Fused tricyclic heterocyclic compounds for treating diseases associated with the modulation of STAT3 protein

Abstract

The invention relates to a heterocyclic derivative represented by formula (I), (see formula I) or a pharmaceutically acceptable salt or a stereoisomer thereof, which has an inhibitory effect on the activation of STAT3 protein, and is useful for the prevention or treatment of diseases associated with the activation of STAT3 protein, such as solid cancers, hematological or blood cancers, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological diseases, diabetes, macular degeneration, human papillomavirus infection or tuberculosis.

Description

FUSED TRICYCLIC HETEROCYCLIC COMPOUNDS FOR TREATING DISEASES ASSOCIATED Wiffl THE MODULATION OF STAT3 PROTEIN 5 FIELD OF THE INVENTION The present invention relates to novel heterocyclic compounds, uses thereof for the prevention or treatment of diseases associated with the activation of STAT proteins, particularly, STAT3 protein and phannaceutical compositions comprising same. BACKGROUND OF THE INVENTION Signal transducer and activator of transcription (STAT) proteins are transcription factors which transduce signals from various extracellular cytokines and growth factors to a nucleus. Seven (7) 15 subtypes of STAT proteins (i.e., STATl, STAT2, STAT3, STAT4, STATSa, STATSb and STAT6) are currently known, and generally they consist of about 750 - 850 amino acids. In addition, each subtype of STAT proteins contains several conserved domains which play an important role in exhibiting the function of STAT proteins. Specifically, five (5) domains from N-terminus to C-terminus of STAT proteins have been reported including coiled-coiled domain, 20 DNA binding domain, linker domain, SH2 domain and transactivation domain (TAD)). Further, X-ray crystalline structures ofSTATl, STAT3, STAT4 and STATS have been reported since 1998 (Becker Set 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, 25 G-CSF, GM-CSF, LIF, thrombopoietin, etc., bind to Class I receptors, while INF-a, INF-y, IL-10, etc., bind to Class II receptors (SchindlerC etal., Annu. Rev. Biochem., 1995, 64; NovickD eta!., 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 30 family, an interferon family and a receptor tyrosine kinase family. Interleukin -6 family cytokines are representative multifunctional cytokines which mediate various physiological activities. When interleukin-6 cytokine binds to IL-6 receptor which is present on the cell membrane surface, it attracts gp-130 receptor to form an IL-6-gp-130 receptor complex. At the same time, JAK 1 Date Re9ue / Date Received 2022-06-13 kinases (JAKl, JAK2, JAK.3 and Tyk2) in the cytoplasm are recruited to a cytoplasmic region of gp130 to be phosphocylated and activated. Subsequently, latent cytoplasmic STAT proteins are attracted to a receptor, phosphorylated by JAK. kinases and activated. la Date Re9ue / Date Received 2022-06-13 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 Tyrosine-705 adjacent to the SH2 domain located in 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 translocalized into a nucleus a.pd bind to a specific DNA 5 binding promoter to promote the transcription. Through its transcription process, various proteins (Myc, Cyclin D1 / D2, Bcl-xL, Mel, survivin, VEGF, HIF-1, immwie suppressors, etc.) associated with cell proliferation, survival, angiogenesis and immun.e evasion are produced (Stark et al., Annu. Rev. Biochem., 1997, 67; Levy et al., Nat. Rev. Mol. Cell Biol., 2002, 3). 10 In particular, STAT3 protein is known to play a c~cial role in the acute inflammatory response and the signal transduction pathway ofIL-6 and EGF (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, uterine, ovary, head and neck, etc., and 'also in 15 patients with blood cancer such as acute and chronic leukemia, multiple myeloma, etc. Further, it has been reported that the survival rate of a patient group with activated STAT3 is remarkably lower than that of a patient group with inactivated STAT3 (Masuda et al., Cancer Res., 2002, 62; Benekli et al., Blood, 2002, 99; Yuichi·et al., Int. J. Oncology, 2007, 30). Meanwhile, STAT3 was identified to be an essential factor for the growth and 20 maintenance of murine embryonic stem cells in a study employing a STAT3 knockout mouse model. Also, 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 tissuespecific manner (Akira et al., Oncogene 2000, 19). Moreover, since apoptosis induced by anti-sensing STAT3 was observed in various cancer cell lines, STAT3 is considered as a 25 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; Meanwhile, newly identified Thl 7 cells have been reported through a number of recent articles to be associated with various autoimmune diseases (Jacek Tabarldewicz et 30 at. Arch. hmnunol. Ther. Exp., 2015, 11). Based on these reports, a control of the differentiation and function ofThl 7 cells is considered as a good target in the treatment of related diseases. In particular, since STAT3-dependent IL-6 and IL-23 signal transductions are known as important factors in the differentiation of Thl 7 cells (Xuexian 0. Yang et al., J. Biol. Chem., 2007, 282; Harris T J et al., J. Immunol., 2007, 179), an 35 inhibition of the fimction of STAT3 is expected to be effective in the treatment of diseases associated with Thl 7 cells such as systemic lupus erythematosus, uveitis, :rheumatoid arthritis, autoimmune thyroid disease, inflammatory bowel disease, psoriasis and psoriatic arthritis (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Ex.p., 2015, 11 ). Recently, IL-6 and IL-23 antibodies are under clinical studies on the treatment of 40 arthritis and psoriasis associated with Thl 7 cells and exhtl>it a clinical efficacy (Nishimoto 2 N. et al., Arthritis Rheum., 2004, 50; Gerald G. et al., N. Engl. J. Med., 2007, 356). This also confirms that the inhibition of STAT3 signal transduction is an effective therapeutic method for such diseases. In contrast, while having intracellular response pathways of identical cytokines and growth 5 factors to those of STAT3, STATl increases inflammation and congenital and acquired immunities to inhibit the proliferation of cancer cells or cause pro-apoptotic responses, unlike STAT3 (Valeria Poli et al., Review, Landes Bioscience, 2009). In order to develop STAT3 inhibitors, the following methods can be considered: i) inhibition of the phosphorylation of STAT3 protein by IL-6 / gp-130 / JAK kinase, ii) inhibition of 10 the dimerization of activated STAT3 proteins, and iii) inhibition of the binding of STAT3 dimer to nuclear DNA Small molecular STAT3 inhibitors are currently under development. Specifically, OPB-31121 and OPB-51602 are under clinical studies on patients with solid cancers or blood cancers by Otsuka Pharmaceutical Co., Ltd. Further, S31:-201 (Siddiquee et al., Proc. Natl. Acad Sci., 2007, 104), S3I-M2001 (Siddiquee et al., Chem. Biol., 2007, 2), LLL-12 (Lin et 15 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 to be effective in a cancer cell growth inhibition experiment and in animal model (in vivo Xenograft model). Furthermore, although peptide compounds mimicking the sequence of amino acid ofpY-705 (STAT3) adjacent 20 to the binding site to SH2 domain or the amino acid sequence of gp-130 receptor in which JAK kinases bind were studied (Coleman et al., J. Med Chem., 2005, 48), the development of the peptide compounds has not been successful due to the problems such as solubility and membrane permeability. 25 SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide novel heterocyclic derivatives for the inhibition of the activation of STAT3 protein. It is another object of the present invention to provide uses of the heterocyclic derivatives 30 for the prevention or treatment of diseases associated with the activation of STAT3 protein. In accordance with one aspect of the present invention, there is provided a compound selected from the group consisting of a heterocyclic derivative represented by formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof: 3 Date Re9ue / Date Received 2022-06-13 wherein one ofX1 and X2 is -C(-Rx)(-Rx")-, -C(-Rx')(-Rx")-,, -N(Rx)-, or -N(-Rx')-, and the other 5 is -C(-Rx")(-Rx")-, -N(-Rx")-, -C(=O)- or -0-; 0 Rs-M-i II ~ Rx is Xs Xs is =O or =NH; Rs is C1-6alkyl, haloC1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C2- 1alkenyl, amino, or aminoC1-6alkyl; 10 Rx' is haloC1-6alkyl, C1-4alkoxycarbonyl, cyano, nitro, azido, amino, a 3- to 6-membered heterocyclyl unsubstituted or substituted with Rx", or a 5- to 6-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N, S and 0, unsubstituted or substituted with oxo; Rx" is each independently hydrogen, halogen, nitro, amino, C1-6alkyl, C1-6alkoxy, haloCi- 15 6alkoxy, carbamoylC1-6alkyl, C1-6alkylamino-C1-6alkyl, C1-4alkoxycarbonyl, or diC1-6alkylaminoC1- 6alkyl; Y is -CH= and Z is -S-; Lx is a saturated or unsaturated Ci-4 hydrocarbon chain not containing or containing 1 to 3 heterogroups selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2- in 20 the chain, unsubstituted or substituted with at least one Rx" moiety; 25 A is benzene or a 6- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; B is a monocyclic- saturated or unsaturated C6carbocycle; Re is =O, =NH, =N(-C1-6alkyl), or =N(-OH); RN is hydrogen or C1-6alkyl; LB is -[C(-RL)(-RL')]m-, -[C(-RL)(-RL')]n-O-, -0-, -C(=O)-, or -C(=CH2)-, wherein mis an integer of O to 3, n is an integer of 1 to 3, RL and RL' are each independently hydrogen, or C 1-6alky 1, or RL and RL' are linked together to form C1-6alkylene; RA is hydrogen, halogen, cyano, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, C1- 6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, C1-6alkylamino, diC1-6alkylamino, 4 Date Re9ue / Date Received 2023-11-29 C1-6alkylthio, C1-6alkylaminocarbonyl, diC1-6alkylaminocarbonyl, 6alkoxycarbonylamino-C1-6alkoxy, aminoC1-6alkoxy, or 3- to 6-membered heterocyclyl; RB is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6alkylamino, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1- 5 6alkoxy, C3-scycloalkyloxy, C2-salkenyl, C2-salkenyloxy, C2-salkynyl, C2-salkynyloxy, C1- 6alkylamino-C 1-6alkoxy, di C 1-6alkylamino-C 1-6alkoxy, C 1-6alkoxy-carbonyl, carbamoy 1, carbamoyl-C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, 5- to IO-membered heterocyclyl, 5- to IO-membered heterocyclyl-C1-6alkyl, 5- to IO-membered heterocyclyl-C1- 6alkoxy, or 5- to IO-membered heterocyclyl-oxy; p is an integer of Oto 4, and, when pis 2 to 4, RA moieties are the same as or different from each other; q is an integer of Oto 4, and, when q is 2 to 4, RB moieties are the same as or different from each other; and each of said 5- to IO-membered heterocycle, 3- to 6-membered heterocyclyl, and 5- to 10- 15 membered heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-. In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable additive. 20 In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable additive, and wherein the pharmaceutical composition is for preventing or treating a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, 25 human papillomavirus infection, tuberculosis, 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 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, hepatitis or auto-immune disease. 30 In accordance with another aspect of the present invention, there is provided a use of the compound of the invention for the manufacture of a medicament for prevention or treatment of a disease associated with the activation of STAT3 protein. The invention provides a use of the 5 Date Re9ue / Date Received 2023-11-29 compound of the invention for the manufacture of a medicament for prevention or treatment of a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection, tuberculosis, breast cancer, lung cancer, stomach cancer, prostate 5 cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, hepatitis or auto-immune disease. In accordance with another aspect of the present invention, there is provided a use of the 10 compound of the invention for prevention or treatment of a disease described above. In accordance with another aspect of the present invention, there is provided the compound of the invention for use in prevention or treatment of a disease described above. In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating diseases associated with the activation of 15 STAT3 protein, including a disease described above, 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. In accordance with a still further aspect of the present invention, there is provided a method for preventing or treating diseases associated with the activation of STAT3 protein in a mammal, 20 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. The heterocyclic derivative represented by formula (I) above, or a pharmaceutically acceptable salt or a stereoisomer thereof has an excellent inhibitory effect on the activation of 25 STAT3 protein, and thus it can be used for the prevention or treatment of diseases associated with the activation of STAT3 protein. 30 DETAILED DESCRIPTION OF THE INVENTION The present invention will be further described in detail herein below. In the specification of the present invention, the term "halogen" refers to fluoro, chloro, bromo or iodo, unless specified otherwise. The term "alkyl" refers to a linear or branched hydrocarbon moiety, unless specified otherwise. Sa Date Re9ue / Date Received 2023-11-29 The terms "haloalkyl", "haloalkoxy", "halophenyl", etc., respectively refer to alkyl, alkoxy, and phenyl substituted with at least one halogen. 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 Sb Date Re9ue / Date Received 2023-11-29 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 "carbocyclyl'' refers to a radical of "carbocycle'\ and is used as a tenn inclusive of "cycloa1kyl" and "aryl". The term "cycloa1kyl" refers to a saturated hydrocarbon radical, which may be monocyclic or polycyclic. The tenn '"aryl" -refers to an aromatic hydrocarbon ring, which may be monocyclic or polycyclic. 5 The terms "carbocycle", "carbocyclyl", "cycloalkyl" and "aryl" may refer to, for example, a monocycle or polycycle having 3 to 20 carbon atoms, and will be indicated as "Cs.20 carbocycle", "C3.20 carbocyclyl'\ "C3.20 cycloalkyl", and "C3.20 aryl't, respectively. The term "heterocycle" refers to an aromatic or non-aromatic ring having at least one heteroatom, which may be saturated or unsaturated, and a monocycle or polycycle. 10 The term "heterocyclyl" refers to a radical of "heterocycle", which is used as a term inclusive of "heterocycloalkyl" and "heteroaryl". The term "heterocycloalkyl" refers to a saturated ring radical having at least one heteroato~ 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. 15 The tenn ''heteroatom" may be selected from N, 0 and S. The terms •'beterocycle", "heterocyclyl", "heterocycloalkyl" and "heteroaryl" may refer to, for example, a mono- or •polycycle having 3 to 20 heteroatoms and / or carbon ~ms,. and will be indicated as "3- to 20-membered heterocyclen, "3- to 20-membered heterocyclyl", "3- to 20-membered heterocycloalkyl", and "3- to 20-membered heteroaryl". 20 The terms '"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 C2.1ohydrocarbon chain containing at least one heterogroup selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and - S(=O)2- in the· chain, for example, -CH2-0-CH2-, -CH2-O-CH2-O-CH2-, -CH2-CH=CH- 25 NH- and -CH2-CH2-S(=0)2-CH2-O-, unless specified otherwise. The chain may be substituted with at least one selected from the group consisting of halogen, C1-6alkyl and C1-6alkoxy. wherein X1 and X2 are each independently -C(-Rx)(-Rx")-, -C(-Rx')(•Rx"h -C(-Rxj(- 35 Rx")- ► -C(=O)-, -N(Rx)-, -N(-Rx')-, -N(-Rx1')-, or -0-; 6 WO 2016 / 089062 0 Rs-~-I II ~ Rxis Xs Xs is =O or =NH; CA 02966742 2017-05-03 PCT / KR2015 / 012926 Rs is C1-68lkyl, haloC1-6alkyl, C1-<;alkoxy-C1-6alkyl, C1-6alkylcarbo11yl-C1.6alkyl, C2.7alkenyl, amino, or aminoC1 .. 64llkyl; 5 Rx' is haloC1-6a1kyl, Ca-4alkoxycarbonyl, cyano, nitro, azido, amino, or a 3- to 6- membered heterocyclyl unsubstituted or substituted with Rx"; Rx" is each independently hydrogen, halogen, nitro, amino, C1.6alkyl, C1_6alkoxy, haloC1-6alkoxy, carbamoylC 1.681kyl, C 1-6alkylamino-C1-6alk:yl, or diC1-<;alkylamino-C 1- 6ft}kyl; 10 one ofY and Z is -S- or -NH-, and the other is -CH= or-N=; Lx is a saturated or unsaturated C1.4 hydrocarbon chain not containing or containing 1 to 3 heterogroups 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 Rx" moiety; 15 A and B are each independently a monocyclic- or bicyclic-saturated or unsaturated C3.10carbocycle or 5- t? 12-membered heterocycle; Re is =O, =NH, =N(-C1~lkyl), or =N(-OH); RN is hydrogen or C1.6alkyl; Ls is -[C(-RL)(-RL')]m·, -[C(-RL)(-RL')]n-O-, -0-, -NH-, -N(C1-6alkyl)-, -S(=O)2-, - 20 C(=O)-, or -C{=CH2)-, wherein m is an integer of 0 to 3, n is an integer of 1 to 3, RL and RL' are each independently hydrogen. hydroxy, halogen or C1.6alkyl, or RL and RL' are linked together to form C1-6alkylene; RA is hydrogen, halogen, cyano, C1.5alkyl, ~loC1-6alkyl, cyanoC1-6alkyl, C1. 6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, C1-6alkylamino, diCi- 25 6alkylamino, C1~lkylthio, C1.6alk:ylaminocarbonyl, diC1-6alkylaminocarbonyl, C2. salkynyl, C1.6ftlkoxycarbonylamino-C1.6alkoxy, aminoC1.5alkoxy, or 3- to 6-membered heterocyclyl; Rs is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6Blkylamino, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alk:yl, C1-6alkoxy, 30 haloC1.6ftlkoxy, cyanoC1-6alkoxy, C3.gcycloalkyloxy, C2.salkenyl, C2-salkenyloxy, C2. 8alkynyl, C2..galkynyloxy, C1-6alkylamino-C1-6alkoxy, diC14ilkylamino-C1_6alk:oxy, C1 .. 631koxy-carbonyl, carbamoyl, carbamoyl-C1.6alkoxy, C1.6alkylthio, C1-6alk:ylsulfinyl, C1. 