H-thiopyran-2-yl)benzo[b]thiophene-2- carboxamide; 75) N-(2-chloro-6-(4-chlorophenoxy)pyrimidin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 76) N-(6-chloro-2-(4-chlorophenoxy)pyrimidin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 77) N-(2-(4-chlorophenoxy)-6-fluoropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 78) N-(2-(bicyclo[2,2,1]hept-5-en-2-yloxy)-6-chloropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 79) N-(2-chloro-6-(3,4-difluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 80) N-(2-chloro-6-(3-chlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 81) N-(2-chloro-6-(3-(trifluoromethoxy)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 82) N-(2-chloro-6-(3,4-dichlorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 83) N-(2-chloro-6-(4-chloro-2-fluorophenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 84) N-(2-chloro-6-(4-(trifluoromethoxy)phenoxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 85) N-(2-chloro-6-((5-chloropyridin-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 86) N-(2-chloro-6-((4-chlorobenzyl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 87) N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2- (methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 88) N-(1-(tert-butyl)-3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 89) N-(3-(2-(4-chlorophenyl)propan-2-yl)-1H-pyrazol-5-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 90) N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 91) N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 92) N-(3-chloro-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 93) tert-butyl (2-(3-(4-chlorophenoxy)-5-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)phenoxy)ethyl)carbamate ; 94) N-(3-(2-aminoethoxy)-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 95) N-(5-chloro-2',4'-difluoro-[1,1'-biphenyl]-3-yl)-5-((methylsulfonyl)methyl)benzo[b]thiophene-2-carboxamide; 96) (8-chloro-6-(4-chlorophenoxy)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-(methylsulfonyl)propan -2-yl)benzo[b]thiophen-2-yl)methanone; 97) N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 98) N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide ; 99) N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamide; 100) N-(2-chloro-6-((4-chlorophenyl)(methyl)amino)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2 -carboxamide; 101) N-(2-chloro-6-((4-chlorocyclohex-3-en-1-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl) benzo[b]thiophene-2-carboxamide; 102) N-(2-chloro-6-((octahydroindolizin-7-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 103) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboximidamide 2,2,2-trifluoroacetate ; 104) N-(2-chloro-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2- yl)benzo[b]thiophene-2-carboxamide; 105) N-(2-(4-(tert-butyl)piperidin-1-yl)-6-chloropyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide; 106) N-(2-chloro-6-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 107) N-(2-chloro-6-(7-ethyl-2,7-diazaspiro[4,4]nonan-2-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2 -yl)benzo[b]thiophene-2-carboxamide; 108) N-(2-chloro-6-(octahydroisoquinolin-2(1H)-yl)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 109) N-(2-chloro-6-((5-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 110) N-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide; 111) N-(2-chloro-6-((1,3,5-trimethyl-1H-pyrazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2- yl)benzo[b]thiophene-2-carboxamide; 112) N-(2-chloro-6-((1-methyl-1H-pyrazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[ b]thiophene-2-carboxamide; 113) N-(2-chloro-6-((3,5-dimethylisoxazol-4-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 114) N-(2-chloro-6-((5-methylthiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 115) N-(2-chloro-6-((2-methylthiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 116) N-(2-chloro-6-((4,5-dimethylisoxazol-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b] thiophene-2-carboxamide; 117) N-(2-chloro-6-((5-(trifluoromethyl)thiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b ]thiophene-2-carboxamide; 118) 3-((6-chloro-4-(5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene-2-carboxamido)pyridin-2-yl)oxy)isoxazole-5-carboxylate of methyl; 119) N-(2-chloro-6-((4-methylthiazol-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; 120) N-(2-chloro-6-((5-methylthiophen-2-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene- 2-carboxamide; and 121) N-(2-chloro-6-((2-chlorothiophen-3-yl)oxy)pyridin-4-yl)-5-(2-(methylsulfonyl)propan-2-yl)benzo[b]thiophene -2-carboxamide. 10. Composição farmacêutica, CARACTERIZADA pelo fato de que compreende o composto, conforme definido na reivindicação 1, como um ingrediente ativo e um veículo farmaceuticamente aceitável.10. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises the compound, as defined in claim 1, as an active ingredient and a pharmaceutically acceptable vehicle. 11. Uso do composto, de acordo com a reivindicação 1, CARACTERIZADO pelo fato de que é para a fabricação de um medicamento para prevenção ou tratamento de doenças associadas com a ativação da proteína STAT3 em um mamífero, em que o medicamento é formulado para ser administrado a um mamífero, em que as doenças são selecionadas a partir do grupo que consiste em câncer de mama, câncer de pulmão, câncer de estômago, câncer de próstata, câncer uterino, câncer ovariano, câncer renal, câncer pancreático, câncer de fígado, câncer de cólon, câncer de pele, câncer de cabeça e pescoço, câncer da tireoide, osteossarcoma, leucemia aguda ou crônica, mieloma múltiplo, linfoma de células B ou T, linfoma não-Hodgkin, artrite reumatoide, psoríase, hepatite, doença inflamatória intestinal, doença de Crohn, diabetes, degeneração macular, infecção por papilomavírus humano e tuberculose.11. Use of the compound, according to claim 1, CHARACTERIZED by the fact that it is for the manufacture of a medicine for the prevention or treatment of diseases associated with the activation of the STAT3 protein in a mammal, in which the medicine is formulated to be administered to a mammal, wherein the diseases are selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B or T cell lymphoma, non-Hodgkin lymphoma, rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease , Crohn's disease, diabetes, macular degeneration, human papillomavirus infection and tuberculosis.
BR112017011312-0A 2014-12-02 2015-11-30 COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND BR112017011312B1 (en)

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