68,lkylsulfonyl, 5- to IO-membered heterocyclyl, 5- to 10-membered heterocyclyl-C1.6alkyl, 5- to 10-membered heterocyclyl-C1-6alkoxy, or 5- to 10-membered heterocyclyl-oxy; 35 p is an integer of_O to 4, and, when p is 2 or higher, RA moieties are the same as or different from each other; q is an integer of Oto 4, and, when q is 2 or higher, Ro moieties are the same as or different from each other; and 7 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and - S(=0)2-. In a preferred embodiment of the compound of formula (I), one ofY and Z is -S- or -NH-, and the other is -CH=; Lx is a saturated C1.3 hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of 0, N and S in the chain, and unsubstituted or substituted with at least one substituent selected from the group consisting 10 ofhalogen, C1-6alkyl and C1.6alkoxy; one of X1 and X2 is -C(-Rx)(-Rx•~-, -C(-Rx')(-Rx11)-, -C(=O)-, -N(Rx)- or -N(- Rx'h and the other is -C(-Rx")(-Rx"h -N(-Rx")- or -0-; 0 II I Rs-w- Rx is Xs Xs is =O or =NH; 15 Rs is C1-6alkyl or haloC1-6alkyl; Rx' is haloC1-6alk:yl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl containing at least one heteroatom selected ftom the group consisting ofN, S and O and unsubstituted or substituted with oxo; Rx" is hydrogen, halogen, C1-6alkyl, or C1-4alkoxycarbonyl; and 20 Re, RN, A, B, LB, RA, RB, p and q are the same as defined above in formula (I). In a preferred embodiment of the compound of formula (I), Yis-CH=; Z is-S-; 25 Re is=O; RN is hydrogen; Lx is a saturated C1_3 hydrocarbon chain not containing or containing oxygen atom in the chain~ and unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C1-6alkyl and Cu;alkoxy; 30 X1 is-C(-Rx)(-Rx"h -C(-Rx')(-Rx")-, or-N(Rx)-; X2 is -C(-Rx")(-Rx")-, -C(=O)-, -N(-Rx")-, or -0-; 0 II I HaC-S- 11 Rxis Xs Xs is =O or =NH; Rx' is haloC1-6alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered 35 heterocyclyl containing 1 to 2 heteroatoms selected • from N and O and unsubstituted or substituted with oxo; 8 5 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 Rx" is hydrogen, halogen, C1,68lkyl, or C14alkoxycarbonyl; and A, B, L8 , R& R8 , p and q are the same as defined above in formula (I). In a preferred embodiment of the compound of formula (1), Yis :..cH=; Z is-S-; Rcis=O; RN is hydrogen; Lx is a saturated C1_3 hydrocarbon chain not containing or containing oxygen atom 10 in the chain, and unsubstituted or substituted with at least one substituent selected from the group consisting ofhalogen, C1-68lkyl and C1-6alkoxy; X1 is-C(-Rx)(-Rx")-, -C(-Rx')(-Rx"h or-N(Rx)-; X2 is-C(-Rx")(-Rx")-, -C(=O)-, -N{-Rx")-, or -0-; w Hac-s-1 II Rxis Xs 15 Xs is =O or =NH; Rx' , is haloC1.6alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl containing I to 2 heteroatoms selected from N and O and unsubstituted or substituted with oxo; Rx''. is hydrogen, halogen, C1-6alkyl, or C1-4alkoxycarbonyl; 20 A is benzene or a 5- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; B is a monocyclic- or bicyclic-saturated or unsaturated C6-10carbocycle or 5- to I 0- membered heterocycle; Ls is -[C(-RL)(-RL')]m-, -0-, -NH- or -N(C1-6alkylh wherein mis 0 or 1, RL and Ri.' are each independently hydrogen, hydroxy, halogen or C1-6alkyl, or RL and RL' are 25 linked together to fonn C2.salkylene; RA is halogen, Cualkoxycarbonylamino-C1.6alkoxy, aminoC1.6alkoxy, or 3- to 6- membered heterocyclyl; RB is halogen, C1.6a1kyl, C1-6alkoxy, haloC1-6alkyloxy, C2~enyloxy, C3. 1ocarbocyclyl-oxy, or 3- to 10-membered heterocyclyl-C1.3alkoxy; and 30 each of said heteroaryl, heterocycle and heterocyclyl moieties independently contains 1 to 3 heteroatoms selected from the group consisting of 0, N and S. In a preferred embodiment of the compound of fonnula (I), X1 is-N(-Rx)-; 35 X2 is-C(-Rx")(-Rx")-or-N(-Rx")-; Yis-CH=; Z is-S-; Rcis=O; 9 CA 02966'142 201'1-05-03 WO 2016 / 089062 RN is hydrogen; Lx is ethylene substituted with one or two Rx" moieties, 0 Rs-~-1 II Rxis Xs ; Xsis=O; 5 Rs is methyl; Rx" is the same as defined above in fonnula (I); and PCT / KR2015 / 012926 A, B, L8 , RA. Rs, p and q are the same as defined above in formula (I). In a preferred embodiment of the compound offonnula (I),· 10 X1 is -CH(-Rx)-; X2 is -N(-Rxu)-; Yis-CH=; Z is -S-; Re is=O; 15 RN is hydrogen; Lx is ethylene; 0 Rs-!-i 11 I Rx is Xs Xsis=O; Rs is methyl; 20 Rx" is the same as defined above in fonnula (I); and A, B, La, RA. Ra, p and q are the same as defined above in fonnula (I). In a preferred embodiment of the compound of formula (I), X1 is -C(-Rx)(-Rx")-; 25 X2 is-O-; Yis-CH=; Z is -S-; Re is=O; RN. is hydrogen; 30 Lx is ethylene; 0 Rs-!-1 11 i Rx is Xs Xs is=O; Rs is methyl; Rx" is the same as defined above in formula (I); and 10 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 A, B, LB, RA, Rs, p and q are the same as defined above in formula (I). In a preferred embodiment of the compound of fonnula (I), X1 is-C(-Rx')(-Rx")-; S X2 is -0-; Yis-CH=; Z is-S-; Re is=O; RN is hydrogen; 10 Lx is ethylene; Rx' and Rx.11 are the same defined above in formula (I); and A, B, L8 , RA, RB, p and q are the same as defined above in fonnula (I). In a preferred embodiment of the compound of formula (I), 15 X1 is -CH(-Rx)-; X2 is -C(-Rx")(-Rx")- or -C(=O)-; Yis-CH=; Z is-S-; Rcis=O; 20 RN is hydrogen; Lx is ethylene; , 0 ' Rs-~-I 11 I Rx is Xs Xsis=O; Rs is methyl; 25 Rx" is the same as defined above in formula (I); and A, B, L1;11 RA, Rs, p and q are the same as defined above in fonnula (I), In a preferred embodiment of the compound of formula (I), X1 is -CH(-Rx)-; 30 X2 is -C(-Rx")(-Rx")-; Yis-CH=; Z is-S-; Rcis=O; RN is hydrogen; 35 Lx is -CH2-0-; 0 Rs-!-1 II I Rxis Xs 11 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 Xs is=O; Rs is methyl; Rx" is the same as defined above in fonnula (I); and A, B, La, RA, R8, p and q are the same as defined above in formula (I). In a preferred embodiment of the compound offonnula (I), X1 is -C(-Rx)(-Rx")- or -N(Rx)-; X2 is-O-; Yis-NH-; 10 Z is-CH=; Rcis=O; RN is hydrogen; Lx is propylene; Rx and Rx" are the same as defined above in formula (I); and 15 A, B, LB, RA, RB, p and q are the same as defined above in formula (I). Preferable examples of the compound according to the present invention are listed below, and a pharmaceutically acceptable salt and a stereoisomer thereof are also included in the scope of the present invention: . 20 I) N-{2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)~ l-(methylsulfonyl)~2,3-dihydro- 1H-thieno [3',2':4,S]benzo[l ,2-b ][ l ,4 ]oxazine-7-carboxamide; 2) N-{2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-3,3-dimethyl-1- (me!hylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,S]benzo[l,2-b][l,4]oxazine-7-carboxamide; 3) N-{2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-1-(methylsulfonyl)-1,2,3,4- 25 tetrahydrothieno[3',2':4,5]benzo[l,2-b][l,4]oxazepine-8-carboxamide; • '" 4) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-8,8-dimethyl-5- (methylsulfonyl)-S,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxamide; 5) tert-butyl 7-((2-chloro-6-(4-chloropbenoxy)pyridin-4-yl)carbamoyl)-1- (methylsulfonyl )-2,3-dihydrothieno[2,3-g ]quinoxaline-4(1H)-carboxylate; 30 6) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-S-(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3-g]quinoline-2-carboxamide; 7) N-(2..chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-methyl-1-(methylsulfonyl)- l,2,3 ,4-tetrahydrothieno[2,3-g]quinoxaline-7-carboxamide; 8) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro- 35 2H-thieno[3,2-g]chromene-7-carboxamide; 9) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonyl)-2,3,4,5- tetrahydrothieno[3',2':4,S]benzo[l,2-b]oxepine-8-carboxamide; 10) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-S-(methylsulfonyl)-S,6,7,8- tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide; 40 11) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-methyl-4-(methylsulfonyl)- 12 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 3,4-dihydro-2H-thieno[3,2-g] chromene-7-carboxamide; 12) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl )-5-(methylsulfonyl)-5,8- dihydro-6H-thieno[3,2-g]isochromene-2-carboxa:mide; 13) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-fluoro-4-(methylsulfonyl)- 5 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 14) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-8 ,8-difluoro-5 - (methylsulfonyl)-5,6, 7 ,8-tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide; • 15) N-(2-cbloro-6-(p-tolyloxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide; 10 16) N-(2-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)· 3,4-dihydro-2H-thieno[3 ,2-g] chromene-7-carboxamide; 17) N-(2-chloro--6-( 4-(trifluoromethyl )phenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3).-g]chromene-7-carboxamide; 18) N-(2-chloro-6-(3,S-dichlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 15 dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 19) N-(2-chloro-6-( 4-chloro-3 -fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3).-g]chromene-7-carboxamide; 20) N-(2-chloro-6-( 4-chloro-3-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 20 21) N-(2-chloro-6-( 4-chloro-2-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 22) N-(2-chloro-6-( 4-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl )-3,4- dillydro-2H-thieno[3,2-g]chromene-7-carboxamide; 23) N-(2-chloro-6-( 4-chloro-2-fluorophenoxy)pyridhl-4-yl)-4-(methylsulfonyl)- 25 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 24) N-(2-chloro-6-(3,4-dichlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3Adihydro- 2H-thieno[3,2-g]chromene-7-carboxamide; 25) 1V-(2-chloro-6-(3-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 30 26) N-(2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro- 2H-thieno[3,2-g]chromene-7-carboxamide; 27) N-(2-chloro-6-(3-chloro-4-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g] chromene-7-carboxamide; 28) N-(2-chloro-6-(4-(trifluoromethoxy)phenoxy)pyridin-4-yl)-4- 35 (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 29) N-(2-chloro-6-(3-(trifluoromethoxy)phenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 30) N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 40 31) N-(2-chloro-6-(3-chloro-5-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 13 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 3,4-dihydro-2H-thieno[3,2-g ]chromene-7-carboxamide; 32) N-(2-chloro-6-(3-fluoro-5-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 33) N-(2-chloro-6-(m-tolyloxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hs thieno[3,2-g]chromene-7-carboxamide; 34) N-(2-chloro-6-(3,4-difluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxarnide; 3 5) N-(2-chloro-6-(5-chloro-2-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g] chromene-7-carboxamide; 10 36) N-(2-chloro-6-(3-chloro-2-tluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g] chromene-7-carboxamide; 37) N-(2-chloro-6-(5-chloro-2-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno [ 3,2-g] chromene-7-carboxamide;· 38) N-(2-chloro-6-(3-chloro-4-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 15 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; -39) N-(2-chloro-6-(2-(trifluoromethyl)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-21 / -thieno [ 3,2-g] chromene-7-carboxamide; 40) N-(2-chloro-6-(2-(trifluoromethoxy)phenox.y)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 20 41) N-(2-chloro-6-(2-fluoro-3-methylphenoxy)pyridin-4-yl)-4-(inethylsulfonyl)- 3,4-dihydro-2H-thieno(3,2-g] chromene-7-carboxamide; 42) N-(2-chloro-6-(4-chloro-2-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[ 3,2-g]chromene-7-carboxamide; 43) (S)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 25 dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 44) (R)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxarnide; 45) (S)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl )-4-fluoro-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 30 46) (R)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-tluoro-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 4 7) (S)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-methyl-4- (methylsulfony1)-3,4-dihydro-2H-thieno[3 ,2-g] chromene-7-carboxamide; 48) (R)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-methyl-4- 35 (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 49) (S)-N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 50) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-l-(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxaline-7-carboxamide; 40 51) . N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonyl)-8-oxo- 14 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 5,6, 7,8-tetrahydronaphtho[2 ,3-b )thiophene-2-carboxamide; 52) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-(IH-pyrazol-1-yl)-3,4- dihydro-2H-tbieno[3,2-g]chromene-7-carboxamide; 53) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-(2-oxopyrrolidin-1-yl)-3 ,4- s dihydro-2H-tbieno[3,2-g]chromene-7-carboxamide; 54) N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4-cyano-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide; 55) 4-azido-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide; and 10 56) N-{3-chloro-5-(2-( 4-chlorophenyl)propan-2-yl)phenyl)-l-(methylsulfonyl)- 2,3-dihydro-1H-thieno[3',2':4,5]benzo[l ,2-b )[l ,4]oxazine-7-carboxamide. The above-listed names of the compounds are described in accordance with the nomenclature method provided by ChemBioDraw Ultra software (Version 13.0.0.3015) of 15 PerkinElmer. The present invention provides a phannaceutically acceptable salt of a heterocyclic derivative represented by fonnula (I) above. The pharmaceutically acceptable salt should have low toxicity to humans, and should not have any negative impact on the biological 20 activities and physicochemical properties of parent compounds. . Examples of the phannaceutically acceptable salt may include an acid addition salt between a pharmaceutically usable free acid and a basic compound represented by formula (1), an alkaline 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 25 fonnula (I), amino acid addition salt, etc. Examples of a suitable form of salts according to the present invention may be a salt with an inorganic acid or organic acid, wherein the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc., and the organic acid may be acetic acid, metbanesulfonic acid, ethanesulfonic acid, p- 30 toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. The organic base which may be used for the preparation of the organic base addition salt may include tris(hydroxymethyl)methylamine, dicyclohexylamine, etc. Amino acids which may be 35 used for the preparation of amino acid addition.base may include natural amino acids.such as alanine, and glycine. The salts may be prepared using a conventional method. For example, the salts may be prepared by dissolving the compound represented by fonnula (I) in a watermiscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, adding a free acid or 40 a free base, and then crystallizing the resultant thereafter. 15 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 Additionally, the compounds of the present invention may have a chiral carbon center, and thus they 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 belopg to the scope of the present invention. 5 Additionally, the compounds of the present invention may also include a hydrate or 10 solvate of the heterocyclic derivative represented by fonnula (I). The hydrate or solvate may be prepared using a known method, and they are preferred to be non-toxic and watersoluble, and in particular, they are preferably water or a hydrate or solvate having 1-5 molecules of alcoholic solvent (especially ethanol, etc.) bound thereto. 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 medicament for preventing or treating diseases associated with the activation of STAT3 15 protein. Further, the present invention provides method for preventing or treating diseases associated with the activation of 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 20 stereoisomer thereof to the mammal. Further, the present invention provides a pharmaceutical composition for preventing or treating diseases associated with the activation of 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 25 active ingredients. Specifically, the diseases associated with the activation of STAT3 protein is selected from·the group consisting of solid cancers, hematological or blood cancers, radioor chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological 30 diseases, diabetes, macular degeneration, human papillomavirus infection and tuberculosis. More specifically, the diseases associated with the activation. of STAT3 protein 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 35 leukemia, multiple myeloma, .B- or T-cell lymphoma, non-Hodgkin's lymphoma, autoimmune diseases comprising rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis. 40 In particular, a heterocyclic derivative represented by formula (I) above, or a 16, 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 pharmaceutically acceptable salt or a stereoisomer thereof has an excellent inhibitory effect on the activation of STAT3 protein, and thus the present invention also provides a composition for the inhibition of STAT3 protein comprising the same. as an active ingredient. 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 further include as active ingredients, common and non-toxic pharmaceutically acceptable additives, for example, a carrier, an excipient, a 10 diluent, an adjuvant, etc., to be formulated into a preparation according to a conventional method. The pharmaceutical composition of the present invention may 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, 15 intravenous or subcutaneous injections, etc., and preferably in the form of a preparation for oral administration. Examples of the additives to 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, 20 preservatives, lubricants, fillers, flavoring agents, etc. For example, they may include, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium alluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, 25 orange essence, strawberry essence, vanilla flavor, etc. The phannaceutical composition of the present invention may be fonnulated into a preparation for oral administration by adding additives to active ingredients, wherein the additives may include cellulose, calcium s~icate, com stl1rch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, caicium stearate, gelatin, talc, 30 surfactants, suspension agents, emulsifiers, diluents, etc. The pharmaceutical composition of the present invention may be formulated into a preparation for injection by adding additives to the active ingredients, for example, water, a saline solution, a glucose solution, an aqueous glucose solution analog, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactants, suspension agents, emulsifiers, 35 etc. The compound of the present invention may be administered preferably in an amount ranging from 0.1 to 2,000 mg / day based on an adult subject with 70 kg body weight. The compound of the present invention may be administered once daily or a few 40 divided doses. The dosage of the compound of the present invention may vary depending 17 5 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 on the health conditions, age, body weight, sex of the subject, administration route, severity of illness, etc., and the scope of the present invention will not be limited to the dose suggested above. Example Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes and the present invention is 10 not limited thereto. The definition of the abbreviations used in the following examples is as follows. [Table 1] Abbreviation Full name A1Cl3 Aluminwn chloride ACN Acetonitrile AcOH Acetic acid AIBN 2,2'-Azobis(2-methylpropionitrile) BH3-THF complex 'Borane tetrahydrofuran complex BINAP 2,2'-Bis(diphenylphosphino)-l, l 1-binaphthyl BBr3 Boron tnbromide Boc20 IDi-tert-butyl dicarbonate Brine Brine is water saturated or nearly saturated with a brine salt (generally, sodium chloride) CH3CN Acetonitrile CDCh Deuterated chloroform CH2Cb Dichloromethane CH,I Methyl iodide '"'"' CH3S02Cl Methanesulfonyl chloride (COCI)i Oxalyl chloride Cs2C03 Cesium carbonate Cu20. Copper (I) oxide DAST (Diethylarnino )sulfin trifluride DIPEA N ,N-diisopropylethylamine DMA N.N-dimethylacetamide DME 1,2-Dimethoxyethane - DMF N.N-dimethylformamide DMSO Dimetbylsulfoxide DMSO-dc, Dimethylsulfoxide-d6 EtOAc Ethyl acetate EtOH Ethyl alcohol • 18 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 Et2O Diethyl ether HBr Hydrogen bromide HCl Hydrogen chloride H2SO,. Sulfuric acid n-Hex n-Hexane ·~~ HN03 Nitric acid H2O Water K2C~ Potassium carbonate LDA Lithium diisopropylamide LiOHH2O Lithium hydroxide. monohydrate MeOH Methyl alcohol NaB~ Sodium borohydride NaCN Sodium cyanide Na2CO3 Sodium carbonate Na2SO4 Sodium sulfate NaH Sodium hydride NaHC~ Sodium bicarbonate NaOH Sodium hydroxide NH4Cl Ammonium chloride NFS IN-fluorobenzenesulfonimide Ox.one Potassium peroxymonosulfate Pd(PPh.,)4 Tetrakis(triphenylphosphine)palladium(0) • Pd{OAch Palladium(II) acetate PBr3 Phosphorus tribromide PPh3 Triphenylphosphine SOCh Thionyl chloride THF Tetrahydrofuran TFA Trifluoroacetic acid Zn Zinc Intermediate 1) Synthesis of 1-(methylsulfonyl)-2,3-dihydro-1Hthieno[ 3' ,%':4,5] benzo[t,2-b] [1,4] o:uzine-7.:.carboxyllc acid (a) Synthesis of 2-fluoro-4-methoxy-5-nitrobenzaldehyde 2-Fluoro-4-methoxybenzaldehyde (1.0 g, 6.49 mmol) was dissolved in cone. H2SO4 (6.0 mL), and 70% HNO3 aqueous solution (0.8 mL, 6.49 mmol) and cone. H2SO4 (0.8 mL, 14.92 mmol) were slowly added at -15°C. The reaction mixture was stirred at - 10 15°C for 2 hours and poured into ice water. • The precipitate was filtered and dissolved in CH2Clz and neutralized with sat. NaHCO3 aqueous solution. 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: CH2Clz = 3 : 1) to obtain 2- 19 fluoro-4-methoxy-5-nitrobenzaldehyde (1.2 g, 91 %) as a white solid. 1H-NMR (400MHz, CDCh): <> 10.21 (s, lH), 8.46 (d, lH, J=7.2Hz), 6.88 (d, lH, J=ll.6Hz), 4.06 (s, 311) 5 (b) Synthesis of methyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (1.2 g, 6.43 mmol) was dissolved in anhydrous DMF(16.0 mL), and methyl 2-mercaptoacetate (575.0 μL, 6.43 mmol) and K2CO3 (1.8 g, 12.80 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours, H2O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 10 and concentrated under reduced pressure to obtain methyl 6-methoxy-5-nitrobenzo[b]thiophene- 2-carboxylate (1.5 g) as a yellow solid without purification. 1H-NMR (400MHz, CDCh): 8 8.34 (s, IH), 8.03 (s, 111), 7.47 (s, lH), 4.04 (s, 3H), 3.96 (s, 311) 15 (c) Synthesis of methyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate Methyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (1.3 g, 4.83 mmol) was dissolved in a mixture ofMeOH / IbO (44.0 mL, 10 / 1 v / v), and Zn (3.1 g, 65.30 mmol) and NH4Cl (2.6 g, 53.40 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 15 hours, filtered through Celite™, and concentrated under reduced pressure. 20 The residue was purified by flash column chromatography (amine silica gel, n-Hex : EtOAc = 4 : 1) to obtain methyl-5-amino-6-methoxybenzo[b ]thiophene-2-carboxylate (1.1 g, 93%) as a yellow solid. 25 1H-NMR (400MHz, CDCh): 8 7.84 (s, lH), 7.17 (s, lH), 7.12 (s, lH), 3.94-3.96 (m, SH), 3.91 (s, 311) ( d) Synthesis of methyl 5-amino-6-hydroxybenzo[b ]thiophene-2-carboxylate Methyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (500.0 mg, 4.83 mmol) was dissolved in CH2Cb (40.0 mL), and IM solution of BBn in CH2Ch (6.7 mL, 6.74 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, H2O was 30 added, and extracted with CH2Ch. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C 18-silica gel, 0.1 % formic acid in CHJCN : 0.1 % 20 Date Re9ue / Date Received 2022-06-13 formic acid in H2O) to obtain methyl 5-amino-6-hydroxybenzo[b]thiophene-2-carboxylate (398.0 mg, 85%) as a gray solid. LC / MS ESI (+): 224 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.15 (brs, lH), 7.85 (s, lH), 7.15 (s, lH), 7.07 (s, lH), 5 4.86 (hrs, 2H) 3.82 (s, 3H) ( e) Synthesis of methyl 2,3-dihydro-1H-thieno[3',2':4,5]benzo[l,2-b][l ,4]oxazine 20a Date Re9ue / Date Received 2022-06-13 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 7-carboxylate Methyl 5-amino-6-hydroxybenzo[b]thiophene-2-carboxylate (85.0 mg, 0.3 8 mmol) was dissolved in anhydrous DMF (3.8 mL), and 1,2-dibromoethane (215.0 mg, 1.14 mmol) and K2CO3 (116.0 mg, 0.83 mmol) were added at room temperature. The reaction 5 mixture was stirred at 75°C for 15 hours, H20 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 reversed-phase column chromatography (Cl8-silica gel, 0.1 % fonnic acid in CH3CN : 0.1 % fonnic acid in H20) to obtain methyl 2,3-dihydro-lH-thieno[3',2':4,5]benzo[l ,2-b][l ,4]oxazine-7-carboxylate 10 (45.2 mg, 47%) as a gray solid. LC / MS ESI(+): 250 (M+l) 1H-NMR (400MHz, DMSO-t4): o 7.89 (s, IH), 7.26 (s, lH), 7.07 (s, lH), 6.16 (s, lH), 4.19 (t, 2H, J= 4.6Hz), 3.82 (s, 3H), 3.30-3.32 (m, 2H) 15 (f) Synthesis of methyl 1-(methylsulfonyl)-2,3-dihydro-lH- . thieno[3',2' :4,5]benzo[ 1,2-b] [ 1 A]oxazine-7-carboxylate Methyl 2,3-dihydro-1H-thieno[3',2':4,5]benzo[l ,2-b] [ 1,4]oxazine-7-carboxylate (69.0 mg, 0.27 mmol) was dissolved in CH2Clz (2.7 mL), CH3SO2Cl (28.0 μL, 0.36 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temp~e for 1 20 hour, H2O was added, and extracted with CH2CI:i. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% fonnic acid in H20) to obtain methyl 1-(methylsulfonyl)-2,3- dihydro-1H-thieno[3't2':4,S]benzo[1,2-b][l,4]oxazine-7-carboxylate (42.3 mg, 46%) as a 25 white solid. LC / MS ESI (+): 328 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 8.21 (s, lH), 8.12 (s, lH), 7.63 (s, lH), 4.35 (t, 2H, J= 4.3Hz), 3.86-3.89 (m, SH), 3.17 (s, 3H) 30 (g) Synthesis of l-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[l,2- b][l,4]oxazine-7-carboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using methyl 1-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,S]benzo[l,2-b][l,4]oxazine-7- carboxyJate (42.0 mg, 0.12 mmol) to obtain l-(methylsulfonyl)-2,3-dihydro-lH- 35 thieno[3',2':4,5]benzo[l,2-b][l,4]oxazine-7-carboxylic acid (35.1 mg, 87%) as a white solid. 40 LC / MS ESI (-): 312 (M-1) 1H-NMR (400MHz, DMSO-d<>): 6 13.32 (brs, lH), 8.18 (s, lH), 8.00 (s, lH), 7.60 (s, lH), 4.36 (t, 2H,J= 4.7Hz), 3.89 (t, 2H,J=4.7Hz), 3.18 (s, 3H) 21 CA 02966742 201'1•05•03 WO 2016 / 089062 PCT / KR2015 / 012926 . Intermediate 2) Synthesis of 3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-lHthieno[ 3',2':4,5]benzo[1,2-b][1,4Joxazine-7-earboxyllc acid 5 (a) Synthesis of methyl 5-(2-bromo-2-methylpropanamido)-6- hydroxybenzo[b ]thiophene-2-carboxylate • Methyl 5-amino-6-hydroxybenzo[b]thiophene-2-carboxylate (110.0 mg, 0.49 mmol) was dissolved in DMA (5.0 mL), and 2-bromo-2-methyl propanoyl bromide (73.0 μL, 0.59 rnmol) and DIPEA (258.0 μL, 1.47 mmol) were added. The reaction mixture 10 was stirred at room temperature 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 reversed-phase column chromatography (Cl8-silica gel, O. l % formic acid in CH3CN : 0.1 % formic acid in H2O) to obtain methyl 5-(2-bromo-2-methylpropanamido )-6-hydroxybenzo[ b ]thiophene-2- 15 carboxylate (161.0 mg, 88%) as a white solid. LC / MS ESI (+): 372 (M+I) 1H-NMR (400MHz, DMSO-d6): 6 11.15 (hrs, lH), 9.24 (s, 1H), 8.49 (s, lH), 8.08 (s, lH), 7.43 (s, lH), 3.85 (s, 3H), 2.03 (s, 6H) 20 (b) Synthesis of methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1Hthieno[ 3' ,2' :4,S]benzo[ 1,2-b ][ 1,4]oxazine-7-carboxylate Methyl 5-(2-bromo-2-methylpropanamido)-6-hyd.roxybenzo[b]thiophene-2- carboxylate (161.0 mg, 0.43 mmol) was dissolved in DMA (4.3 mL) and K2CO3 (132.0 mg, 0.95 mmol) was added. The reaction mixture• was stirred at 60°C for 15 hours, H2O 25 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 reversed-phase column chromatography (Cl 8-silica gel, 0.1 % formic acid in CH3CN : 0.1 % formic acid in H2O) to obtain methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1Hthieno( 3',2':4,5]benzo[1,2-b][ l ,4]oxazine-7-carboxylate (112.0 mg, 89%) as a gray solid. 30 LC / MS ESI (-): 290 (M-1) 1H-NMR (400MHz, DMSO-d6): 6 10.95 (s, lH), 8.14 (s, lH), 7.66 (s, lH), 7.46 (s, lH), 3.86 (s, 3H), 1.44 (s, 6H) (c) Synthesis of methyl 3,3-dimethyl-2,3-dihydro-1H-thieno[3',2'~4,5]benzo[1,2-. 35 b][l,4]oxazine-7-carboxylate Methyl 3,3-dimethyl-2-oxo-2,3--dihydro-1H-thieno[3 ',2':4,5]benzo[l,2- b ][ l ,4 ]oxazine-7-carboxylate (112.0 mg, 0.38 mmol) was dissolved in THF (4.0 mL), and lM solution of BH3-THF complex (1.9 mL, 1.92 mmol) was added at. 0°C. The reaction mixture was stirred at room temperature for 3 hours, H20 was added, and extracted with 40 EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and 22 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1 % formic acid in CH3CN: 0.1 % formic acid in H20) to obtain methyl 3,3-dimethyl-2,3-dihydro~lif-thieno[3',2':4,S]be~o[l,2-b][l 14]oxazine-7- carboxylate (80.0 mg, 75%) as a gray solid. 5 LC / MS ESI (+): 278 (M+l) 1H-NMR (400MHz, DMSO-d6): 8 7.90 (s, IH), 7.23 (s, lH), 7.11 (s, HI), 6.26 (brs, lH), 3.83 (s, 3H) 3.06 (d, 2H, J=2.3Hz), 1.29 (s, 6H) (d) Synthesis of methyl 3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-IH- 10 thieno(3',2':4,5]benzo[l,2-b][1A]oxazine-7~carboxylate Methyi 3,3--dimethyl-2,3-dihydro-1H-thieno[3',2':4,S]benzo[l,2-b][l,4]oxazine-7- carboxylate (65.0 mg. 0.88 mmol) was dissolved in pyridine (2.3 mL) and CH3SOiCl (95.0 μL, 1.06 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 15 hours, H2O was added, and extracted with EtOAc. The organic extract • 15 was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (Cl8- silica gel, 0.1% fonnic acid in CH3CN :. 0.1% fonnic acid in H2O) to obtain methyl 3,3- dimethyl-l-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,S]benzo(1,2-b][l,4]oxazine-7- carboxylate (52.2 mg. 63%) as a white solid. 20 LC / MS ESI(+): 356 (M+l) 1H-NMR (400MHz, DMSO-dci): 8 8.20 (s, IH), 8.11 (s, lH), 7.56 (s, 'lH), 3.87 (s, 3H), 3.67 (s, 2H), 3.37 (s, 3H), 1.36 (s, 6H) • (e) Synthesis. of 3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-lH- 25 thieno[3',2':4,5]benzo[l ,2-b][ 1,4]oxazine-7-carboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using methyl 3,3-dimethyl-l-(methylsulfonyl)-2,3-dihydro-1H-thieno[3' ,2' :4,S]benzo[l ,2- b ][l ,4 ]oxazine-7-carboxylate (52.0 mg, 0.14 mmol) as a starting material to obtain 3,3- dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo(l,2-b)[l,4]oxazine-7- 30 carboxylic acid (45.0 mg, 90%). 35 LC / MS ESI (+): 342 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 13.30 (s, lH), 8.17 (~ lH), 8.01 (s, lH), 7.53 (s, 1H), 3.66 (s, 2H), 3.34 (s, 3H), 1.36 (s, 6H) Intermediate 3) Synthesis of 1-(methylsuJfonyl)-1,2,3,4- tetrahydrothieno[3',2':4,S]benzo(l,2-b][l,4]oxazephlne-8-carboxylic acid (a) Synthesis of methyl 6-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2- 40 carboxylate 23 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 Methyl 5-amino-6-hydroxybenzo[b]thiophene-2-carboxylate (126.0 mg, 0.56 mmol) was dissolved in pyridine (2.8 mL), and CH3SO2CI (50.6 μL, 0.64 mmol) was added dropwise. 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 S over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase colmnn chromatography (C18-silica gel, 0.1 % formic acid in CH3CN 0.1 % formic acid in H2O) to obtain methyl 6-hydroxy-5- (methylsulfonamido)benzo[ b]thiophene-2-carboxylate (131.0 mg, 77%) as a white solid. LC / MS ESI(-): 300 (M-1) 10 1H-NMR (400MHz, DMSO-d«;): o 9.92 (brs, lH), 8.08 (s, lH), 7.85 (s, lH), 7.43 (s, lH), 3.86 (s, 3H), 2.99 (s, 3H) (b) Synthesis of methyl 1-(methylsulfonyl)-1,2,3;4- tetrahydrothieno[3',2':4,5]benzo[ 1,2-b][ 1,4]oxazephine-8-carboxylate 15 Methyl 6-hydroxy-5-(methylsulfonamido )benzo[ b ]thiophene-2-carboxylate (5. 0 mg, 0.02 mmol) as a starting material was dissolved in OMA (160.0 μL). and 1,3- dibromopropane (16.7 mg, 0.08 mmol) and K2CO3 (116.0 mg, 0.83 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours, H2O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous 20 Na2SO4 and concentrated. under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 2 : 1) to obtain methyl 1- (methylsulfonyl)-l,2,3,4-tetrahydrothieno[3',2':4,5]benzo[l,2-b][l,4]oxazephine-8- carboxylate (1.2 mg, 21 %) as a white solid. LC / MS ESI (+): 342 (M+l) 25 1H-NMR (400MHz, DMSO-d6): 6 8.20 (s, lH), 8.07 (s, lH), 7.86 (~ lH), 4.13-4.15 (m, 2H), 3.89 (s, 3H), 3.72-3.75 (m, 2H), 3.09 (s, 3H), 2.04-2.07 (m, 2H) (c) Synthesis of l-(methylsulfonyl)-l ,2,3A-tetrahydrothieno[3',2':4,5]benzo[l,2- b][l ,4]oxazephine-8-carboxylic acid 30 The synthesis procedure of Intermediate 1-g was repeated except for using methyl 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[3 ',2 ':4,S]benzo[ 1,2-b] [ 1,4 ]oxazephine-8- carboxylate (42.0 mg, 0.12 mmol) as a starting material to obtain 1-(methylsulfonyl)~ l,2,3A-tetrahydrothieno[3',2':4,5]benzo[l ,2-b ][ 1,4]oxazephine-8-carboxylic acid (22.3 mg, 55%). 35 LC / MS ESI(+): 328 (M+l) 1H-NMR (400MHz, DMSO-d6): c5 13.52 (hrs, lH), 8.09 (s, lH), 8.04 (s, lH), 7.83 (s, lH), 4.12-4.14 {m, 2H), 3.73-3.75 (m, 2H), 3.09 (s, 3H), 1.99-2.07 (m, 2H) 40 Intermediate 4} Synthesis of 8,8-dimethyl-S-(methylsulfonyl}-5,6,7,8- 24 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 tetrahydrothieno[2,3-g)quinoline-2-earboxylic acid (a) Synthesis of ethyl 5-(3-methylbut-2-enamido )benzo[b ]thiophene-2-carboxylate Ethyl S-aminobenzo[b]~iophene-2-carboxylate (1.5 g, 6.78 mmol) was dissolved 5 in pyridine (33.9 mL), and 3-methylbut-2-enoyl chloride (755.0 ·μL, 6.78 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 purified by flash column chromatography (silica gel, n-Hex : EtOAc = 9 : 1) to obtain ethyl 5-(3- 10 methylbut-2-enamido)benzo[b]thiophene-2-carboxylate (1.3 g, 63%) as a colorless liquid. 1H-NMR (400MHz, CDC13): 6 8.29 (s, lH), 7.99 (s, lH), 7.77 (d, lH, .1=8.7Hz), 7.44 (d, lH, J=8.6Hz), 7.17 (s, lH), 5.74 (s, lH), 4.40 (q, 2H, .1=7.lHz), 2.26 (s, 3H), l.93 (s, 3H), 1.41 (t, 3H,J=7.1Hz) 15 (b) Synthesis of ethyl 8,8-dimethyl-6-oxo-5,6,7,8-tetrahydrothieno[2,3- g]quinoline-2-carboxylate Ethyl 5-(3-methylbut-2-enamido )benzo[b ]thiophene-2-carboxylate ( 1.3 g, 4.29 mmol) was dissolved in CH2Cl2 (42.9 mL), and AlC13 (1.7 g, 12.86 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, H20 was added, 20 and extracted with CH2Cl2, The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Th.e residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN : 0.1% formic acid in H2O) to obtain ethyl 8,8-dimethyl-6-oxo-5,6,7,8-tetrahydrothieno[2,3- g]quinoline-2-carboxylate (250.0 mg, 19%) as a yellow solid. 25 1H-NMR (400MHz, CDCl:3): 6 8.44 (s, lH), 8.41 (s, lH), 7.94 (s, lH), 7.76 (s, lH), 4.42 (q, 2H, J=7.1Hz), 2.55 (s, 2H), 1.59 (s, 6H), 1.43 (t, 3H, J=7.1Hz) (c) Synthesis of ethyl 8,8-dimethyl-5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2- carboxylate 30 The synthesis procedure of Intermediate 15-p was repeated except for using ethyl 8,8-dimethyl-6-oxo-5,6, 7 ,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate (217.0 mg, 0.72 mmol) as a starting material to obtain ethyl 8,8-dimethyl-S,6, 7,8-tetrahydrothieno[2,3~ g]quinoline-2-carboxylate (56.0 mg, 27%). 1H-NMR (400MHz, CDCh): 6 7.78 (s, lH), 7.63 (s, lH), 6.88 (s, lH), 4.37 (q, 2H, 35 fa:7.lHz), 3.37 (t, 2H, J=5.8Hz), 1.78 (t, 2H,J=5.8Hz), 1.37-1.41 (m, 9H) (d) Synth.esis of ethyl 8,8-dimethyl-5-(methylsulfonyl)-5,6~7,8- tetrahydrothieno[2,3-gJquinoline-2-carboxylate The synthesis procedure of Intennediate 16-f was repeated except for using ethyl 40 8,8-dimethyl-5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate (56.0 mg, 0.19 mmol) 25 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 as a starting material to obtain ethyl 8,8-dimethyl-S-(methylsulfonyl)-S,6, 7,8- tetrahydrothieno[2,3-g]quinoline-2-carboxylate (57.0 mg, 80%). 1H-NMR (400MHz, CDC13): 6 8.21 (s, lH); 7.97 (s, lH), 7.83 (s, 1H), 4.40 (q, 2H, J=7.1Hz), 3.90 (t, 2H, J=5.8Hz), 2.92 (s, 3H), 1.88 (t, 2H, J=S.8Hz), 1.39-1.43 (m, 9H) ( e) Synthesis of 8 ,8-dimethyl-5-(methylsulfonyl)-5,6, 7 ,8-tetrahydrothieno[2,3- g]quinoline-2-carboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using ethyl 8,8-dimethyl-5-(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate • 10 (57.0 mg, 0.16 rnmol) as a starting material to obtain 8,8-dimethyl-5-(methylsulfonyl)- 5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylic acid (52.0 mg, 80%). 15 LC / MS ESI (+): 340 (M+l) 1H-NMR (400MHz, CDCh): 6 8.25 (s, IH}, 8.08 (s, lH), 7.87 (s, IH), 3.91 (t, 2H, J=S.8Hz), 2.94 (s, 3H), 1.89 (t, 2H, J=5.8Hz), 1.43 (s, 6H) Intermediate 5) Synthesis of 4-(tert-butoxycarbonyl)-1-(methylsulfonyl)- 1,2,3,4-tetrahydrothleno(2,3-g]quinoxaline-7-carboxylic acid 20 (a) Synthesis of 4-bromo-2-fluoro-5-nitrobenzaldehyde 4-bromo-2-fluorobenzaldehyde (2._0 g, 9.85 mmol) was dissolved in cone. H2SO4 (5.2 mL, 98.50 mmol), and 60% HNO3 (1.0 mL~ 12.80 mmol) was added at 0°C. The reaction mixture was stirred for 4 hours, and extracted with CH2Ch. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced 25 pressure. The residue was recrystallized using i-Pr2O to obtain 4-bromo-2-fluoro-5- nitrobenzaldehyde (900.0 mg, 37%) as a white solid. 1H-NMR (400MHz, CDCl3): 6 10.31 (s, lH), 8.42 (d, lH, J=6.4Hz), 7.67 (d, lH, J=9.0Hz). 30 (b) Synthesis of methyl 6-bromo-5-nitrobenzo(b]thiophene-2-carboxylate 4-bromo-2-fluoro-5-nitrobenzaldehyde (S.O g, 20.10 mmol) was dissolved in anhydrous DMF (50.0 mL), and methyl 2-mercaptoacetate (2.1 ·g, 20.10 mmol) and K2CO3 (5.6 g, 40.30 mmol) were added, followed by heating at 80°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract 35 was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% fonnic acid in H2O) to obtain 6-bromo-Snitrobenzo[ b]thiophene-2-carboxylate (3.4 g, 53%) as a yellow solid. 1H-NMR (400MHz, DMSO-d6): o 8.38 (s, lH), 8.23 (s, lH), 8.09 (s, lH), 3.98 (s, 3H) 40 26 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 ( c) Synthesis of methyl 6-amino-5-nitrobenzo[ b ]thiophene-2-carboxylate 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate (3.0 g, 9.49 mmol) was dissolved in DMSO (10.0 ml) and Cu2O (830.0 mg, 10.40 mmol), sodium azide (1.2 g, 18.90 mmol) were added at room temperature. The mixture was stirred at 100 °C for 1 5 hour 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 reversed-phase column chromatography (C18-silica gel, 0.1 ¾ formic acid in CH3CN: 0.1 ¾ formic acid in H2O) to obtain methyl 6-amino-S-nitrobenzo[b]thiophene-2-carboxylate (1.6 g, 66%).as an off-white solid. 10 LC / MS ESI (+): 253 (M+l) 1H-NMR(400MHz, CDCh): 6 8.77 (s, lH), 8.11 (s, lH), 7.44 (s, lH), 7.39 (s, 2H), 3.33 (s, 3H) (d) Synthesis of methyl 6-((tert-butoxycarbonyl)amino)-5-nitrobenzo[b]thiophene- 15 2-carboxylate Methyl 6-amino-5-nitrobenzo[b]thiophene-2-carboxylate (800.0 mg, 3.17 mmol) was dissolved in DMA (10,0 mL) and B0C2O (831.0 mg, 3.81 mmol), DIPEA (1,6 mL, 9.51 mmol) were added at room temperature. The mixture was stirred at l 00 °C for 2 hours and extracted with EtOAc. The organic extract was washed with brine, dried over 20 anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1 ¾ fonnic acid in CH3CN: 0.1 ¾ formic acid in H20) to obtain methyl 6-((tert-butoxycarbonyl)amino)-5- nitrobenzo[b]thiophene-2-carboxylate (663.0 mg, 59%), as an off-white solid. 1H-NMR(400MHz, CDC13): ~ 9.59 (s, lH), 8.74 (s, lH), 8.32 (s, lH), 8.31 (s, lH), 25 3.91 (s, 3H), 1.46 {s, 9H) (e) Synthesis of methyl 5-amino-6-((tertbutoxycarbonyl) amino)benzo[b]thiophene-2-carboxylate Methyl 6-((tert-butoxycarbonyl)amino)-5-nitrobenzo[b]thiophene-2-carboxylate 30 (662.0 mg, 1.87 mmol) was dissolved in a mixture solvent of MeOH / H20 (20.0 mL, 9 / 1 v / v), and Zn (18.7 g, 18.70 mmol) and NH4Cl (l.O g, 18.70 mmol) were added thereto, and an ultrasonic reaction was conducted at 30°C for 15 hours. The reaction mixture was filtered through Celite and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH3CN: 35. 0.1 % formic acid in H2O) to obtain methyl 5-amino-6-((tert-butoxycarbonyl) amino) benzo [b]thiophene-2-carboxylate (633.0 mg, 104%) as an off-white solid. LC / MS BSI(+): 323 (M+l) 1H-NMR(400MHz, CDCl)): 6 8.56 (s, lH), 8.01 (s, lH), 7.92 (s, lH), 7.21 (s, lH), 5.14 (s, 2H), 3.85 (s, 3H), 1.50 (s, 9H) ' 40 27 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 (f) Synthesis of methyl 6-((tert-butoxycarbonyl)amino )-5-(methylsulfonamido) benzo[b]thiophene-2-carboxylate Methyl 5-amino-6-((tert-butoxycarbonyl) amino) benzo [ b ]thiophene-2- carboxylate (633.0 mg, 1.96 mmol) was dissolved in pyridine (9.8 mL), and 5 methanesulfonyl chloride (168.0 μL, 2.16 mmol) was slowly added thereto at 0°C. The reaction mixture was wanned to room temperature, followed by stirred for 3 hours 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 reversedphase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% fonnic 10 acid in H2O) to obtain • methyl 6-((tert-butoxycarbonyl)amino)-5- (methylsulfonamido)benzo[b]thiophene-2-carboxylate (694.0 mg, 88%), as an off-white solid. LC / MS ESI (-): 399 (M-1) 1H-NMR (400MHz, DMSO-d6): o 9.28 (s, lH), 8.55 (s, IH), 8.41 (s, lH), 8.16 (s, 15 IH), 7.99 (s, lH), 3.89 (s, 3H), 3.02 (s, 3H), 1.51 (s, 9H) • (g) Synthesis of 4-(tert-butyl) 7-methyl 1-(methylsulfonyl)-2,3- dihydrothieno[2,3-g]quinoxaline-4, 7(1H)-dicarboxylate Methyl 6-((tert-butoxycarbonyl )amino )-5-( methylsulfonamido) 20 benzo[b]thiophene-2-carboxylate ( 684.0 mg, 1. 70 mmol) was dissolved in DMA (17.1 mL), ancl 1,2-dibromoethane (963.0 mg, 5.12 mmpl) and ~CO3 (472.0 mg, 3.42 mmol) were slowly added at room temperature. The mixture was stirred for l hour, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO,1, and concentrated under reduced pressure. The residue was purified by· 25 reversed-phase column chromatography (C18-silica gel, 0.1 % fonnic acid in CH3CN: 0.1 % formic acid in H2O) to obtain 4-(tert-butyl) 7-methyl l-(methylsulfonyl)-2,3- dihydrothieno[2,3-g]quinoxaline-4,7(1H)-dicarboxylate (495.0 mg, 68%), as an off-white solid. 1H-NMR (400MHz, DMSO-d6): 6 8.42 (s, 1 H), 8.17 (s, lH), 8.12 (s, lH), 3.85- 30 3.92 (m, 4H), 3.89 (s, 3H), 3.12 (s, 3H), 1.51 (s, 9H) (h) Synthesis of 4-(tert-butoxycarbonyl)-1-(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxaline-7-carboxylic acid 4-(tert-butyl) 7-methyl 1-(methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline- 35 4,7(18)-dicarboxylate (495.0 mg, 1.16 mmol) was dissolved in THF / H2O (10.0 mL, 3 / 1 v / v), and LiOH·H2O (146.0 mg, 3A8 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under a reduced pressure. The residue was diluted in H2O (1.0 mL), and acidified with lN HCl (pH 1-2). The precipitate was filtered to obtain 4-(tert-butoxycarbonyl)-1-(methylsulfonyl)-1,2,3,4- 40 tetrahydrothieno[2,3-g]quinoxaline~ 7-carboxylic acid (422.0 mg, 88%) as a white solid. 28 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 LC / MS ESI H: 411 (M-1) 1H-NMR (400MHz, DMSO-d6): 6 13.47 {brs, lH), 8.37 (s, lH), 8.09 (s, lH), ,8.05 (s, lH), 3.83 ~ 3.92 (m, 4H), 3.11 (s, 3H), 1.50 (s, 9H) 5 Intermediate 6) Synthesis of 5-(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3- g)quinoline-2-carboxylic acid (a) Synthesis of methyl nitrobenzo[b]thiophene-2-carboxylate 10 Methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate (0.4 g, 1.26 mmol) was dissolved in anhydrous DMF(12.6 ml), and Pd(OAc)2 (28.0 mg, 0.13 mmol), PPh3 (66.0 mg, 0.25 mmol), TEA (0.4 ml, 2.53 mmol) and methyl acrylate (0.6 ml, 6.33 mmol) were added. The reaction mixture was stirred at 130°C for 30 minutes, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated 15 under reduced pressure. The residue was recrystallized with diethyl ether to obtain methyl (E)-6-(3-metboxy-3-oxoprop-l-en-1-yl)-5-nitrobenzo[ b]thiophene-2-carboxylate as a white solid. LC / MS ESI (+): 322 (M+l) 1H-NMR {400MHz, CDCh): 6 8.62 (s, lH), 8.16-8.22 (m, 2H), 8.09 (s, lH), 6.43 20 (d, lH, J=l6.0Hz), 4.00 (s, 3H), 3.85 {s, 3H) {b) Synthesis of methyl 6-oxo-5,6,7,8-tetrahydrothieno[2,3-g]quino~ine-2- carboxylate (E)-methyl 6-(3-methoxy-3-oxoprop-1-en-1-yl)-5-nitrobenzo[b ]thiophene-2- 25 carboxylate (0.2 g, 0.62 mmol) was dissolved in anhydrous MeOH(lS.6 mL), and 5% Pd-C (20.0 mg, 0.19 mmol) was added. The reaction mixture was charged with H2 gas and stirred at 2S°C for 4 days. The residue was _filtered through Celite and concentrated under reduced pressure to • obtain methyl 6-oxo-S,6,7,8-tetrahydrothieno[2,3-g]quinoline-2- carboxylate (100.0 mg, 61 %) as a white solid without purification. 30 LC / MS ESI (+): 262 (M+l) 1H-NMR (400MHz, CDCl3): 6 7.95 (s, lH), 7.80 (brs, lH), 7.66 (s, lH), 7.21 (s, lH), 3.94 (s, 3H), 3.11 (t, 2H, J=7.2Hz), 2.69 (t, 2H, J=7.2Hz) ( c) Synthesis of methyl 5,6, 7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate 35 Methyl 6-oxo-5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate (100.0 mg, 0.38 mmol) was dissolved in THF (4.0 mL), and IM solution of BH3-THF complex (1.9 mL, 1.91 mmol) was added at 0~C. The reaction mixture was stirred at room temperature for 3 hours, H2O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous N a2SO4 and concentrated under reduced pressure. The 40 residue was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1% 29 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 formic acid in CH3CN: 0.1% formic acid in H20) to obtain methyl 5,6,7,8- tetrahydrothieno[2,3-g]quinoline-2-carboxylate (65.0 mg, 69%) as a gray solid. LC / MS ESI (+): 248 (M+l) 1H-NMR (400MHz, CDCh): 6 7.80 (s, lH), 7.40 (s, 1H), 6.89 (s, 1H), 3.91 (s, s 3H), 3.35 (t, 2H, J=5.3Hz), 2.92 (t, 2H, J=6.3Hz), 1.96-1.99 (m, 2H) (d) Synthesis of methyl 5-(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3- g]quinoline-2-carboxylate Methyl 5,6,7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylatee. (50.0 mg, 0.20 10 ·mmol) was dissolved in CH2Ch (2.0 mL), and CH3S02Cl (23.6 μL, 0.30 mmol) and DIPEA (70.6 μL, 0.40 mmol) were added at 0°C. The reaction mixture was stirred for 3 hours and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2S04 and concentrat1;1d under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 2 : 1) to obtain methyl 5- 15 (methylsulfonyl)-5,6, 7,8-tetrahydrothieno[2,3-g]quino1ine-2-carboxylate (57 .0 • mg, 87%) as a white solid. 20 LC / MS ESI (+): 326 (M+l) I • H-NMR (400MHz, CDCh): 6 8.21 (s, lH), 7.99 (s, lH), 7.63 (s, lH), 3.94 (s, 3H), 3.87 (t, 2H, J=6.0Hz), 2.99 (t, 2H, J=6.0Hz), 2.90 (s, 3H), 2.04-2.07 (m, 2H) (e) Synthesis of 5-(methylsulfonyl)-s:6,7,8-tetrahydrothieno[2,3-g]quinoline-2- carboxylic acid The synthesis procedure of Intennediate 5-h was repeated except for using methyl 5-(methylsulfonyl)-5,6, 7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylate(60.0 mg, 0.18 25 mmol) to obtain 5-(methylsulfonyl)-5,6, 7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxylic acid (450.0 mg, 87 %), as a white solid. LC / MS ESI (+): 312 (M+l) Intermediate 7) Synthesis of 4-methyl-1-(methylsulfonyl)-1,2,3,4- 30 tetrahydrothieno[l,3-g]quinoxaline-7-carboxylic acid (a) Synthesis of methyl f-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxaline-7-carboxylate Unpurified tert-butyl 7-( chlorocarbonyl)-1-(methylsulfonyl)-2,3- 35 dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate (40.0 mg, 0.09 mmol) was dissolved in CH2Ch / MeOH (1.6 mL, 1 / 1 v / v), and TFA (0.3 mL) was slowly added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (Cl 8-silica gel, ·o.1% formic acid in CH3CN: 0.1% fomii.c acid in H20) to obtain methyl 1- 40 . (methylsulfonyl)-1,2,3 14-tetrahydrothieno[2,3-g]quinoxaline-7-carboxylate (21.0 mg, 30 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 69%) as a white solid. LC / MS ESI ( +): 32 7 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 6 7.97 (s, lH), 7.90 (s, lH), 7.09 (s, IH), 7.00 (s, lH), 3.82 (s, 3H), 3.67-3.69 (m, 2H), 3.43-3.45 (m, 2H), 3.00 (s, 3H) (b) Synthesis of methyl 4-methyl-l-(methylsulfonyl)-l,2,3,4- tetrahydrothieno[2,3-g]quinoxaline-7-carboxylate Methyl 1-(methylsulfonyl)-l ,2,3,4-tetrahydrothieno[2,3-g]quinoxaline-7- carboxylate (63.0 mg, 0.19 mmol) was dissolved in MeOH (1.9 mL), and formaldehyde 10 (76.0 μL, 0.96 mmol) and sodium cyanoborohydride (36.4 mg, 0.57 mmol) and AcOH (11.0 μL, 0.19 mmol) were added thereto at room temperature. The mixture was stirred for 15 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filt~ed and concentrated under a reduced pressure. The residue was separated on reversed-phase silica by column 15 chromatography (0.1 % formic acid in CH3CN: 0.1 % formic acid in H20 = 70: 30), and :fractions including the product were combined and evaporated to obtain methyl 4-methyll-( methylsulfonyl)-1,2,3A-tetrahydrothieno[2,3-g]quinoxaline-7-carboxylate (51.0 mg, 78%) as a white solid. LC / MS ESI (+): 341 (M+ 1) 20 1H-NMR (400MHz, DMSO-d6): 6 8.00 (s, lH), 7.90 (s, lH), 7.28 (s, lH), 3.84 (s, 3H), 3.76 (t, 2H, J=5.3Hz), 3.51 (t, 2H, J=5.3Hz), 3.02 (s, 3H), 3.01 (s, 3H) ( c) Synthesis of 4-methyl-1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxaline-7-carboxylic acid 25 Methyl 4-methyl-1-(methylsulfonyl)-l,2,3,4-tetrahydrothieno[2,3-g]quinoxaline~ 7-carboxylate (50.0 mg, 0.14 mmol) was dissolved in THF / H2O (1.5 mL, 3 / 1 v / v), and LiOH· H2O (18.4 mg, 0.44 mmol) was added thereto. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under a reduced pressure. The residue was diluted in H20 (1.0 mL), and acidified with IN HCI (pH 1-2). The precipitate was 30 :filtered to obtain 4-methyl-1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxaline-7-carboxylic acid ( 42.0 mg, 88%) as a white solid. 35 LC / MS ESI (+): 327 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 13.02 (hrs, IH), 7.89 (s, IH), 7.87 (s, lH), 7.26 (s, 1H), 3. 76 (t, 2H, J==5.4Hz), 3.50 (t, 2H, J=5.4Hz), 3.01 (s, 3H), 3.00 (s, 3H) Intermediate 8) Synthesis of 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylle acid (a) Synthesis of 2-chloro-4-(3,3-diethoxypropoxy)-1-methylbenzene 40 3-Chloro-4-methylphenol (3.0 g, 21.04 mmol) was dissolved in anhydrous DMF 31 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 (105.0 mL), and 3-chloro-1,1-diethoxypropane (4.2 g, 25.20 mmol) and K2C03 (8.7 g, 63. l O mmol) were added. The reaction mixture was stirred at 80°C for 15 hours, H20 was added, and extracted with EtOAc. The organic extract was washed with brine, dried over . anhydrous Na2S04 and con.centrated under reduced pressure. The residue was purified by 5 flash column chromatography (silica gel, n-Hex : EtOAc = 95 : 5) to obtain 2-chloro-4- (3,3-diethoxypropoxy)-1-methylbenzene (4.0 g, 690 / o) as a colorless liquid. 10 1H-NMR (400MHz, CDCh): 6 7.16 (d, 1H, J=8.4Hz), 6.91 (d, lH, J=2.6Hz), 6.71 (dd, lH, J=8.4Hz, 2.6Hz), 4.75 (t, lH, J=5.7Hz), 4.1 (t, 2H, J=6.3Hz), 3.66-3.73 (m, 2H), 3.49-3.57 (m, 2H), 2.29 (s, 3H), 2.05-2.10 (m, 2H), 1.22 (t1 6H,J=7.1Hz). (b) Synthesis of 7-chloro-6-methyl-4-(methylsulfonyl)chromane Sodium methane sulfinate (4.5 g, 44.00 mmol) was dissolved in TFA (61.1 mL) and stirred at 0°C for 10 minutes. A solution of 2-chloro-4-(3,3-diethxypropoxy)-1- methytbenzene (4.0 g, 14.66 mmol) in CH2Cl2 (12.2 mL) was added to the reaction 15 mixture for a period of 1 hour, and stirred at room temperature for 30 minutes. The reaction mixture was basified with sat. NaHC03 aqueous solution (pH=9-10), and extracted with CH2Ch. The organic extract was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = l : 2) to obtain 7-chloro-6-methyl-4- 20 (methylsulfonyl)chromane (2.3 g, 60%) as an off-white solid. 1H-NMR (400MHz, CDCh): 6 7.36 (s, lH), 6.95 (s, lH), 4.40-4.46 (m, lH), 4.17- 4.25 (m. 2H), 2.83 (s, 3H), 2.55-2.62 (m, lH), 2.32-2.42 (m, lH), 2.31 (s, 3H). ( c) Synthesis of 6-(bromomethyl)-7-chloro-4-(methylsulfonyl)chromane 25 7-Cploro-6-methyl-4-(methylsulfonyl)chromane (2.3 g, 8.63 mmol) was dissolved in anhydrous 1,2-dichloroethane (86.0 mL), and N-bromosuccinimide (1.5 g, 8.63 mmol) and AIBN (142.0 mg, 0.86 mmol) were added. The reaction mixture was refluxed at 100°C for 15 hours, cooled to room temperature, H20 was added, and extracted with CH2Ch. The organic extract was washed with brine, dried over anhydrous Na2S04 and concentrated 30 under reduced pressure. The residue was purified by flash column chromatography (silica 35 gel, n-Hex EtOAc = 4 1) to obtain 6-(bromomethyl)-7-chloro-4- (methylsulfonyl)chromane (2.5 g, 85%) as a yellow solid. 1H-NMR (400MHz, CDCb): ~ 7.59 (s, lH), 7.00 (s, lH), 4.47-4.62 {m, 3H), 4.25- 4.31 (m, lH), 4.19-4.22 (m, lH), 2.87 (s, 3H), 2.56-2.62 (m, lH), 2.34-2.43 (m, lH). ( d) Synthesis of 7-chloro-4-(meth ylsulfonyl)chromane-6-carbaldehyde 6-(Bromomethyl)-7-chloro-4-(methylsulfonyl)chromane (2.5 g, 7.36 mmol) was dissolved in anhydrous CH,CN (73.6 mL), and 4-methylmorpholineN-oxide (1.7 g, 14.72 rrnnol) and a molecular sieve (3.0 g) were added. The reaction mixture was stirred at room 40 temperature for 2 hours, H20 was added to the reaction mixture, and extracted with 32 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was recrystallized with Et2O to obtain 7- chloro-4-(methylsulfonyl)chromane-6-carbaldehyde (1.3 g, 64%) as a pale yellow solid. LC / MS ESI (+): 275 (M+l). 5 1H-NMR (400MHz, CDC13): 6 10.32 (s, lH), 7.97 (s, lH), 7.03 (s, lH), 4.64-4.71 (m, lH), 4.39-4.44 (m, lH), 4.23 (m, lH), 2.99 (s, 3H), 2.73-2.78 (m, lH), 2.30-2.34 (m, lH). { e) Synthesis of methyl 4--(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- 10 g]chromene-7-carboxylate 7-Chloro-4-(methylsulfonyl)cbromane-6-carbaldehyde (300.0 mg, 1.09 mmol) was dissolved in anhydrous DMF (10.0 mL), and methyl 2-mercapto 'acetate (117.0 μL, 1.31 mmol) and ~s2CO3 (1.1 g, 3.28 mmol) were added. The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, H2O was added, and extracted with EtOAc. 15 The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was recrystallized with CH2Ch and EhO to obtain methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3 ,2-g]chromene-7-carboxylate (20010 mg, 56%) as a white solid. 1H-NMR (400MHz, DMSO-d6): 8 8.17 (s, IH), 8.09 (s, IH), 7.57 {s, IH), 4.82 (m, 20 lH), 4.45-4.50 (m, 1H), 4.31-4.35 (m, lH), 3.88 (s, 3H), 3.17 (s, 3H), 2.59-2.69 (m, lH), • 2.26-2.37 (m, lH). LC / MS ESI (+): 327 (M+l). (f) Synthesis of 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chrome.ne-7- 25 carboxylic acid Methyl 4-{methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]cbromene-7-carboxylate (200.0 mg, 0.61 mmol) was dissolved in THF (4.0 mL) / H2O (2.0 mL), and LiOH·H2O (257.0 mg, 6.13 mmol) was added. The reaction mixture was stirred at 60°C for 15 hours, IN HCI (3.0 mL) was added, and extracted with CH2Cli and MeOH. The organic extract 30 was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 4-(methylsulfonyl)-3,4-dihydro-2H-thi~o(3,2~g]chromene-7-carboxylic acid (140.0 mg, 73%) as an off-white solid. LC / MS ESI (-): 311 (M-1). 1H-NMR (400MHz, DMSO-d6): 6 13.34 (bs, lH), 8.06 (s, 2H), 7.54 (s, lH), 4.82 35 (m, lH), 4.45-4.54 (m, 1H), 4.30-4.34 (m, lH), 3.16 (s, 3H), 2.60-2.74 (m, lH), 2.28-2.39 (m, lH). Intermediate 9) Synthesis of S-(methylsulfonyl)-2,3,4,Stetrahydrothieno[ 3' ,2' :4,S}benzo[l,2-b] oxepine-8-carboxylie acid 40 33 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 (a) Synthesis of 2-chloro-4-( 4,4-diethoxybutoxy)-l-methylbenzene The synthesis procedure of Intermediate 8-a was repeated except for using 3- chloro-4-methylphenol (1.0 g, 7.01 mmol) to obtain 2-chloro-4-(4,4-diethoxybutoxy)-1- methylbenzene (1.8 g, 89 %) as a colorless liquid. 5 LC / MS ESI (+): 287 (M+l) 1H-NMR (400MHz, CDCh): ~ 7.09 (d, lH, J=8.0Hz), 6.89 (d, lH, J=2.8Hz), 6.69 (dd, lH, .!=8.6, 2.8Hz), 4.54 (t, lH, .T-1.6Hz), 3.93 (t, 2H, .1-6.0Hz), 3.62-3.70 (m, 2H), 3.47-3.54 (m, 2H), 2.28 (s, 3H), 1.74-1.87 (m. 4H), 1.21 (t, 6H, J=7.2Hz) 10 (b) Synthesis of 1 8-chloro-7-methyl-5-(methylsulfonyl)-2,3,4,5- te1rahydrobenzo[b]oxepine The synthesis procedure of Intermediate 8-b was repeated except for using 2- chloro-4-(4,4-diethoxybutoxy)-1-methylbenzene (1.8 g, 6.20 mmol) to obtain 8-chloro-7- methyl-S-(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine (421.0 mg, 23%) as a 15 white solid. 20 LC / MS ESI (+): 275 (M+l) 1H-NMR (400MHz, CDC13): 6 7.20 (s, lH), 7.10 (s, lH), 4.34-4.39 (m, lH), 4.16 . ' (t, lH, J=l.6Hz), 3.71-3.77 (m, lH), 2.78 (s, 3H), 2.64-2.70 (m, lH), 2.33 (s, 3H), 2.22- 2.29 (m, lH), 2.07-2.15 (m, lH), 1.82-1.89 (m, lH). (c) Synthesis of 7-(bromomethyl)-8-chloro-5-(methylsulfonyl)-2,3,4,5- tetrahydrobenzo[b]oxepine The synthesis procedure of Intermediate 8-c was repeated except for using 8- chloro-7-methyl-5-(methylsulfonyl)-2,3,4,S-tetrahydrobenzo[b ]oxepine (421 mg, 1.53 25 mmol) to obtain 7-(bromomethyl)-8-chloro-5-(methylsulfonyl)-2,3,4,5- tetrahydrobenzo[b]oxepine (342~0 mg, 63%) as a white solid. LC / MS ESI (+): 353 (M+l) 1H-NMR (400MHz, CDCh): 6 7.42 {s, lH), 7.15 (s, lH), 4.44 (m, 2H), 4.39-4.44 (m, lH), 4.20 (t, 1H, J=l.6Hz), 3.76-3.82 (m, lH), 2.78 (s, 3H), 2.68-2.72 (m, IH), 2.28- 30 2.38 (m, lH), 2.09-2.18 (m, lH), 1.86-1.94 (m, lH) (d) Synthesis of 8-chloro-5-(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b ]oxepine-7- carbaldehyde The synthesis procedure of Intermediate 8-d was repeated except for using 7- 35 (bromomethyl)-8-chloro-S-(methylsulfonyl)-2,3,4,S-tetrahydrobenzo[b]oxepine (342.0mg, 0.97 mmol) to obtain 8-chloro-5-(methylsulfonyl}2,3,4,5-tetrahydrobenzo[b]oxepine-7- carbaldehyde (164.0 mg, 57%), as a white solid. LC / MS ESI (+): 289 (M+l) 1H-NMR (400MHz, CDCh): 6 10.36 (s, lH), 7.89 (s, lH), 7.21 (s, lH), 4.55-4.59 40 (m, lH), 4.31 (t, lH, J=l.6Hz), 3.78-3.84 (m, lH), 2.79-2.84 (m, 4H), 2.42-2.53 (m, lH), 34 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 2.02-2.11 (m, lH), 1.91-1.96 (m, lH). (e) Synthesis of 5-(methylslilfonyl)-2,3,4,5-tetrahydrothieno[3\2':4,S]benzo[l ,2- b ]oxepine-8-carboxylic acid 5 The synthesis procedure of Intermediate 8-e was repeated except for using 8- chloro-5-(methylsulfonyl)-2,3 ,4,5-tetrahydrobenzo[ b ]oxepine-7-carbaldehyde (164. 0 mg, 0.57 mmol) to obtain 5-(methylsulfonyl)-2,3A,S-tetrahydrothieno[3',2':4,5]benzo[1,2- b]oxepine-8-carboxylic acid (116.0 mg, 62 %) as a white solid. LC / MS ESI (+): 341 (M+l) 10 1H-NMR (400MHz, DMSO-d6): 6 13.48 (s, lH), 8.07 (s, lH), 8.05 (s, lH), 7.73 (s, lH), 4.80 (t, lH, J=l.2 Hz), 4.33-4.39 (m, lH), 3.75-3.80 (m, lH), 2.89 (s, 3H), 2.50-2.53 (m, lH) 2.18-2.27 (m, 1H), 2.06-2.14 (m, 1H), 1.75-1.88 (m, 1H) Intermediate 10) Synthesis of S-(methylsulfonyl)-S,6,7,8- 15 tetrahydronaphtho[2,3-b)thlophene-2-carboxylie acid (a) Synthesis of2-ethylhexyl 3-((5-bromo-2-fonnylphenyl)thio)propanoate To a solution of 4-bromo-2-fluorobenzaldehyde (3.0 g, 14.78 mmol) in DMF (73.9 ml) were added 2-Ethylhexyl 3-mercaptopmpionate (3.7 ml, 16.26 mmol). The reaction 20 mixture was stirred at 40°C for 36hours. The reaction mixture was purified by reversedphase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% fonnic acid in H20) to obtain 2-ethylhexyl 3-((5-bromo-2-formylphenyl)thio)propanoate (4.2 g, 71 %) as a light brown oil. LC / MS ESI (+): 401 (M+l) 25 1H-NMR (400MHz, CDCh): li 10.28 (s, lH), 7.70 (d, lH, J=8.2Hz), 7.57 (d, lH, J=l.7Hz), 7.46 (dd, lH, .1=8.2, 1.7Hz), 4.03-4.05 (m, 2H), 3.24 (t, 2H, J=7.4Hz), 2.72 (t, 2H; J=7.4Hz), 1.32-1.40 (m, 3H), 1.26-1.30 (m, 6H), 0.90 (t, 6H, J=7.4Hz) (b) Synthesis of 2-ethylhexyl 3-((5-(4,4-diethoxybutyl)-2- 30 (hydroxymethyl)phenyl)thio )propanoate A solution of 4,4-diethoxybut-1-ene (503.0 mg, 3.49 mmol) in 9- borabicyclo(3.3.l)nonane (7.7 ml, 3.84 mmol) was stirred for lhour and concentrated. The residue was dissolved in benzene (7.7 ml) / EtOH (3.9 ml). 2N Na2CO3 aqueous solution (35.0 ml, 6.98 mmol) and Pd(PPh3)4 (202.0 mg, 0.17 mmol) were added and the reaction 35 mixture at 80°C for 90minutes. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by nonnal phase column chromatography (EtOAc:n-Hex=l: 15) to give 2-ethylhexyl 3-((S-(4,4-diethoxybutyl)-2- formylphenyl)thio)propanoate (695.0 mg, 85 %) as crude. To a solution of2-ethylhexyl 3- 40 ((5-( 4,4-dietb.oxybutyl)-2-formylphenyl)thio)propanoate (610.0 mg, 1.31 mmol) in EtOH 35 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 (6.5 ml) was added NaBH4 (64.3 mg, 1.70 mmol). The reaction mixture was stirred for 30 minutes. NH.Cl was added, and the resulting mixture was stirred for 15 minutes and filtered through celite, The filtrate was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was 5 purified by normal phase column chromatography (EtOAc:n-Hex=l:3) to give 2- ethylhexyl 3-(( 5-(4,4-diethoxybutyl)-2-(hydroxymethyl)phenyl)thio )propanoate ( 550.0 mg, 90 %) as a colorless oil. 1H-NMR (400MHz, CDC}:;): 6 7.31 (d, lH, J=7.7Hz), 7.24 (d, lH, J=l.7Hz), 7.07 (d, lH, J=7.7Hz), 4.74 (d, 2H, J=3.3Hz ), 4.49 (t, lH, J=5.2Hz), 4.00-4.02 (rn, 2H), 3.59- 10 3.67 (m, 2H), 3.44-3.52 (m, 2H), 3.16 (t, 2H, J=7.2Hz), 2.61 (t, 4H, J=7.1Hz), 2.39 (hrs, IH), 1.65-1.68 (m, 4H), 1.51-1.57 (m, 2H), 1.26-1.37 (m, 2H), 1.26-1.31 (m, 4H), 1.20 (t, 6H, J=1.1Hz), 0.89 (t, 6H,J=7.1Hz) (c) Synthesis of • 2-ethylhexyl . 3-((5-(methylsulfonyl)-3-((2,2,2- 15 trifluoroacetoxy)methyl)-5,6, 7,8-tetrahydronaphthalen-2-yl)thio )propanoate Sodium methanesulfinate (359.0 mg, 3.52 mmol) was dissolved in TFA (9.8 ml) and the reaction mixture was stirred for 10 minutes. After cooling to 0°C, a solution of 2- ethylhexyl 3-((5 -( 4,4-diethoxybutyl)-2-(hydroxymethyl)phenyl)thio )propanoate (550.0 mg, 1.17 mmol) in CH2Ch (1956.0 μ1) was added dropwise and the reaction mixture was 20 stirred at 23°C for lhour. The reaction mixture was extracted with EtOAc, and the organic extract was washed with sat. NaHCO3 aqueous solution and brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by reversed-phase cohnnn chromatography (C18-silica gei 0.1 % fonnic acid in CH3CN: 0.1 % formic acid in H2O) to obtain 3-( ( 5-(methylsulfonyl)-3-((2,2,2-trifluoroacetoxy)methyl)-5,6, 7,8- 25 tetrahydronaphthalen-2-yl)thio)propanoate (217,0 mg, 34 %) as a colorless oil. 30 1H-NMR (400MHz, CDCh): 6 7.63 (s, lH), 7.26 (s, lH), 5.45 (q, 2H, .1=20.8Hz), 4.28 (t, lH, J=5.1Hz), 4.01-4.04 (m, 2H), 3.20 (t, 2H, J=7.5Hz), 2.87-2.93 (m, lH), 2.76- 2.81 (m, 4H), 2.65 (t, 2H, J=7.6Hz), 2.47-2.52 (m, lH), 2.19-2.23 (m, 2H), 1.75-1.86 (m, lll), 1.56-1.58 (m, lH), 1.29-1.39 (m, 8H), 0.89 (t, 6H, J=7.4Hz) (d) Synthesis of tert-butyl 2-((3-(hydroxymethyl)-5-(methylsulfonyl)-5,6,7,8- tetrahydronaphthalen-2-yl)thio )acetate To a solution of 2-ethylhexyl 3-((5-(methylsulfonyl)-3-((2,2,2- trifluoroacetoxy)methyl)-5,6, 7,8-tetrahydronaphthalen-2-yl)thio )propanoate (150.0 mg, 35 0.27 mmol) in DMF (2714.0 μl) was added lM solution ofpotassium-t-butoxide·in THF (543.0 μI, 0.54 mmol) at -60~-50°C._ The reaction mixture was stirred for lOminutes. tertbutyl 2-bromoacetate (42.1 μ1, 0.29 mmol) was added at -60~-50°C and the reaction mixture was stirred at room temperature for lhour. The reaction mixture was purified by • reversed-phase column· chromatography (C18-silica gel, 0.1 % formic acid in CH3CN: 0.1 % 40 formic acid in H2O) to obtain tert-butyl 2-((3-(hydroxymethyl)-5-(methylsulfonyl)-5,6,7,8- 36 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 tetrahydronaphthalen-2-yl)thio)acetate (67.0 mg, 64 %) as a white amorphous. 1H-NMR (400MHz, CDCIJ): 6 7.60 (s, lll), 7.26 (s, lH), 4.77 (q, 2H, r-32.7Hz), 4.27 (t, lH, J=5.9Hz), 3.60 (s, 2H), 2.83-2.89 (m, lH), 2.71-2.79 (m, 4H), 2.49-2.SS (m, lH), 2.15-2.20 (m, 2H), 1.73-1.46 (m, lH), 1.40 (s, 9H) (e) Synthesis of tert-butyl 2-((3-formyl-5-(methylsulfonyl)-5,6,7,8- tetrahydronapht~alen-2-yl)thio )acetate To a solution of tert-butyl 2-((3-(hydroxymethyl)-5-(methylsulfonyl)-5,6,7,8- tetrahydronaphthalen-2-yl)thio)acetate (65.0 mg, 0.17 mmol) in CH2Ch (1682.0 μ1) was 10 added Dess-Martin periodinane (107.0 mg, 0.25 mmol). The reaction mixture was stirred at 24°C for lhour. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give tertbutyl 2-( (3-fonnyl-S-(methylsulfonyl)-5,6, 7,8-tetrahydronaphthalen-2-yl)thio )acetate (71. 0 mg, 110 %) as crude. The crude was used the next step without purification. 15 1H-NMR (400MHz, CDCb): 6 10.23 (s, lH), 8.04 (s, lH), 7.29 (s, lH), 4.31-4.34 (m, lH), 3.63 (s, 2H), 2.92-2.99 (m, IH), 2.80-2.87 (m, 4H), 2.52-2.57 (m, lH), 2.22-2.25 (m, 2H), 1.77-1.82 (m, lH), 1.44 (s, 9H) (f) Synthesis of tert-butyl 5-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3- 20 b ]thiophene-2-carboxylate To a solution of tert-butyl 2-((3-formyl-5-(methylsulfonyl)-5,6,7,8- tetrahydronaphthalen-2-yl)thio)acetate (67.0 mg, 0.17 mmol) in DMF (1742.0 μI) was added Cs2CO3 (85.0 mg, 0.26 mmol). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was extracted with EtOAc. The organic extract was washed with 25 brine, dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl 5- (methylsulfonyl )-5,6, 7 ,8-tetrahydronaphtho[2,3-b ]thiophene-2-carboxylate ( 65.0 mg, 102 %) as crude, The crude was used the next step without purification. 1H-NMR (400MHz, CDCh): 6 8.11 (s, lH), 7.93 (s, lH), 7.66 (s, lH), 4.43-4.46 (m, lH), 3.00--3.08 (m, lH), 2.90-2.98 (m, 4H), 2.53-2.59 (m, lH), 2.31-2.35 (m, lH), 30 2.17-2.19 (iμ, lH), 1.71-1.83 (m, lH), 1.61 (s, 9H) (g) Synthesis of 5-(methylsulfonyl)-5,6, 7,8-tetrahydronaphtho [2,3-b ]thiophene-2- carboxylic acid To a solution of tert-butyl 5-(methylsulfonyl)-S,6,7,8-tetrahydronaphtho[2,3- 35 b]thiophene-2-carboxylate (65.0 mg, 0.18 mmol) in CH2Clz (0.5 ml) was added TFA (0.5 ml, 6.53 mmol). The reaction mixture was stirred at 24°C for 30minutes. The reaction mixture was purified by reversed-phase column -chromatography (C18-silica gel, 0.1% formic acid in CH3CN: 0.1 % formic acid in H2O) to obtain 5-(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3-b]thiophene-2-carboxylic acid (30.0 mg, 55 %) as a white 40 amorphous. 37 -5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 LC / MS ESI (-): 309 (M-1) 1H-NMR {400MHz, DMSO-d6): 6 8.13 {s, lll), 8.10 (s, lH), 7.90 (s, lH), 4.80- 4.82 (m, lH), 3.05 (s, 3H), 2.91-3.02 (m, 2H), 2.48-2.51 (m, lH), 2.19-2.23 (m, 2H), 1.67- 1:72 (m, lH) Intermediate 11) Synthesis of 4-methyl-4-{methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxylic acid (a) Synthesis of methyl 4-methyl-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- 10 g]chromene-7-carboxylate To a suspension of methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylate (50.0 mg, 0.15 mmol) in THF (1.0 ml) / CH3CN (1.0 ml) was added NaH (30.6 mg, 0.77 mmol). After lhour, CH3I (0.1 ml, 1.53 mmol) was added and the reaction mixture was stirred for 3days. The reaction mixture was purified by reversed- 15 phase column chromatography (C18-silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in H20) to obtain methyl 4-methyl-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromen~ 7-carboxylate (29.0 mg, 56 %) as an off-white amorphous. LC / MS ESI (+): 341 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 8.29 (s, lH). 8.16 (s, lH), 7.56 (s, IH), 4.49- 20 4.56 (m, lH), 4.20-4.26 (m1 lH), 3.88 (s, 3H), 3.00 (s, 3H), 2.61-2.68 (m, lH), 2.16-2.23 (m, lH), 1.83 (s, 3H) (b) Synthesis of 4-methyl-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylic acid 25 To a suspension of methyl 4-methyl-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxylate (27.0 mg, 0.08 mmol) in THF (529.0 μ1) / H20 {264.0 μI) was added LiOHH20 (33.3 mg, 0~79 mmol). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated and the residue was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1 o / o formic acid in CH3CN: 0. lo / o 30 fonnic acid .in H20) to obtain 4-methyl-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylic acid (20.0 mg, 77 %) as a white amorphous. LC / MS ESI(-): 325 (M-1) 1H-NMR (400MHz, DMSO-d,): o 8.22 {s, lH), 7.96 (s, lH), 7.49 (s, lH), 4.47- 4.52 (m, lH), 4.18-4.22 (m, lH), 2.97 (s, 3H), 2.59-2.67 (m, lH), 2.13-2.20 (m, lH), 1.81 35 (s, 3H) Intermediate 12) Synthesis of 5-(methylsulfonyl)-S,8-dihydro-6H-thieno(3,2- g]lsochromene-2-earboxyllc aeld 40 (a) Synthesis of methyl 2-bromo-4-(bromomethyl)ben.zoate 38 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 2-Bromo-4-methylbenzoate (4.6 g, 20.08 mmol) was dissolved in anhydrous 1,2- dichloroethane (60_0 ml), and N-bromosuccinimide (4.3_ g, 24_10 mmol) and AffiN (0-3 g, 2.01 mmol) were added at room temperature. The mixture was refluxed at 90°C for 1 hour, followed by cooling to room temperature and extracted with CH2Cl2. The organic extract S was washed with brine, dried over anhydrous Na2SO4, and concentrated undet a reduced pressure. The residue was purified by reversed-phase column ~hromatography (Cl 8-silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in H2O) to obtain methyl 2-bromo-4- (bromomethyl)benzoate (3.0 g, 48%) as a colorless liquid. LC / MS ESI(+): 309 (M+l) 10 1H-NMR(400MHz, CDC13): a 7.78 (d, lH, J=8.0Hz), 7.69 (d, lH, J=l.6Hz), 7.38 (dd, 1H, J=S.0, 1.6Hz), 4.42 (s, 2H), 3.94 (s, 3H) {b) Synthesis of methyl 2-bromo-4-((2,2-diethoxyethoxy)methyl )benzoate Glycolaldehyde diethyl acetal (1.6 ml, 12.14 mmol) was dissolved in anhydrous 15 THF (50.0 ml), and NaH (0.5 g, 13.25 mmol) was added at 0°C. The mixture was stirred at D°C for 30 minutes. Methyl 2-bromo-4-(bromomethyl)benzoate (3.4 g, 11.04 mmol) in THF (50.0 ml) was added at 0 °C. The mixture was stirred at 0°C for 3 hours and extracted with EtOAc. The organic extract was washed with water, dried over anhydrous Na2SO4, and concentrated under a reduced pressure. The residue was purified by flash column 20 chromatography (silica gel, n-Hex : EtOAc = 9 : 1) to obtain methyl 2-bromo-4-((2,2- diethoxyethoxy)methyl)bertzoate ( 1, 7 g, 42%) as a colorless liquid. 25 1H-NMR(400MHz, CDCh): 6 7.78 (d, lH, J=8.0Hz), 7.66 (d, lH, J=l.2Hz), 7.31- 7.34 (~ lH), 4.67 (t, IH, J=l0.4, 5.2Hz), 4.59 (s, 2H), 3.93 (s, 3H), 3.68-3.75 {m, 2H), 3.53-3.62 (m, 4H), 1.23 (t, 6H, J=14.0, 6.8Hz) (c) Synthesis of 4-((2,2-diethoxyethoxy)methyl)-2-(metbylthio )benzoic acid Methyl 2-bromo-4-((2,2-diethoxyetboxy)methyl)benzoate (480.0 mg, 1.33 mmol) was dissolved in DMF (4.0 ml), and sodium metbanetbiolate (466 mg, 6.64 mmol) was added at room temperature. The mixture was stirred at 80°C for 15 hours, followed by 30 cooling to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous N a2SO4 and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C 18-silica gel, 0.1 o / o formic acid in CH3CN: 0.1 % formic acid in H20) to obtain 4-((2,2- diethoxyethoxy)metbyl)-2-(methy]thio)benzoic acid (380.0 mg, 91 %) as a colorless liquid 35 LC / MS ESI(-): 313 (M-1) 1H-NMR(400MHz, CDCl3): 6 8.10 (d, lH, J=8.0Hz), 7.30 (s, lH), 7.14 (dd, lH, J=S.0, 0.8Hz), 4.70 (t, lH, J=l0.4, 5.2Hz), 4.65 (s, 2H), 3.68-3.76 (m, 2H), 3.55-3.63 (m, 4H), 2.48 (s, 3H), 1.24 (t, 6H, J=l4.0, 6.8Hz) 40 (d) Synthesis of (4-{(2,2-diethoxyethoxy)methyl)-2-(methylthio )phenyl)methanol 39 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 4-((2,2-diethoxyethoxy)methyl)-2-(methylthio)benzoic acid (380.0 mg:, 1.21 mmol) was dissolved in THF (12.0 ml), and I.OM solution ofLiAlH4 in THF (1.2 ml, 1.20 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour and H2O was added at 0°C. The reaction mixture was filtered through Celite and extracted 5 with CH2Ch. The organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% formic acid in H2O) to obta~ (4-((2,2-diethoxyethoxy)methyl)-2-(methylthio)phenyl)methanol (280.0 mg, 77%) as a colorless liquid. 10 1H-NMR(400Mffz, CDCh): 6 7.34 (d, lH, J=8.0Hz), 7.26 (m, lH), 7.12-7.14 (m, lH), 4.75 (brs, 2H), 4.66 (t, lH, J=l0.4, 5.2Hz), 4.58 (s, 2H), 3.66~3.74 (m, 2H), 3.51-3.61 (m, 4H), 2.50 (s, 3H), 2.08 (brs, lH), 1.22 (t, 6H, J=l 4.0, 7.2Hz) ( e) Synthesis of (4-(methylsulfonyl)-7-(methylthio )isochroman-6-yl)methanol 15 Sodium methanesulfinate (285.0 mg, 2.80 mmol) was dissolved in TFA (7.5 ml) and stirred at room temperature for 30 minutes. (4-((2,2-diethoxyethoxy)methyl)-2- (methylthio)phenyl)methanol (280.0 mg, 0.93 mmol) iri CH2Ch (1.5 m_l) was slowly added at room temperature. The mixture was stirred at room temperature for 30 minutes and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous 20 Na2SO4 and concentrated under a reduced pressure. The mixture was dissolved in THF (4.0 m1) / MeOH (1.0 ml) / H2O (1.0 ml) and LiOHH2O (223.0 mg, 932.00 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered • and concentrated to obtain (4-(methylsulfonyl)-7- 25 (methylthio)isochroman-6-yl)methanol (208.0 mg, 77%)%) as a colorless liquid. LC / MS ESI (-): 287 (M-1) 1H-NMR(400MHz, CDC13): 6 7.66 (s, lH), 6.91 (s, 1H), 4.86-4.91 (m, 2H), 4.70- 4.80 (m, 3H), 3.97-4.01 (m, lH), 3.87-3.88 (m, lH), 2.67 (s, 3H), 2.50 (s, 3H) 30 (t) Synthesis of 4-(methylsulfonyl)-7-(methylthio )isochromane-6-carbaldehyde ( 4-(Methylsulfonyl)-7-(methylthio )isochroman-6-yl)methanol (208.0 mg, 0. 72 mmol) was d~solved in CH2Ch (7.0 ml).and Dess-Martin Periodinane (398.0 mg, 0.94 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and extracted with CH2Ch, The organic extract was washed with brine, dried over 35 anhydrous Na2SO4 and concentrated ~n.der a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = I : 1) to obtain 4- (methylsulfonyl)~ 7-(methylthio)isochromane-6-carbaldehyde (150.0 mg, 72%) as a colorless liquid. LC / MS ESI (+): 287 (M+l) 40. 1H-NMR(400MHz, CDCI3): o 10.16 (s, lH), 8.10 (s, lH), 7.00 (s, IH), 4.93-4.97 40 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 (m, 2H), 4.80-4.84 (m, IH), 4.02-4.06 (m, lH), 3.94-3.95 (m, lH), 2.69 (s, 3H), 2.48 (s, 3H) (g) Synthesis of 5-(methylsulfonyl)-s·,8-dihydro-6H-thieno[3,2-g]isochromene-2- s carboxylic acid A mixture of 4-(Methylsulfonyl)-7-(methylthio)isochroman-6-carbaldehyde (150.0 mg, 0.52 mmol), magnesium oxide (21.1 mg, 0.52 mmol) and 2-chloroacetic acid (990.0 mg, 10.48 mmol) was stirred at 110°C for 16 hours and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated under a 10 reduced pressure. The residue' was purified by reversed-phase column chromatography • (C18-silica gel, 0.1% formic acid in CH3CN: 0.1% 'formic acid in HzO) to obtain 5- (methylsulfonyl)-5,8-dihydro-6H-thieno[3,2-g]isochromene-2-carboxylic acid (50.0 mg, . 30%) as a white solid. LC / MS ESI (-): 311 (M-1) 15 1H-NMR(400~ CDCh): 3 8.26 (s, lH), 8.14 (s, lH), 7.64 (s, lH), 4.91-5.08 20 (m, 3H), 4.07-4.11 (m, 2H), 2.66 (s, 3H) Intermediate 13) Synthesis of 4-fluoro-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g)chromene-7-carboxylic acid ( a) Synthesis of 7-chloro-4-fluoro-6-methyl-4-(methylsulfonyl)chromane 7-chloro-6-methyl-4-(methylsulfonyl)chromane (850.0 mg. 3.26 mmol) was dissolved in THF (30.0 mL), and LOA (2.6 mL, 3.91 mmol) was slowly added at -78°C and stirred for 0.5 hour. NFS (2.3 g, 7.17 mmol) was added, followed by stirring at -78°C 25 for 3 hours. The reaction was quenched with H2O, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 85 : 15) to obtain 7-chloro-4-fluoro-6- methyl-4-(methylsulfonyl)chromane (600.0 mg, 66%) as a a white solid • 30 1H-NMR (400MHz, DMSO-d6): 6 7.53 (s, lH), 6.97 (s, IH), 4.59-4.65 (m, lH), 4.28-4.35 (m, lH), 3.05 (s, 3H), 2.72-2.80 (m, 1H), 2.49-2.56 (m, 1H), 2.33 (s, 3H) (b) Synthesis of 6-(bromomethyl)-7-chloro-4-fluoro-4-(methylsulfonyl)chromane The synthesis procedure of Intermediate 8-c was repeated except for using 7- 35 chloro-4-fluoro-6-methyl-4-(methylsulfonyl)chromane (500.0 mg, 1.79 mmol) to obtain 6- (bromomethyl)-7-chloro-4-fluoro-4-(methylsulfonyl)chromane (520.0 mg, 81 %). 40 1H-NMR (400MHz, DMSO-d6): 6 7.75 (s, lH), 7.01 (s, lH), 4.67-4.68. (m, lH), 4.56 (q, 2H, J=l0.4, 21.lHz), 4.35-4.41 (m, lH), 3.06 (s, 3H), 2.74-2.82 (m, 1H), 2.49- 2.60 (m, lH) 41 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 ( c) Synthesis of 6-(bromomethyl)-7-chloro-4-tluoro-4-(methylsulfonyl)chromane The synthesis procedure of Intermediate 8-d was repeated except for using 6- (bromomethyl)-7-chloro-4-fluoro-4-(methy)sulfonyl)chromane ( 400.0 mg, 1.11 1111nol) to obtain 7-chloro-4-tluoro-4-(methylsulfonyl)chromane-6-carbaldehyde (225.0 mg, 68%). 5 LC / MS ESI ( + ): 293 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 6 10.32 (s, lH), 8.20 (s, IH); 7.04 (s, lH), 4.73- 4.80 (m, lH), 4.49-4.55 (m, lH), 3.09 (s, 3H), 2.86-2.93 (m, lH), 2.47-2.59 (m, lH) ( d) Synthesis of 4-.fluoro-4-(methylsulfonyl)-3 ,4-dihydro-2H-thieno[3,2- 10 g]chromene-7-carboxylic acid 7-chloro-4,;.fluoro-4-(methylsulfonyl)chromane-6-carbaldehyde (210.0 mg, O. 71 mmol) was dissolved in anhydrous DMF (7.1 mL), and methyl 2-mercaptoacetate {114.0 mg, 1.07 mmol) and CS2CO3 (514.0 mg, 1.57 mmol) were added, followed by heating at 80°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with 15 EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by reversed-phase column chro~atography (Cl 8-silica gel, 0.1 % formic acid in CH3CN: 0.1 % formic acid in H2O) to obtain 4-fluoro-4-(methylsulfonyl)-3,4-dihydro-2H-tbieno[3,2-g]chromene-7-carboxylic acid (72.0 mg, 30%) as a yellow solid 20 LC / MS ESI (-): 329 (M-1) 1H-NMR (400MHz, DMSO-d,,): S 13.47 (s, lH), 8.32 (s, lH), 8.13 (s, lH), 7.66 (s, lH), 4.53-4.56 (m. lH), 4.40-4.44 (m, 2H). 2.95-2.97 (m, 2H), 2.64-2.67 (m, 2H) Intermediate 14) Synthesis of 8;8-diftuoro-5-(methylsulfonyl)-5,6,7,8- 25 tetrahydronaphtho[2,3-b]thiophene-2-carboxylie acid (a) Synthesis of 7-chloro-6-methyl-4-(methylsulfonyl)-3,4-dihydronaphthalen- 1(2H)-one To a solution of 6-chloro-7-methyl-1-(methylsulfonyl)-1,2,3,4- 30 tetrahydronaphthalene (700.0 mg, 2.71 mmol) in acetic anhydride (5114.0 pl, 54.10 mmol) was added chromium oxide(VI) (812.0 mg, 8.12 mmol) at 0°C. The reaction mixture was stirred at 0°C for • 2hours. The residue was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1 % formic acid in CH3CN: 0.1 % formic acid in H20) to obtain 7-chloro-6-methyl-4-(methylsulfonyl)-3,4-dihydronaphthalen-1 (2H)-one ( 430.0 mg, 3S .58 %) as a white amorphous. 40 LC / MS ESI (+ ): 273 (M+ 1) 1H-NMR {400MHz, CDCb): 6 8.12 (s, lH), 7.40 (s, lH), 4.31-4.33 (m, lH), 3.16- 3.26 (m, lH), 2.93 (s, 3H), 2.86-2.91 (m, lH), 2.64-2.71 (m, lH), 2.51-2.60 (m, lH), 2.47 (s, 3H) 42 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 (b) Synthesis of 7-chloro-1 ,1-difluoro-6-methyl-4-(methylsulfonyl)-1,2,3,4- tetrahydronaphthalene A suspension of 7-chloro-6-methyl-4-(methylsulfonyl)-3,4-dihydronaphthalen- 1(2H)-one (430.0 mg, l.58 mmol) in DAST (2.0 ml, 15.14 mmol) was stirred at 65°C S overnight. The reaction mixture was purified by reversed.phase column chromato~phy (Cl 8-silica gel, 0.1 % fonnic acid in CH3CN: 0.1 % formic acid in H20) to obtain 7-chloro- 1,l-difluoro-6-methyl-4-(methylsulfonyl)-1,2,3 ,4-tetrahydronaphthalene (186. 0 mg, 40 % ) as a white amorphous. LC / MS ESI(-): 293 (M-1) 10 1H-NMR (400MHz, CDCh): 3 7.77 (s, lH), 7.60 (s, lH), 4.22-4.26 (m, 1H), 2.77 (s, 3H), 2.65-2.73 (m, lH), 2.51-2.62 (m,,2H), 2.43 (s, 3H), 2.23-2.35 (m, _lH) ( c) Synthesis of 6-(bromomethyl)-7-chloro-1, 1-difluoro-4-(methylsulfonyl)- 1,2,3 ,4-tetrahydronaphthalene • 15 To a solution of 7-chloro-1,1-difluoro-6-methyl-4-(methylsulfonyl)-1,2,3.4- tetrahydronaphthalene (150.0 mg, 0.51 mmol) and N-bromosuccinimide (109.0 mg, 0.61 mmol) in 1,2-dichloroethane (2545.0 μ1) was added AIBN (8.4 mg, 0.05 mmol). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was purified by flash column chromatography (silica gel, n-Hex: EtOAc = 5: 1) to obtain 6-(bromomethyl)-7- 20 chloro-1, 1-difluoro-4-(methylsulfonyl)-1,2,3A-tetrahydronaphthalene (105.0 mg, 55 %) as a white amorphous. 25 LC / MS ESI (-): 371 (M-1) 1H-NMR (400MHz, CDCh): o 7.85 (s, 2H), 4.55-4.64 (m, 2H), 4.25-4.29 (m, IH), 2.82 (s, 3H), 2.68-2.73 (m, lH), 2.56-2.59 (m, 2H), 2.27-2.34 (m, lH) (d) Synthesis of 3-chloro-5,5-difluoro-8-(methylsulfonyl)-5,6,7,8- tetrahydronaphthalene-2-carbaldehyde A suspension of 6--(bromomethyl)-7-chloro-1, 1-difluoro-4-(methylsulfonyl)- 1,2,3,4-tetrahydronaphthalene (105.0 mg, 0.28 mmol), N-methyl morpholiue-N-oxide (49.4 30 mg, 0.42 mmol) and molecular sieve (4A) in CH3CN (2.8 ml) was stirred at 25°C for 1 hour. The reaction mixture was purified by reversed-phase column chromatography (Cl 8~ silica gel, 0.1 % formic acid in CH3CN: 0.1 % formic acid in H20) to obtain 3-chloro-5,5- difluoro-8-(methylsulfonyl)-5,6, 7,8-tetrahydronaphthalene-2-carbaldehyde (60.0 mg, 69 % ) as a light brown amorphous. 35 LC / MS ESI(-): 307 (M-1) 1H-NMR (400MHz, CDCh): 6 10.49 (s, IH), 8.15 (s, lH), 7.92 (s, lH), 4.30-4.33 (m, lH), 2.92 (s, 3H), 2.83-2.87 (m, lH), 2.68-2.75 (m, lH), 2.47-2.57 (m, 1H), 2.34-2.39 (m, lH) 40 (e) Synthesis of 8,8-difluoro-5-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3- 43 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 bjthiophene-2-carboxylic acid To a solution of 3-chloro-5,5-difluoro-8-(me1hylsulfonyl)-5,6,7,8- tetrahydronaphthalene-2-carba1dehyde (58.0 mg, 0.19 mmol) and CsiCO3 (122.0 mg, 0.38 mmol) in DMF (939.0 μ1) was added methyl thioglycollate (18.S μl, 0.21 mmol). The 5 reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to 60°C and LiOHH2O (79.0 mg. 1.88 mmol) was added and stirred for 1 hour. The reaction mixture was purified by reversed-phase column chromatography (Cl 8-silica gel, 0.1 % formic acid in CHsCN: 0.1% formic acid in H2O) to obtain 8,8-difluoro-5- (methylsulfonyl)-5,6, 7 ,8-tetrahydronaphtho[2,3-b ]thiophene-2-carboxylic acid (33 .0 mg, 10 51 %) as an off-white amorphous. LC / MS ESI (-): 345 (M-1) 1H-NMR (400MHz, DMS-d6): o 8.48 (s, lH), 8.18 (s, lH), 8.13 (s, lH), 4.89-4.90 (m, lH), 3.17 (s, 3H), 2.66-2.73 (m, 2H), 2.32-2.42 (m, 2H) 15 Intermediate 15) Syntllesis of 4-(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-earboxylic acid (a) Synthesis of 3-(3-chloro-4~methylphenoxy)propanoic acid To a solution of 2-chloro-4-(3,3-diethoxypropoxy)- l-methylbenzene (3.0 g, 11.00 20 mmol) in THF (27.5 ml) / H2O (27.5 ml) was added Oxone (10.1 g, 33.00 mmol). The reaction mixtme was stirred at 25°C overnight and filtered. The filtrate was extracted with EtOAc. The organic extract was washed with brin~ dried over anhydrous Na2S04, filtered and concentrated to give 3-(3~chloro-4-methylphenoxy)propanoic acid (2.4 g, 100 %) as a white amorphous. 25 LC / MS ESI (-): 213 (M-1) 1H-NMR (400MHz, CDCh): 6 7.11 (d, lH, J=8.4Hz), 6.92 (d, lH, J=2.5Hz), 6.73 (dd, 1 H, J=8.4, 2.4Hz), 4.21 (t, 2H, J=6.2Hz), 2.84 (t, 2H, J=6.2Hz), 2.29 (s, 3H) (b) Synthesis of 7-chloro-6-methylchroman-4-one 30 3-(3-chloro-4-methylphenoxy)propanoic acid (2.4 g, 10.95 mmol) was dissolved in trifluoromethansulfonic acid (4.8 ml, 54.70 mmol) and the reaction mixture was stirred for 2.5 hours. Ice chip was added slowly and the resulting mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2S04, filtered and concentrated. • The residue was purified by reversed-phase column chromatography 35 (Cl 8-silica gel, 0.1 % formic acid in CH3CN: 0.1 % formic acid in H2O) to obtain 7-chloro- 6-methylchroman-4-one (795.0 mg, 37 %) as a white amorphous. 40 LC / MS ESI (+): 197 (M+l) 1H-NMR (400MHz, CDCh): 6 7.74 (s, lH), 7.01 (s, lH), 4.52 (t, 2H, J=6.SHz), 2.84 (t, 2H, J=6.5Hz), 2.32 (s, 3H) 44 CA 02966'142 201'1-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 ( c) Synthesis of 6-(bromomethyl)-7-chlorochroman-4-one The synthesis procedure of Intennediate 8-c was repeated except for using 7- chloro-6-methylchroman-4-one (950.0 mg, 4.83. mmol) to obtain 6-(bromomethyl)-7- chlorochroman-4-one (1.4 g, 87 % ) as an ivory solid. 5 LC / MS ESI (+): 275 (M+l) 1H-NMR (400MHz, CDC13): ~ 7.97 (s, HI), 7.10 (s, lH), 4.54-4.58 (~ 4H), 2.82 (t,2H,J.=6.5Hz) (d) Synthesis of7-chloro-4-oxochromane-6-caibaldehyde 10 The synthesis procedure of Intennediate 8-d was repeated except for using 6- (bromomethyl)-7-chlorochroman-4-one (1.3 g, 4.72 mmol) to obtain 7-chloro-4- oxochromane-6-caibaldehyde (660.0 mg, 66%) as a white solid LC / MS ESI(+): 211 (M+l) 1H-NMR (400MHz, CDCl3): 6 10.34 (s, lH), 8.50 (s, lH), 7.10 (s, lH), 4.64 (t, 2H, 15 J=6.5Hz), 2.87 (t, 2H, J=6.5Hz) (e) Synthesis of methyl 4-oxo-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate The synthesis procedure of Intermediate 8-d was repeated except for using 7- 20 chloro-4-oxochromane-6-carbaldehyde (660.0 mg, 3.13 mmol) to obtain 4-oxo-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (580.0 mg, 71 % ) as an off white solid. 25 LC / MS ESI (+): 263 (M+l) 1H-NMR (400MHz, CDCh): 6 8.49 (s, lH), 8.26 (s, lH), 7.74 (s, lH), 4.59 (t, 2H, J=6.4Hz), 3.87 (s, 3H), 2.87 (t, 2H, J=6.4Hz) (f) Synthesis of methyl 4-hydroxy-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate • To a solution of methyl 4-oxo-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate (810.0 mg, 3.09 mmol) in EtOH (15.0 ml) was added NaBH4 (140.0 mg, 3.71 30 mrnol). The reaction mixture was stirred at 26°C for 2hours. H2O was added and insoluble white solid was filtered to give methyl 4-hydroxy-3,4-dihydro-2H-thieno[3,2-g]chromene- 7..carboxylate (665.0 mg, 81 %) as a white solid. LC / MS ESI (+): 265 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 8.11 (s, lH), 7.79 (s, lH), 7.40 (s, lH), 5.SS (m, 35 lH), 4.75-4.79 (m, lH), 4.23-4.33 (m, 2H), 3.85 (s, 3H), 2.02-2.09 (m, lH), 1.88-1.94 (m, lH) (g) Synthesis of methyl 4-chloro-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate 40 To a solution of methyl 4-hydroxy-3,4-dihydro-2H-thieno[312-g]chromene-7- 45 5 CA 02966'142 201'1-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 carboxylate (200.0 mg, 0. 76 mmol) in toluene (3784.0 μl) was added SOC}z (110.0 μI, 1.51 mmol). The reaction mixture was stirred at 60°C for 2 hours. After cooling. the reaction mixture was concentrated to give methyl 4-chloro-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylate (210.0 mg, 98%) as a white amorphous without purification. I , • H-NMR (400MHz, DMS0-14): 8 8.13 (s, lH), 8.02 (s, lH), 7.51 (s, 1H), 5.72 (t, 1H, J=3.4Hz), 4.36-4.46 (m, 2H), 3.86 (s, 3H), 2.42-2.48 (m, 1H), 2.26-2.31 (m, lH) (h) Synthesis of methyl 4-(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylate 10 A solution of methyl 4-chloro-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate (80.0 mg, 0.28 mmol), pyrazole (57.8 mg, 0.85 mmol) and KzC03 (117.0 mg, 0.85 mmol) in DMA (2829.0 μl) was stirred at 60°C for lhour and then stirred at 80°C. After lhour, the reaction mixture was stirred at 100°C for lhour. The reaction mixture was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1% fonnic acid in 15 CH3CN: O.lo / o formic acid in H20) to obtain methyl 4-(1H-pyrazol-1-yl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxylate (26.0 mg, 29 %) as a white amorphous. LC / MS ESI (+): 315 (M+l) 1H-NMR (400MHz, CDC13): 6 7.87 (s, lH), 7.61 (d, lH, J=l.SHz), 7.51 (s, lH), 7.37 (s, lH), 7.22 (d, lH, J=2.1Hz), 6.25-6.26 {m, lH), 5.72 (t, lH, J=5.1Hz), 4.31-4.37 20 (m, 1H), 4.15-4.21 (m, lH), 3.92 (s, 3H), 2.56-2.64,(m, lH), 2.40-2.48 (m, lH) (i) Synthesis of 4-(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylic acid To a suspension of methyl 4-(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2- 25 g]chromene-7-carboxylate (25.0 mg, 0.08 mmol) in THF (530.0 μ1) / HzO (265.0 μl) was added LiOHH20 (33.4 mg. 0.78 mmol). The reaction mixture was stirred at 60°C for lhour. The reaction mixture was cooled to room temperature. lN-HCl was added and insoluble white solid was filtered to give ~(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxylic acid (17.0 mg. 71 o / o) as a white solid 30 LC / MS ESI(-): 299 (M-1) Intermediate 16) Synthesis of 4-(2-oxopyrrolidin-t-yl)-3,4-dihydro--2Hthieno[ 3,2-g]chromene-7-carboxylic acid 35 To a solution of2-Pyrrolidinone (64.5 μl, 0.85 mmol) in DMA (4.2 ml) was added NaH (33.9 mg. 0.85 mmol). The reaction mixture was stirred at 100°C for 30 minutes. methyl 4-chloro-3,4-dihydro-2H-thieno[3,2-g]chromene-7-camoxylate (120.0 mg, 0.42 mmol) was added and stirred for lhour. The reaction mixture was cooled to 80°C. LiOHH20 (53.4 mg. 1.27 mmol) was added and stirred for lhour. The reaction mixture 40 was purified by reversed-phase column chromatography (Cl8-silica gel, 0.1% fonnic acid 46 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 in CH3CN: 0.1% fonnic acid in H2O) to obtain 4-(2-oxopyrrolidin-l-yl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxylic acid (13.0 mg, 10 %) as a white amorphous. LC / MS ESI (+): 318 (M+l) 1H-NMR (400MHz, DMS-d6): 6 7.93 (s, lH), 7.57 (s, lH), 7.42 (s, lH), 5.41-5.45 5 (m, lH). 4.27-4.40 (m, 2H), 3.23-3.32 (m. lH), 2.95-3.01 (m, lH), 2.36-2.43 (m, 2H), 2.10-2.19 (m, IH), 1.90-2.01 (m. 3H) 10 Intermediate 17) Synthesis of 4-cyano-3,4-dihydro-2H-thieno[3,2-g)chromene- 7-carboxylic acid (a) Synthesis of methyl 4-bromo-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate Methyl 4-hydroxy-3 ,4-dihydro-2H-thieno[3 ,2-g]chromene-7-carboxylate (210.0 mg, 0.79 mmol) was dissolved in CH2Ch (3.9 mL), and PBr3 (323.0 mg, 1.19 mmol) was 15 added. After stirring at room temperature for 2 hours, and the reaction mixture was concentrated under a reduced pressure to obtain crude solid compound of methyl 4-bromo- 3,4-dihydro-2H-thieno[3,2-g] chromene-7-carboxylate (250.0 mg. 95%). 20 1H-NMR (400MHz, DMSO-'4): 6 8.18 (s, lH), 8.07 (s, lH), 7.54 (s, lH), 6.05- 6.06 (m, lH), 4.54-4.57 (m. 2H), 3.92 (s, 3H), 2.39-2;45 (m, 2H) (b) Synthesis • of methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate Methyl 4-bromo-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (300.0 mg, 0.91 mmol) was dissolved in DMA (9.1 mL), and NaCN'(90.0 mg, 1.83 mmol) was added 25 at room temperature. The mixture was stirred at 60°C for 2 hours, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under a reduced pressure. The residue was purified by reversedphase column chromatography (C18-silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in H2O) to obtain methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromene-7- 30 carboxylate (39.0 mg, 15%) as an off-white solid. LC / MS ESI(+): 274 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 8.17 (s, lH), 8.03 (s, lH), 7.56 (s, lH), 4.68 (t, lH, J=6.0Hz), 4.31 (t 2a .J=5.2Hz), 3.87 (s. 3H), 2.29-2.39 (m, 2H) 35 (c) Synthesis of 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid Methyl 4-cyano-3,~-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (39.0 mg, 0.14 mmol) was dissolved in THF / H2O (1.5 mL, 3 / 1 v / v), and LiOH· H2O (17.9 mg, 0.43 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was concentrated wider a reduced pressure. The residue was purified by reversed-phase 40 column chromatography (CI8~silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in 47 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 H2O) to obtain methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (17.0 mg, 46%) as a white solid. LC / MS ESI (+): 260 (M+l) 1H-NMR (400MHz, DMSO-d6): o 13.3 (br, lH), 7.96 (s, lH), 7.91 (s, lH), 7.44 (s, 5 lH), 4.60 (t, lH, J=6.0Hz), 4.22 (t, 2H, J=5.2 Hz), 2.20-2.26 (m, 2H) lnterm.ediate 18) Synthesis of 4-azido-3,4-dihydro-2H-thienof3,2-g]chromene- 7-carboxyUc acid 10 (a) Synthesis of methyl 4-azido-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxylate Methyl 4-bromo-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (95 .0 mg, 0.29 mmol) was dissolved in DMA (2.9 mL), The mixture was stirred at 60°C for 3 hours, and extracted with EtOAc. The organic extract was washed with brine, dried over 15 anhydrous Na2SO4, and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 6 : 1) to obtain methyl 4- azido-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (50.0 mg, 60%) as a white solid. LC / MS ESI (+ ): 290 (M+ 1) 20 1H-NMR (400MHz, CDC13): 8 7.97 (s, lH), 7.72 (s, lH), 7.32 (s, lH), 4.77 (t, lH, J=4.1 Hz), 4.31-4.35 (m, 2H), 3.93 (s, 3H), 2.10-2.23 (m, 2H) (b) Synthesis of 4-azido-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid Methyl 4-azido-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (15.0 mg, 25 0.05 mmol) was dissolved in THF / H2O (0.5 mL, .3 / 1 v / v), and LiOH·H2O (21.7 mg, 0.52 mmol) was added. The reaction mixture was stirred at 60°C for 15 hours, lN HCI (3 .0 mL) was added, and extracted with CH2Cli. The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 4-azido-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid (10.0 mg, 70%) as an off-white solid. 30 LC / MS ESI (-): 274 (M-1) 35 Example 1) Synthesis of N-(2-ehloro--6-(4-ehlorophenoxy)pyridin-4-yl)-1- (m.ethylsulfonyl)-2,3-dihydro-lH-thieno[3' .;J,' :4,5)benzo(l,2-bJ [1,4]oxazine-7- earboxamide (a) Synthesis of2-chloro-6-(4-cblorophenoxy)pyridin-4-amine 2,6-Dichloropyridine-4-amine (3.0 g, 18.40 mmol) and 4-chlorophenol (4.7 g, 36.80 mmol) were dissolved in sulfolane (96.0 mL) and K2C03 (5.1 g, 36.80 mmol) was added. The reaction mixture was stirred at 160°C for 24 hours, cooled to room 40 temperature, H20 was added, and extracted with EtOAc. The organic extract was washed 48 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 with lN NaOH aqueous solution and brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN: 0.1% fonnic acid in H2O) to obtain 2-chloro-6-(4-chlorophenoxy)pyriclin-4-amine (2.5 g, 53%) as a white solid. S LC / MS ESI (+): 255 (M+l) 1H-NMR (400MHz, DMSO-d6): o 7.45 (d, 2H, J=8.8Hz), 7.12 (d, 2H, J=8.8Hz), 6.55 (brs, 2H), 6.31 (d, lH, J=L6Hz), 5.93 (d, lH, J=l.6Hz) (b) Synthesis of N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-1- 10 (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[l ,2-~ ][ 1,4 ]oxazine-7-carboxamide 1-(Methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[l,2-b][l,4]oxazine-7- carboxylic acid (190.0 mg. 0.61 mmol) was dissolved in CH2Clz (6.1 mL), and DMF (1.2 μL, 0.01 mmol) and (COCl)2 (51.6 μL, 0.61 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours and concentrated under reduced pressure to obtain 1- 15 (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[l ,2-b ][1,4]oxazine-7-carboriyl chloride. To the residue, 2-chloro-6-(4-chlorophenoxy)pyridin-4-amine (155.0 mg, 0.61 mmol) and 1,4-Dioxane (2.0 mL) were added and the reaction mixture was stirred at 80°C for 1 S hours and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography {Cl8-silica gel, 0.1% fonnic acid in CH3CN: 0.1%. 20 fonnic acid in H20) to obtain N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-1- (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,S]b~zo[l,2-b][l,4]oxazine-7-carboxamide (166.0 mg, 500 / o) as a white solid. LC / MS ESI(+): 550 (M+l) 1H-NMR(400MHz, DMSO-d6): o 10.87 (hrs, lH), 8.20 (s, lH), 8.10 (s, lH), 7.58 25 (s, 2H), 7.45 (dd, 2H, J=8.8, 2.lHz), 7.22 (s, lH), 7.18 (dd, 2H, J=8.8, 2.lHz), 4.29 (t, 2H, J=4.9Hz), 3.82 (t, 2H, J=4.6Hz), 3 .11 (s, 3H) 30 Compounds from Examples 2 to 14 were synthesized through the synthesis route of Example 1, and data of these compounds are listed as follows. [Table 2] Ex. Compound Analysis data N-(2-chloro-6-( 4-chlorophenox.y )pyridin- LC / MS ESI (+): 578 (M+l) 1H-NMR(400MHz, DMSO-c'6): ~ 10.94 (s. 4-yl)-3,3-dimethyl-l -(methylsulfonyl)- lH), 8.28 (s, lH), 8.18 (s. lH), 7.67 (s, IH), 2 2,3-dihydro-lH- 7.58 (s, lH), 7.53 (d, 2H, J=8.8Hz), 7.31 (s, thieno[3 ',2':4,5]benzo [ 1,2-b] [ l ,4]oxazinelH), 7.25 (d, 2H, J=8.8Hz), 3.68 (s, 2H), 3.38 7-carboxamide (s. 3H), 1.36 (s, 6H) . 49 3 4 s 6 7 8 CA 02966742 2017-05-03 WO 2016 / 089062 N-(2-chloro--6-( 4-chlorophenoxy)pyridin- 4-yl)-1-(methylsulfonyl)-1,2,3,4- tetrahydrotbieno[3',2':4,5]benzo[l,2- b] [ 1,4]oxazepine-8-carboxamide N-(2-chloro--6-( 4-chlorophenoxy)pyridin- 4-y1)-8,8-dimethyl-5-(m.ethylsulfonyl)- 5,6,7,8-tetrahydrothieno[2,3-g]quinoline- 2-carboxamide tert-buty1 7-((2-chloro-6-(4- chlorophenoxy)pyridin-4-yl)carbamoyl)- 1-(methylsulfonyl)-2,3- dihydrothieno[2 ,3-g]quinoxaline-4( 1 H)carboxylate N-(2-chloro-6-( 4-chlorop~enoxy)pyridin- 4-yl)-5-( methylsulfonyl)-5,6, 7,8- tetrahydrotbieno[2,3-g]quinoline-2- carboxamide N-(2--chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-4-methyl-1-(methylsulfonyl)- l ,2,3,4-tetrahydrothieno[2,3- g]quinoxaline-7-carboxamide N-(2-chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-4-(methylsulfonyl)-3.4-dihydro-2Hthieno[ 3 ,2-g]chromene-7--carboxamide 50 PCT / KR2015 / 012926 LC / MS ESI (+): 564 (M+l) 1H-NMR( 400MHz, DMSO-d5): o 11.10 (s, lH), 8.36 (s, lH), 8.08 (s, lH), 7.90 (s, lH), 7.70 (d. lH, J-1.2Hz), 7.55 (d, 2H, J==8.8Hz), 7.33 (s, lH, J=l .2Hz), 7.29 (d, 2H, J=8.8Hz), 4.15-4.17 (m, 2H), 3.75-3.77 (m, 2H), 3.11 (s, 3H), 2.08-2.10 (m, 2H) LC / MS ESI (+): 576 (M+l) 1H-NMR(400MHz, DMSO-d5): o 10.98 (s, lH), 8.30 (s, lH), 8.21 (s, lH), 8.14 (s, lH), 7.67 (s, lH), 7.53 (d, 2H, J=8.7Hz), 7.32 (s, IH), 7.26 (d. 2H, J=S.mz), 3.79 (t. 2H, .1=5.7Hz), 3.12 (s, 3H), 1.85 (t, 2H, J=5.1Hz), 1.37 (s, 6H) LC / MS ESI (+): 679 (M+l) 1H-NMR (400MHz, DMSO-d5): 6 10.93 (brs, lH), 8.35 (s, lH), 8.24 (s, lH), 8.03 (d, lH, J=8.7Hz), 7.60 (d, lH, J=l.3Hz), 7.47 (d, 2H, J=S.8Hz), 7.24 (d, lH, J=l.3 Hz), 7.19 (d, 2H, J=8.8Hz), 3.82-3.84 (m, 2H), 3.79-3.80 (m. 2H), 3.05 (s, 3H), 1.43 (s,.9H) LC / MS ESI (+): 548 (M+l) 1H-NMR (400MHz, DMSO-d6): 6. 10.98 (s, lH), 8.32 (s, lH), 8.13 (s, lH), 7.90 (s, lH), 7.66 (s, lH), 7.53 (d, 2H, J=8.8Hz), 7.28 (s, 1H), 7.26 (d. 2H, J=8.8Hz), 3.75 (t. 2H, J=6.3Hz ), 3.06 (s, 3H), 2.93 (t, 2H, J=6.5Hz), 1~95-1.99 (m, 2H) i LC / MS ES!(+): 563 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.81 (brs, lH), 8.20 (s, lH), 7.89 (s, lH), 7.67 (s, lH), 7.55 (d, 2H, .T=8.7Hz), 7.33 (s, lH), 7.32 (s, lH), 7.28 (d, 2H, J=8.7Hz), 3.79 (t, 2H, J=5.3Hz ), 3.53 (t, 2H, J=5.3Hz ), 3.04 (d. 6H, .T=2.6Hz) LC / MS ESI (+): 549 (M+I). 1H-NMR ( 400Mf{z, DMSO-d6): 6 10.94 (s, lH), 8.31 (s, lH), 8.08 (s, lH), 7.67 (d, lH, .T=l.lHz), 7.59 (s, 111), 7.53 (d, 2H, J~8.9Hz), 7.31 (cl. lH, J=l.lHz), 7.27 (d, 2H, J=8.9Hz), 4.82 (m, lH), 4.46-4.53 (m, lH), 4.31-4.36 (m, lH), 3.18 (s, 3H), 2.53-2.69 (m, lH), 229-2.40 (m, lH). 9 10 11 12 13 14 CA 02966742 2017-05•03 WO 2016 / 089062 N-{2-chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-5-(methylsulfonyl)-2,3,4,5- tetrahydrothieno[3',2':4,5]benzo[l,2- b] oxepine-8-carboxamide N-(2-chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-5-(methylsulfonyl)-5,6, 7 ,8- tetrahydronaphtho[2,3-b ]thiophene-2- carhoxamide N-(2-chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-4-methyl-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7- carhoxamide N-(2-chloro-6-{ 4-chlorophenoxy)pyridin- 4-yl)-5-(methylsulfonyl)-5,8-dihydro-6Hthieno[ 3,2-g]isochromene-2-carboxamide N-(2-chloro-6-( 4-chlorophenoxy)pyridin- 4-yl)-4-fluoro-4-(methylsulfonyl)-~,4- dihydro-2H-tbieno[3,2-g]chromene-7- carboxamide N-(2-chloro-6-( 4-chJorophenoxy)pyridin- 4-y 1)-8,8-difluoro-5-{methylsulfony l)- 5,6,7,8-tetrahydronaphtho[2,3- b ]thiophene-2-carhoxamide 51 PCT / KR2015 / 012926 LC / MS ESI (+): 563 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.90 (s, lH), 8.28 (s, lH), 8.03 (s, lH), 7.69 (s, UI), 7.59 (d, lH, J=l.4Hz), 7.44-7.48 (m, 2H), 7.25 (s, lH), 7.17-7.21 (m, 2H), 4.78 (t, lH, .1=5.4Hz), 4.29-4.34 (m, lH), 3.68-3.73 (m, lH), 2.81 (s, 3H), 2.25-2.50 (m, lH), 2.16- 2.19 (m, lH), 2.04-2.04 (m, lH), 1.70-1.74 (m. lH) LC / MS ESI (+): 547 (M+l) 1H-NMR ( 400MHz, DMSO-d6): 6 11.0 (s, lH), 8.35 (s, lH), 8.12 (s, lH), 7.91 (s, lH), 7.66 (d. lH, .l=l.3Hz), 7.53 (d, 2H, J=8.9Hz), 7.31 (d, lH, J=l.3Hz), 7.26 (d, 2H, J=8.9Hz), 4.76-4.79 (m, 1H), 3.01 (s, 3H), 2.82-2.94 (m, 2H), 2.43-2.46 (m, lH), 2.14-2.20 (m, 2H), 1.62-1.66 (m, lH) LC / MS ESI (+): 563 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.94 (hrs, lH), 8.29 (s, lH), 8.25 (s, lH), 7.65 (s, lH), 7.57 (s, IH), 7.52 (d, 2H, .1=8.5Hz), 7.30 (s, lH), 7.25 (d, 2H, J:=8.3Hz), 4.49-4.54 (m, lH), 4.20-4.24 (m, 1H), 2.98 (s, 3H), 2.62 (m, IH), 2.15-2.22 (m, lH), 1.84 (s, 3H) LC / MS ESI (+): 549 (M+I) 1H-NMR(400MHz, DMSO-d6):6 10.96 (hrs, lH), 8.32 (s, lH), 8.09 (s, lH), 7.87 (s, lH), 7.60 (d. lH, .J=l.2Hz), 7.45-7.47 (m, 2H), 7.25 (d, lH, J:=0.8Hz), 7.18-7.22 (m, 2H), 4.96 (d, lH, J=15.6Hz), 4.82 (d, lH, J=15.6Hz), 4.60 (d, lH, J=l2.8Hz), 4.48 (s, 111), 4.03 (dd. lH, .1=12.8, 3.6Hz), 2.63 (s, 3H) LC / MS ESI (+): 567 (M+l) 1H-NMR (400MHz, J?MS0'""6): 6 10.92 (hrs, IH), 8.27 (s, IH), 824 (s, IH), 7.64 (s, lH), 7.58 (s, lH), 7.46 (d, 2H, J=8.8Hz), 7.21 (s, 1H), 7.18 (d, 2~J=8.8Hz), • 4.46-4.52 {m, IR), 4.33-4.38 (m, IH), 2.93 {s, 3H), 2.87-2.93 (m, lH), 2.60-2.67 (m, lH) LC / MS ESI (-): 581 (M-1) 1H-NMR (400MHz, DMSO-d6): 6 I 1.13 (s, IH), 8.57 (s, IH), 8.43 (s, IH), 8.23 (s, lH), 7.67 (d, lH, J=l.lHz), 7.52 (d, 2H, J=8.9Hz), 5 CA 02966742 2017-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 7.31 (d, 1 H, J=O. 7Hz), 7 .26 ( d, 2H, J=8.9Hz), 4.91 (m. lH), 3.19 (s, 3H), 2.80-2.90 (m. lH), 2.70-2.75 (m, lH), 2.36-2.45 (m, 2H) Example 15) Synthesis of N-(2-chloro-6-(p-tolyloxy)pyridin-4-yl)-4- (metbylsulfonyl)-3,4-dlhydro-lH-tbleno[3,2-g]ehromene-7-earboxamide ( a) Synthesis of 2-chloro-6-(p-tolyloxy)pyridin-4-amine To a solution of 2,6-dichloropyridin-4-amine (200.0 mg1 1.23 mmol) in sulfolane (4090.0 μl) were added p-cresol (265.0 mg, 2.45 mmol) and K2CO3 (339.0 mg, 2.45 mmol). The reaction mixture was stirred at 160°C for 30 hours. The reaction mixture was extracted 10 with EtOAc. The organic extract was washed with lN-NaOH and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reversed-phase column chromatography (ClS-silica gel, 0.1% fonnic acid in CH3CN: 0.1% formic acid in H2O) and solidification with ACN / ether / Hex to obtain 2-chloro-6-(p-tolyloxy)pyridin-4- amine (160.0 mg, 56 %) as a light brown amorphous. 15 1H-NMR (400MHz, CDCh): 6 7.17 (d, 2H, J=8.2Hz), 7.00 (d, 2H, J=8.5Hz), 6.30 (d, 1H,J=l.7Hz), 5.81 (d, 1H,J=l.7Hz), 4.22 (brs, 2H), 2.35 (s, 3H) (b) Synthesis of N~(2-chloro-6-(p-tolyloxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7-carboxamide 20 The syrJ.thesis procedure of Example 1-b was repeated except for using 2-chloro-6- (p-tolyloxy)pyridin-4-arnine (41.3 mg,· 0.18 mmol) to obtain N-(2-chloro-6-(ptolyloxy) pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7- carboxamide (51.0 mg, 60 %) as a white amorphous. LC / MS ESI (+): 529 (M+l) 25 1H-NMR (400MHz, DMSO-d6): 6 10.89 (s, lH), 8.29 (s, lH), 8.05 (s, 1H), 7.64 (d, lH, J=l.4Hz), 7.58 (s, lH), 7.27 (d, 2H, J=8.3Hz), 7.21 (d, lH, J=l.4Hz), 7.08 (d, 2H, J==8.4Hz), 4.81 (m, lH), 4.44-4.51 (m, lH), 4.29-4.34 (m, lH), 3.16 (s, 3H), 2.59-2.6r(m, 1H), 2.32-2.34 (m, 4H) 30 Compounds from Examples 16 to 42 were synthesized through the synthesis route of Example 15, and data of these compounds are listed as follows. [Table 3] Compound Analysis data 52 CA 02966'142 201'1-05-03 WO 2016 / 089062 16 17 18 19 20 21 N-(2-chloro-6-(3- ( trifluoromethy l)phenoxy)pyridin-4-yl)- 4--(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-( 4- (trifluoromethyl)phenoxy)pyridin-4-yl)- 4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-(3 ,5- dichlorophenoxy )pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2Htbieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-( 4-chloro-3- fluorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-(4-clitoro-3- methylphenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-( 4-chloro-2- methylphenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide 53 PCT / KR2015 / 012926 LC / MS ESI (+): 583 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.97 (s, 111), 8.32 (s, lB), 8.08 (s, lB), 7.65-7.74 (m, 4H), 7.55-7.59 (m. 2H), 7.40 (d, lH, J=l.2Hz), 4.81-4.84 (m, lB), 4.49-4.53 (m, HI), 4.31-4.34 (m, lH), 3.17 (s, 3H), 2.60- 2.68 (m, lH), 2.35-2.36 (m, 1H) LC / MS ESI (+): 583 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.98 (s, lB), 8.32 (s, lH), 8.08 (s, lH), 7.85 (d, 2H, J=8.6Hz), 7.71 (s, lH), 7.59 (s, lH), 7.41-7.45 (m. 3H), 4.82-4.83 (m, lH), 4.49-4.52 (m, lB), 4.31-4.35 (m, lH), 3.17 (s, 3H), 2.60- 2.65 (m, lH), 2.36-2.39 (m, 1H) LC / MS ESI (+): 583 (M+l) 1H-NMR (400MHz, DMSO-d6): 3 10.98 (s, lH), 8.32 (s, lH), 8.08 (s, lH), 7.70 (d, 2H, J=1.2Hz), 7.59 (s, lH), 7.56 (t, 111. J•2.0Hz), 7.44 (d, 2H, J=2.0Hz), 7.37 (s, lH), 4.82-4.84 (m, lH). 4.46-4.52 (m, lH), 4.32-4.35 (m, lH), 3.17 (s, 3H), 2.60-2.65 (m, lH), 2.36- 2.39 (m, 1H) LC / MS ESI (+): 567 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.96 (s, lH), 8.30 (s, lB), 8.07 (s, lH), 7.67-7.69 (m, 2H), 7.58 (s, lH), 7.47 (d, lH, J=10.3Hz), 7.35 (s, lH), 7.15 (d, lH, J=l0.3Hz), 4.83- 4.85 (m, IH), 4.49-4.52 (m, lH). 4.30-4.34 . (m, lH), 3.17 (s, 3H), 2.60-2.65 (m, lH), 2.36- 2.39 (m., lH) LC / MS ESI (+): 563 (M+l) 1H-NMR (400MHz, DMSO-d6): 10.92 (brs, 1H), 8.29 (s, lH), 8.06 (s, lH), 7.67 (s, lH), 7.58 (s, lH), 7.50 (d, lH, J=8.7Hz), 7.25,..7.26 (m, 2H), 7.09 (dd, 111, J=8.6, 2.8Hz), 4.82 (m, lH), 4.45-4.51 (m, IH), 4.30-4.34 (m, lH), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.32-2.35 (m, 4H) LC / MS ESI (+): 563 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 10.92 (s, lH), 8.30 (s, lH), 8.06 (s, lH), 7.64 (m, ·1H), 7.58 (s, lH), 7.47 (m, lH), 7.35 (dd, lH, J=8.6, 2.6Hz), 7.26 (m, lH), 7.19 (d, 111, J=8.6Hz), 4.81 (m, lH), 4.45-4.51 (m, lH), 4.30-4.34 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 (m, 1 H), 3.19 (s, 3H), 2.60-2.67 (m, l H), 2.32- 2.36 (m, IH), 2.12 (s, 3H) LC / MS ESI (+): 545 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.88 (s, N-(2-chloro-6-( 4- IH), 8.29 (s, III), 8.05 (s, IH), 7.63 (d, IH, 22 methoxyphenoxy)pyridin-4-yl)-4- J=l.2Hz), 7.58 (s, lH), 7.19 (d, lH, J=1.2Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.14 (d, 2H, J=9.0Hz), 7.01 (d, 2H, J=9.0Hz), thieno[3,2-g]chromene-7--carboxamide 4.81 (m. lH), 4.44-4.51 (m, lH), 4.29-4.34 - (m, lH), 3.79 (s, 3H), 3.16 (s, 3H), 2.59-2.67 (m, lH), 2.30-2.39 (m, lH) LC / MS ESI (+): 567 (M+l) N-(2-chloro-6-( 4-chloro-2- 1H-NMR (400MHz, DMSO-d6): 6 10.90 (hrs, fluorophenoxy)pyridin-4-yl)-4- lH), 8.24 (s, IH), 8.00 (s, lH), 7.62 (dd, IH, 23 J=l0.4, 2.4Hz), 7.57 (s, lH), 7.51 (s, lH), (methylsulfonyl)-3,4-dihydro-2H- 7.30-7.41 (m, 3H), 4.73-4.75 (m, lH), 4.38- thieno[3,2-g]chromene-7-carboxamide 4.45 (m, IH), 4.23-4.27 (m, lH), 3.09 (s, 3H), 2.53-2.61 (m, IH), 2.27-2.32 (m, lH) LC / MS ESI (+): 585 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.88 (hrs, N-(2-chloro-6-(3 ,4- 111), 8.23 (s, lH), 8.00 (s, lH), 7.65 (d, IH, 24 dichlorophenoxy )pyridin-4-yl)-4- J=8.8Hz), 7.60 (s, lH), 7.57 (d, lH, J=2.7Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.51 (s, lH), 7.27 (s, 111), 7.20 (dd, lH, J=8.8, thieno[3,2-g]cbromene-7-carboxamide 2.7Hz), 4.73-4.75 (m. IH), 4.38-4.45 (m, IH), 4.23-4.27 (m, IH), 3.09 (s, 3H), 2.53-2.60 (m, lH), 2.27-2.32 (m, lH) LC / MS ESI (+): 549 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.87 (hrs, N-(2-chloro-6-(3-chlorophenoxy)pyridinlH), 8.24 (s, IH), 8.00 (s, lH), 7.60 (s, IH), 25 4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H- 7.51 (s, 1H), 7.43 (t, lH, J=8.1Hz), 7.28-7.31 thieno[3,2-g]chromene-7--carboxamide (m, 2H), 7.26 (d, lH, .fo=l.3Hz), 7.12-7.15 (m, lH), 4.73-4.75 (m, IH), 4.38-4.45 (m, IH), 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.60 (m, lH), 2.27-2.32 (m, lH) LC / MS ESI (+): 533 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.84 (hrs, N-(2-chloro-6-( 4-fluorophenoxy)pyridin- lH), 8.23 (s, lH), 7.99 (s, lH), 7.57 (s, IH), 26 4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H- 7.51 (s, lH), 7.18-7.26 (m, SH), 4.74-4.76 thieno[3,2-g]chromene-7-carboxamide (m, lH), 4.38-4.44 (m, lH), 4.24-4.26 (m, lH), 3.09 (s, 3H), 2.53-2.60 (m, lH), 2.27• 2.32 (m, lH) N-(2-chloro-6-(3-chloro-4- LC / MS ESJ (+): 567 (M+l) 27 fluorophenoxy)pyridin-4-yl)-4- 1H-NMR(400MHz, DMSO-d6): o 10.87 (hrs, (methylsulfonyl)-3,4-dihydro-2H- lH), 8.23 (s, lH), 8.00 (s, lH), 7.59 (d, lH, 54 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 thieno[3,2-g]chromene-7-carbox.amide J=0.8Hz), 7.44-7.53 (m, 3H), 7.19-7.24 (m, 211), 4.74-4. 75 (m, lH), 4.38-4.45 (m, lH), 4.23-4.27 (m, lH), 3.09 (s, 3H), 2.53-2.57 (m, lH), 2.24-2.32 (m, lH) LC / MS ESI (+): 599 (M+l) N-(2--chloro-6-(4- 1H-NMR(400MHz, DMSO-d6): 6 10.95 (hrs, (trifluoromethoxy)phen.oxy)pyridin-4-yl)- 1H), 8.28 (brs, lH), 8.06 (s, IH), 7.66 (s, 1H), 28 4-(methylsulfonyl)-3,4-dihydro-2H- 7.57 (s, lH), 7.47 (d, 2H, J=8.8Hz), 7.33-7.36 thieno[3,2-g]chromene-7-carboxamide (m, 3H). 4.81-4.82 (m, lH), 4.45-4.52 (m, lH), 4.29-4.34 (m, lll); 3.16 (s, 3H), 2.60- 2.64 (m, 1H), 2.31-2.39 (m, 1H) LC / MS ESI (+): 599.(M+l) 1H-NMR(400MHz, DMS0-14): 6 10.96 (brs, N-(2--chloro-6-(3 • lll), 8.30 (s, Ill), 8.07 (s, IH), 7.67 (d, IH, 29 (trifluoromethoxy)phenoxy)pyridin-4-yl)- J=l.2Hz), 7.58-7.62 (m, 2H), 7.37 (d, lH, 4-(methylsulfonyl)-3.4-dihydro-2H- J=0.8Hz), 7.26-7.32 (m, 3H), 4.81-4.82 (m, thieno[3,2-g]chromene-7-carboxamide lH), 4.45-4.52 (m, Ill), 4.30-4.34 (m, IH), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.30-2.39 (m, lH) LC / MS ESI (+): 580 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.87 (hrs, N-(2-chloro-6-(3-chloro-S-· lH), 8.23 (s, 111), 7.99 (s, 1H), 7.61 (s, IH), 30 methoxyphenoxy)pyridin-4-yl)-4- 7 .5() (s, lH), 7 .22 (s, lH), 6.89-6.90 (m, lH), (methylsulfonyl)-3,4-dihydro-2H- 6.85-6.86 (m, lH), 6.74-6.75 (m, lH), 4.74- thieno[3,2-g]chromene-7-carboxamide 4.75 (m, lH), 4.38-4.43 (m. lH), 4.23-4.27 (m. lH), 3.75 (s. 3H). 3.09 (s, 3H), 2.53-2.57 (~ lH), 2.29-2.32 (m, lH) LC / MS ESI (+): 566 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.90 (brs, N-(2-chloro-6-(3-chloro-5- lH), 8.23 (s, lH), 8.00 (s, lH), 7.62 (s, lH), 31 tluorophenoxy)pyridin-4-yl)-4- 7.51 (s, lH), 7.31-7.32 (m, Ill), 7.30 (s, lH), (methylsulfonyl)-3.4-dihydro-2H- 7.20 (s, lH), 7.16-7.19 (m, lll), 4.74-4.75 (m, thieno[3,2-g]chromene-7-carboxamide lH), 4.38-4.43 (m, lH), 4.23-4.27 (m, lH), 3.09 (s, 3H), 2.53-2.57 (m, lH), 2.29-2.32 (m, lH) LC / MS ESI (+): 563 (M+l) N-(2-chloro-6-{3-fluoro-5- 1H-NMR (400MHz, DMSO-d6): 6 10.86 (brs, methoxyphenoxy )pyrldin-4-yl)-4- lH), 8.22 (s, lH), 7.99 (s, 1H), 7.61 (s, lH), . 32 (methylsulfonyl)-3,4-dihydro-2H- 7.50 (s, lll), 7.22 (s, lH), 6.64-6.72 (m, 2H), thieno[3,2-g]chromene-7-carboxamide 6.61 (s, lH), 4.74-4.76 (m, lH), 4.38-4.44 (m, lH), 4.24-4.26 (m, lH), 3.72 (s, 3H), 3.09 (s, 3H), 2.53-2.60 (m, lH), 2.27-2.32 (m. lH) 55 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 LC / MS ESI (+): 529 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.83 (hrs, N-(2-cbloro-6-(m-tolylo,ty)pyridin-4-yl)· lH), 8.22 (s, lH), 7.98 (s, lH), 7.59 (s, lH), 7.50 (s, lH), 7.28 (t, lH, J=7.7Hz), 7.15 (s, 33 4-(metbylsulfonyl)-3,4-dihydro-2HlH), 7.03 (d, 1H,J=7.6Hz), 6.95 (s, lH), 6.91- thieno[3,2-g]chromene-7-carboxamide 6.93 (m. lH), 4.74-4.76 (m. lH), 4.38-4.44 (m, IH), 4.24-4.26 (m, lH), 3.09 (s, 3H), 2.53- 2.60 (m, lH), 2.27 (s, 3H), 2.27-2.32 (m, lH) LC / MS ESI (+): 551 (M+l) 1H-NMR(400MHz, DMSO-d6): o 10.94 (hrs, N-(2-cbloro-6-(3,4- lH), 8.29 (s, lH), 8.06 (s, lH), 7.65 (s, lH), 3.4 difluorophenoxy)pyridin-:4,-yl)-4- 7.47-7.58 (m, 3H), 7.31 (s, lH), 7.10-7.14 (m, (methylsulfonyl)-3,4-dihydro-2HlH), 4.81-4.82 (m, HI), 4.45-4.51 (m, IH), thieno[3,2-g]chromene-7-carboxamide 4.30-4.34 (m, lH), 3.16 (s, 3H), 2.60-2.64 (m, lH), 2.30-2.39 (m, lH) LC / MS ESI (+): 567 (M+l) 1H-NMR (400MHz, DMSO-d6): 10.99 (hrs, N-(2-cbloro-6-(5-chloro-2- lH), 8.32 (s, lH), 8.08 (s, lH), 7.65 (s, lH), fluorophenoxy)pyridin-4-yl)-4- 7.62 (dd, lH, J=6.9, 2.6Hz), 7.59 (s, 1H), 35 (methylsulfonyl)-3,4-dihydro-2H- 7.47-7.52 (m, IH), 7.41-7_45 (m. 2H), 4.82 thieno[3,2-g]chromene• 7-carboxamide (m. lH), 4.45-4.49 (m, IH), 4.31-4.35 (m, lH), 3.17 (s, 3H), 2.60-2.64 (m, lH), 2.35- 2.39 (m, lH) LC / MS ESI (+): 567 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 11.00 (s; lH), N-(2-chloro-6-(3-chloro-2- 8.32 (s, lH), 8.09 (s, lH), 7.66 (d, lH, J=l.2Hz), 7.59 (s, lH), 7.55 (td. lH, J=8.4, 36 fluorophenoxy)pyridin-4-yl)-4- 1.6Bz), 7.47 (s, lII). 7.15 (td, IH, J=9.2, (methylsulfonyl)-3,4-dihydro-2H- 1.6Hz), 7.34 (td, lH, J=S.4, 2.8Hz), 4.82-4.83 thieno[3,2-g]chromene-7-carbox.amide (m, lH), 4.49-4.53 (m.lH), 4.32-4.35 (m, 1H), 3.17 (s, 3H), 2.60-2.65 (m, lH), 2.36-2.39 (m, IH) LC / MS ESI (+): 561 (M+l) 1H-NMR (400MHz, DMSO-d5): 6 10.92 (s, N-(2-chloro-6-(5-chloro-2- IH), 8.30 (s, IH), 8.07 (s, IH), 7.64 (d, IH, 37 methylphenoxy)pyridin-4-yl)-4- J=l.2Hz), 7.58 (s, lH), 7.40 (d, lH, J=7.8Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.28 (m. 3H), 4.81 (m, lH), 4.44-4.52 (m, thieno[3,2-g]chromene-7-carboxam.ide lH), 4.30-4.34 (m, lH), 3.16 (s, 3H), 2.59- 2.64 (m, IH), 2.34-2.39 (m, IH), 2.11 (s, 3H) LC / MS ESI (+): 563 (M+l) N-(2-chloro-6-(3-chloro-4- 1H-NMR (400MHz, DMSO-d6): o 10.86 (brs, 38 methylphenoxy)pyridin-4-yl)-4• lH), 8.23 (s, lH), 7.99 (s, lH), 7.59 (s, lH), (methylsulfonyl )· 3.4-dihydro-2H- 7.51 (s, IH), 7.38 {d, IH~ .1=8.3Hz), 7.29 (s, thieno[3,2-g]cbromene-7-carbox:amide 1H), 7.20 (s, lH), 7.05 (d, lH, J=8.3Hz), 4.74- 56 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 4.76 (m. lH), 4.38-4.44 (m, lH), 4.24-4.26 (m, 1 H), 3.09 (s. 3H), 2.53-2.60 (m, 1 H), 2.30 (s, 3H), 2.27-2.32 (m. lH) LC / MS ESI (+): 583 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.90 (brs, N-(2-chloro-6-(2- lH), 8.2'5 (s, lH), 8.00 (s, lH), 7.78 (d. lH, 39 (tritluoromethyl)phenoxy)pyridin-4-yl)- J=7.8Hz), 7.72 (t, lH, J=7.8Hz), 7.59 (s, lH), 4-(methylsu1fonyl)-3,4-dihydro-2H- 7.51 (s, lH), 7.38-7.44 (m, 2H), 7.33 (s, lH), . thieno[3,2-g]chromene-7-carboxamide 4.74-4.76 (m, IH), 4.38-4.44 (m, IH), 4.24- 4.26 (m, lH), 3.09 (s, 3H), 2.53-2.57 (m, lH), 2.27-2.32 (m, lH) LC / MS ESI (+): 599 (M+ 1) N-(2-chloro-6-{2- 1H-NMR (400MHz, DMSO-d6): 6 10.91 (brs, lH), 8.23 (s, lH), 8.00 (s, 1H), 7.'57 (s, IH), 40 (trifluoromethoxy)phenoxy)pyridin-4-yl)- 7.51 (s, lH), 7.33-7.50 (m, SH), 4.74-4.75 (m, 4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2~g]chromene-7-carboxamide lH), 4.38-4.43 (m, IH), 4.23-4.27 (m, IH), 3.09 (s, 3H), 2.53-2.57 {m, lH), 2.27-2.32 (m, lH) LC / MS ESI (+): 547 (M+l) 1H-NMR (400MHz, DMSO-d5): o 10.94 (s, N-(2-chloro-6-(2-fluoro-3- lH), 8.30 (s, lH), 8.07 (s, lH), 7.64 (d, lH, 41 methylphenoxy)pyridin-4-yl)-4- J=l.3Hz). 7.58 (s, lH), 7.36 (d, lH, J=l.lHz), (methylsulfonyl)-3,4-dihydro-2H- 7.14-7.24 (m, 3H), 4.81 (m, IH). 4.44-4.52 thieno[3,2-g]chromene-7-carboxamide (m, lH), 4.30-4.34 (m, lH), 3.16 (s, 3H), 2.59- 2.64 (m, 1H), 2.33-2.39 (m, 1H), 2.29 (s, 3H) LC / MS ESI (+): 579 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 6 10.81 (brs, N-(2-chloro-6-(4-chloro-2- lH), 8 .. 21 (s, lH), 7.98 (s, 1H), 7.53 (s, lH), 42 methoxyphenoxy)pyridin-4-yl)-4- 7.50 (s, IH), 7.22 (d, lH, .1=2.3Hz), 7.17 (d, (methylsulfonyl)-3,4-dihydro-2H- IH, J=8.4Hz), 7.14 (s, lH), 7.01 (dd, IH, thieno[3,2-g]chromene-7-carboxamide J=8.4, 2.3Hz), 4.73-4.74 (m, lH), 4.38-4.44 (m, lH), 4.23-4.27 (m, lH), 3.69 (s, 3H), 3.09 (s, 3H), 2.52-2.57 (m, lH), 2.20-2.27 (m, lH) Examples 43 and 44) Separation of {S)-N-(2-chloro-6-(4- chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno(3,2- 5 g)chromene-7-carboxamide and (R)-N-(2-chloro-6-{4-chlorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno [3,2-g] chromene-7-carboxamide from rac-N( 2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide 51 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 The racemate of N-(2-cbloro-6-(4-chlorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide (100.0 mg, 0.18 mmol) obtained in Example 8 was separated by preparative HPLC (Daicel Chiralpak IA, s dichloromethane / etbanol=98 / 2, 10.0mL / min, 254nm, 35°C) into (S)-N-(2-chloro-6-(4- chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)--3,4-dihydro-2H-thieno[3,2-g]chromene- 7-carboxamide (45.0 mg, 45%) and (R)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide (44.0 mg, 44%). 10 Example 43) (S)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno [3,2-g] chromene-7-carboxamide LC / MS ESI ( +): 549 (M+ 1 ). 1H-NMR (400MHz, DMSO-d6): 10.96 (s, lH), 8.31 (s, lH), 8.06 (s, lH), 7.66 (s, lH), 7.58 (s, lH), 7.52 (d, 2H, J=8.80Hz), 7.31 (s, lH), 7.27 (d, 2H, J=8.80Hz), 4.82 (m, . 15 lH), 4.45-4.51 (m, lH), 4.30-4.34 (m, lH}, 3.16 (s, 3H}, 2.60-2.64 (m, lH), 2.29-2.39 (m, IH). HPLC: Daicel Chiralpak IA, 0.46 cm I.D. x 15 cm L, dichloromethane / ethanol=98 / 2, 1.0mllmil\ 254nm, 35°C, tR= 3.08 min. 20 Example· 44) (R)-N-(2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)-4- (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide LC / MS ESI (+): 549 (M+l). 1H-NMR (400MHz, DMSO-d6): 11.03 (s, lH), 8.32 (s, lll}, 8.06 (s, lH), 7.66 (s, 1H), 7.57 (s, lH), 7.52 (d, 2H, J=8.79Hz), 7.31 (s, lH), 7.26 (d, 2H, J=8.79Hz), 4.82 (m, 25 lH), 4.45-4.51 (m, lH), 4.30-4.33 (m, lH}, 3.16 (s, 3H), 2.60-2.64 (m, lH), 2.30-2.39 (m~ IH). HPLC: Daicel Chiralpak IA, 0.46 cm I.D. x 15 cm L, dichloromethane / ethanol=98 / 2, 1.0mUmil\ 254nm, 35°C, tR= 3.95 min. 30 Compounds from Examples 45 to 49 were synthesized through the synthesis route of Example 43 and 44, and data of these compounds are listed as follows. [Table4] Ex. Compound Analysis data (S)-N-(2-chloro-6{4- LC / MS ESI (+}: 567 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.97 (brs, chlorophenoxy)pyridin-4-yl)-4-fluoro-4- 45 (methylsulfonyl)-3,4-dihydro-2HlH), 8.26 (s, lH), 8.24 (s, lH), 7.63 (s, lH), thieno[3,2-g]chromene-7-carboxamide 7.58 (s. lH), 7.45 (d, 2H, .1=8.7Hz), 722 (s, lH), 7.19 (d. 2H, J=8.7Hz), 4.46-4.53 (m, 58 s CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 lH), 4.32-4.36 (m, lH), 3.24 (s, 3H), 2.87- 2.94 (m, lH), 2.61-2.71 (m, lH) LC / MS ESI (+): 567 (M+l) (R)-N-(2-chloro-6-(4- 1H-NMR (400MHz, DMSO--d6): 6 10.91 (brs, HI), 8.26 (s, lH), 8.23 (s, lH), 7.63 (s, lH), 46 chlorophenoxy)pyridin-4-yl)-4-fluoro-4- 7.57 (s, 1H), 7.46 (d, 2H, J=8.7Hz), 7.21 (s, (methylsulfonyl)-3,4-dihydro-2HlH), 7.19 (d, 2H, J=8.7Hz), 4.46-4.49 (m, thieno[3,2-g]chromene• 7-carboxamide lH), 4.31-4.37 (m, lH), 3.24 (s, 3H), 2.86- 2.90 (m, lH), 2.64-2.70 (m, lH) LC / MS ESI (+): 563 (M+l) (S),N-(2-chloro-6-(4- 1H-NMR (400MHz, DMSO--d6): 6 10.94 (brs, HI), 8.29 (s, lH), 825 (s, lH), 7.65 (s, lH), 47 chlorophenoxy)pyridin-4-yl)-4-methyl-4- 7.57 (s, lH), 7.52 (d, 2H, J=8.5Hz), 7.30 (s, (methylsulfonyl)-3,4-dihydro-2HlH), 7.25 (d, 2H, J=8.3Hz), 4.49-4.54 (m, thieno[3,2-g]chromene-7-carboxamide lH), 4.20-4.24 (m, lH), 2.98 (s, 3H), 2.62 (m, lH), 2.15-2.22 (m, lH), 1.84 (s, 3H) LC / MS ESI (+): 563 (M+l) (R)-N-(2-chloro-6-(4- 1H-NMR (400MHz, DMSO--d6): 6 10.94 (brs, lH), 8.29 (s, lH), 8.25 (s, lH), 7.65 (s, lH), 48 chlorophenoxy)pyridin-4-yl)-4-methy14 7.57 (s, lH), 7.52 (d, 2H, J=8.5Hz), 7.30 (s, (methylsulfonyl)•3,4-dihydro-2HlH), 7.25 (d, 2H, J=8.3Hz), 4.49-4.54 (m, thieno[3,2-g)chromene-7-ca.rboxamide lH), 4.20-4.24 (m, lH), 2.98 (s, 3H), 2.62 (m, lH), 2.15-2.22 (m, lH), 1.84 (s, 3H) LC / MS ESI (+): 580 (M+l) 1H-NMR (400MHz, DMSO--d6): 6 10.86 (brs, (S)-N-(2-chloro-6-(3-chloro,.S • lH), 8.23 (s, lH), 7.99 (s, lH), 7.62 (s, lH), 49 methoxyphenoxy )pyridin-4-yl)-4- 7.51 (s, lH), 7.22 (s, lH), 6.89-6.90 (m, lH), (methylsulfonyl)-3,4-dihydro-2H- 6.85-6.86 (m, lH), 6.74-6.76 (m, IH), 4.74- thieno[3,2-g]chromene-7-carboxamide 4.75 (m, lH), 4.39-4.44 (m, lH), 4.23-4.27 (m, lH), 3.73 (s, 3H). 3.09 (s, 3H), 2.52-2.57 (m, lH), 2.28-2.32 (m, IH) Exmnples 50) Synthesis of N-(2-chloro-6-(4-c:hlorophenoxy)pyridin-4-yl)-1- (methy)sulfoayl)-1,2,3,4-tetraliydrothieno(2,3-g)quinoxaline-7-carbox:amide tert-butyl 7-((2-chloro-6-( 4-chlorophenoxy)pyridin-4-yl)carbamoyl)-1- (methylsulfonyl)-2,3-dihydrothieno [2,3-g]quinoxaline-4(111)-carboxylate (7 .0 mg, 10. 78 μmol) was dissolved in CH2Clz (108.0 μI), and TFA (300 μl, 3.89 mmol) was added at 20°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction 10 mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% fonnic acid in CH3CN : 0.1% formic acid in H2O) to obtain N-(2-chloro-6-(4- 59 CA 02966'142 201'1-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 chlorophenoxy)pyridin-4-yl)-1..(methylsulfonyl )-1,2,3 ,4-tetrahydrothieno[2,3- g]quinoxaline-7-carboxamide (2.5 mg, 42 %) as white amorphous. Examples 51) Synthesis of N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5- s (methylsulfonyl)-8-oxo-5,6, 7,8-tetrahydronaphtho[2,3-b] thiophene-2-carboxamide To a solution of N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5- (methylsulfonyl)-5,6, 7, 8-tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide (20.0 mg, 0.04 mmol) in acetic anhydride (1.0 ml, 10.58 mmol) was added chromium oxide(VI) (11.0 mg, 10 0.11 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1 % formic acid in CH3CN : 0.1% formic acid in H20) to obtain N-(2-chloro-6-(4- chlorophenoxy)pyridin-4-yl)-5-(methylsulfonyl)-8-oxo-5,6, 7,8-tetrahydronaphtho[2,3- b]thiophene-2-carboxamide (5.0 mg, 24 %) as a white amorphous. 15 LC / MS ESI(+): 561 (M+l) 20 1H-NMR (400MHz, DMSO-d6): 611.14 (s; lH), 8.72 (s, lH), 8.46 (s, lH), 8.23 (s, lH), 7.68 (d, lH, J=l.2Hz), 7.52 (d, 2H, J~8.8Hz), 7.33 (d, lH, J=l.2Hz), 7.26 (d, 2H, J=8.8Hz), 4.99 (m, lH), 3.17 (s, 3H), 3.02-3.09 (m; lH), 2.79-2.83. (m, lH), 2.61-2.67 (m, 2H) Examples 52) Synthesis of N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yJ)-4- (lH-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide To a suspension of 4-(1H-pyrazol-1-yl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7- 25 carboxylic acid (17.0 mg, 0.06 mmol) in CH2Ch (0.3 ml) were added (COCl)2 (9.6 μl, 0.11 mmol) and DMF (0.4 μl, 5.66 μmol). The reaction mixture was stirred at 40°C for lhour, and concentrated under reduced pressure to obtain 4-(1H-pyrazol-l-yl)-3,4-dihydro-2Ht: Jrleno[3,2-g]chromene-7-carbonyl chloride. To the residue, 2-chloro-6-(4- chlorophenoxy)pyridin-4-amine (28.9 mg, 0.11 mmol) and 1,4-dioxane (0.3 ml) was added. 30 The reaction mixture was stirred at 80°C overnight. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1 % fonnic acid in CH3CN: 0.1 % formic acid in H20) to obtain N-(2-chloro-6-(4-chlorophenoxy)pyndin-4-yl)-4-(lHpyrazol- I-yl)-3,4-dihydro-2H-thieno[3,2-g]chromene•7-carboxamide (21.0 mg, 69 %) as a white solid. 35 LC / MS ESI (+): 537 (M+l) 1H-NMR (400MHz, DMSO-d6): o 10.77 (brs, lH), 8.08 (s, lH), .7.74 (d, IH, J=2.0Hz), 1.55 (s, lH), 7.43-7.48 (m, 4H), 7.33 (s, lH), 7.16-7.20 (m, 3H), 6.23-6.25 (m, lH), 5.80 (t, lH, J=6.2Hz), 4.27-4.3 (m, 2H), 2.31-2.43 (m, 2H) 40 Compounds from Examples 53 to SS were synthesized through the synthesis route 60 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 of Example 52, and data of these compounds are listed as follows. Ex. 53 54 55 [Table 5] Compound N-(2-chloro-<H 4- chlorophenoxy)pyridin4-yl)-4-{2- oxopyrrolidm-1-yl)-3,4-dihydro-2Hthieno[ 3,2-g]chromene-7-carboxamide N-(2-chloro-6-( 4- chlorophenoxy)pyridin-4-yl)-4-cyano- 3,4-dihydro-2H-thieno[3,2-g]chromene- 7-carboxamide 4-azido-N-(2-c:hloro-6-( 4- chlorophenoxy)pyridin-4-yl)-3,4- dihydro-2H-thieno[3,2-g]chromene-7- carboxamide Analysis data LC / MS ESI (+): 554 (M+ 1) 1H-NMR (400MHz, DMSO-d6): 6 10.93 (s, lH), 8.23 (s, lH), 7.66 (s, lH), 7.59 (s, lH), 7.48-7.53 (m, 3H), 7.24-7.29 (m, 3H), 5.43- 5.47 (m, lH), 4.29-4.42 (m, 2H), 3.24-3.29 (rn, lH), 2.95-3.00 (m, _ lH), 2.35-2.44 (m, 2H), 2.11-2.22 (m, lH), 1.90-2.03 (m, 3H) LC / MS ESI (+): 496 (M+l) 1H-NMR (400MHz, DMSO-d6): 6 10.89 (brs, IH), 8.21 (s, lH), 7.96 (s, lH), 7.58 (s, lH), 7.49 (s, lH), 7.46 (d, 2H, .T=8.8Hz), 7.23 (s, lH), 7.19 (d, 2H, J=8.8Hz), 4.57-4.60 (rn, lH), 4.23-4.26 (m, 2H), 2.22-2.33 (m, 2H) LC / MS ESI (+): 512 (M+1) 111-NMR (400MHz, DMSO-d6): o 10.96 (brs, lH), 8.31 (s, lH), 8.04 (s, 1H), 7.65 (s, lH), 1.S6 (s, lH), 7.52 (d, 2H, .1=8.8Hz), 7.31 (s, lH), 7.26 (d, 2H, 8.8Hz). 5.09 (t. lH, J=3.9Hz), 4.35-4.40 (m, lH), 4.16-4.23 (m, lH), 2.23-2.25 (m, lH), 1.98-2.05 (m, lH) Examples 56) Synthesis of N-(3-ehloro-5-(l-{4-chlo:rophenyl)propan-2- yl)phenyl)-l-(methylsulfonyl)-2,3-dihydro-1H-thieno[3' ,2' :4,5) benzo[l,2- b] [1,4]oxazine-7-carboxamide 10 (a) Synthesis of 1-chloro-3-nitro-5-(prop-1-en-2-yl)benzene To a suspension of 1-bromo-3-chloro-5-nitrobenzene (7.2 g, 30.59 mmol), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.1 g, 30.59 mmol) and Na2CO3 (9.7 g, 91.76 mmol) in DMB (120.0 mL) / H2O (30.0 mL) was added Pd(PPh3)4 (1.8 g, 1.53 mmol). The reaction mixture was refluxed overnight. Pd(PPh3)4 (0.7 g, 0.61 mmol) was 15 more added and stirred for 4homs. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated and the residue was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by NH-silica column chromatography (hexane only) to give 1-chloro-3-nitro-5-(prop-1-en-2-yl)benzene (6.3 g) as a crude yellow 61 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 oil. 1H-NMR (400MHz, CDCh): o 8.19 (t, lH, J=l.7Hz), 8.11 (t, l~ J=l.8Hz), 7.74 (t, lH, J=l.7Hz), S.30 (s, lH), 2.19 (s, 3H) 5 (b) Synthesis of 1-(2-bromopropan-2-yl)-3-chloro-5-nitrobenzene To a solution of 1-chloro-3-nitro-5-(prop-1-en.-2-yl)benzen.e (6.3 g, 22.14 mmol) in EtzO (100.0 mL) was added 33wt% HBr in ACN (38.8 mL, 221.38 mmol). The reaction mixture was stirred at room temperature for 2 days. Sat.NaHCO3 aqueous solution was added under ice-bath and the resulting mixture was extracted with EhO, The organic 10 extract was washed with sat. NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 19 : 1) to obtain 1-(2-bromopropan-2-yl)-3- chloro-5-nitrobenzene (5.3 g, 62% in 2 steps) as an ivory solid. 1H-NMR,(400MHz, CDCl3): 6 8.34 (t, lH, J=l.9Hz), 8.13 (t, lH, J=l.9Hz), 7.26 15 (t, 1H,.l=l.8Hz), 2.21 (s, 6H) ( c) Synthesis of 1-chloro-3-(2-( 4-chloropbenyl)propan-2-yl)-5-nitroben.zene 1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (2.0 g, 7.18 mmol) and chlorobenzene (10.9 mL, 0.11 mol) were dissolved in 1,2-dichloroethane (70.0 mL), and 20 AlCh (2.9 g, 21.54 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours, H2O was added, and extracted with CH2C12, The organic extract was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by reverse4-phase column chromatography (Cl8-silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in H2O) to obtain 1-chloro-3-(2-(4-chlorophenyl)propan-2- 25 yl)-5-nitrobenzene (1.95 g, 88%) as a yellow oil. 1H-NMR (400MHz, CDCb): 6 8.06 (t, lH, J=l.8Hz ), 7.99 (t, lH, J=l.9Hz ), 7.47 (t, 1H,J=l.7Hz ), 7.29 (d, 2H,J=8.5Hz), 7.12 (d, 2H,J=8.5Hz), 1.70 (s, 6H) (d) Synthesis of3-chloro-5-{2-(4-chlorophenyl)propan-2-yl)aniline 30 1-chloro-3-(2-(4-chlorophenyl)propan-2-yl)-5-nitrobenzene (1.95 g, 6.28 mmol) was dissolved in MeOH / THF / H2O (65.0 mL, 10 / 2 / 1 v / v), and Zn (6.17 mg, 94.3 mmol) and N~Cl (1.68 g, 31.4 mmol) were added at room temperature. The reaction mixture was ultrasonificated at 40°C for 90 minutes, cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was purified by flash column 35 chromatography (amine silica gel, n-Hex : EtOAc = 9 : 1) to obtain 3-chloro-5-(2-(4- chlorophenyl)propan-2-yl)aniline (1.49 g, 85%) as a yellow oil. LC / MS ESI (+): 280 (M+l) 1H-NMR (400MHz, CDCh): .S 7.22 (d, 2H, J=8.7Hz), 7.14 (d, 2H, J=8.7Hz), 6.60 (t, lH, .1=1.7 Hz), 6.50 (t, lH, J=1.9 Hz), 6.32 (t, lH, J=l.9 Hz ),3.64 (s, 2H), 1.59 (s, 40 6H) 62 ( e) Synthesis of N-(3-chloro-5-(2-( 4-chloropheny 1 )propan-2-yl)phenyl)-1- (methy l sulfonyl)-2,3-dihydro-1H-thieno[3 ',2':4,5 ]benzo[l,2-b ][1,4 ]oxazine-7-carboxamide The synthesis procedure of Example 1-b was repeated except for using 3-chloro-5-(2-(4- chlorophenyl)propan-2-yl)aniline (12.1 mg, 0.04 mmol) to obtain N-(3-chloro-5-(2-(4- 5 chlorophenyl)propan-2-yl)phenyl)-l-(methylsulfonyl)-2,3-dihydro-1Hthieno[ 3 ',2':4,5]benzo[l,2-b ][1,4]oxazine-7-carboxamide (12.8 mg, 77%) as a white solid. LC / MS ESI (+): 575 (M+l) 1H-NMR(400MHz, DMSO-d6): o 10.47 (s, lH), 8.24 (s, lH), 8.16 (s, lH), 7.89 (s, lH), 7.65 (s, lH), 7.50 (t, IH, J=l.6Hz), 7.39 (d, 2H, J=8.6Hz), 7.28 (d, 2H, J=8.6Hz), 7.03 (m, IH), 10 4.37 (t, 2H, J=4.2Hz), 3.91 (t, 2H, J=4.4Hz), 3.19 (s, 3H), 1.66 (s, 6H). Experimental Examples 15 Experiments were performed as shown below for the compounds prepared in Examples 20 above. Experimental Example 1) Experiment on the inhibition of STAT3 and STATl activities via reporter gene assay 1-1) Experiment on the inhibition of STAT3 activity A human prostate cancer cell line (LNCaP stable cell line; plasmid pSTAT3-TA-luc ), which contains a stably operating STAT3 promoter, was cultured in RPMI1640 medium (Cat No. 11875, Life Technologies) containing 10% fetal bovine serum (FBS) (Cat No. SH30396, Thermo 25 Scientific™) and 150 μg / mL G-418 solution (Cat No. 04 727 894001, Roche). The reporter gene assay using LNCaP stable cell line was performed in RPMI1640 medium containing 3% DCCFBS without G-418 solution. LNCaP stable cells were plated in two (2) white 96-well plates with 30,000 cells / 50 μL in each well. The cells were cultured at 37°C, under 5% CO2 for 24 hours, and then treated with the compounds listed in Examples which were diluted in various 30 concentrations. Subsequently, lL-6 was added to each well with a final concentration of I 0 ng / mL. Upon completion of the treatment with the compounds and lL-6, the cells were cultured at 37°C, under 5% CO2 for 24 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded. 63 Date Re9ue / Date Received 2022-06-13 The luciferase assay and the cell viability assay were performed respectively with one of the two plates. For the luciferase assay, the liquid media 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, luciferase activities of each well were measured in a PHERAstar™ microplate reader 5 (BMG LABTECH) using a luciferase assay system (Cat No. E1501, PromegaTM). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL / well ofCellTiter-Glo solution (Cat No. G7573, Promega), and shaken for 10 minutes in order to measure cytotoxicity caused by the compounds listed in Examples with a PHERAstar™ microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulation were used as 10 a negative control and wells with 0.1% DMSO and stimulation were used as a positive control. 1-2) Experiment on the inhibition of STATl activity A human osteosarcoma cell line (U2OS stable cell line; pGL4-STATl-TA-luc), which contains a stably operating STAT I promoter, was cultured in McCoy 5'A medium (Cat No. 16600, 15 Life Technologies) containing 10% FBS (Cat No. SH30396, Thermo Scientific) and 1000 μg / mL G418 solution (Cat No. 04 727 894 001, Roche). The reporter gene assay using U2OS stable cell line was performed in McCoy 5'A medium containing I 0% FBS without G-418 solution. U2OS stable cells were plated in two (2) white 96-well plates with 25,000 cells / SO μLin each well. The cells were cultured at 37°C, under 5% CO2 for 24 hours, and then treated with the compounds 20 listed in Exam pies which were diluted in various concentrations. Subsequently, IFN-y was added to each well with a final concentration of 50 ng / mL. Upon completion of the treatment with the compounds and IFN-r, the cells were cultured at 37°C, under 5% CO2 for 8 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded. 25 The luciferase assay and the cell viability assay were performed respectively with one of two plates. For the luciferase assay, the liquid media in the 96-well plate was removed, and then, 20 μL of passive cell lysi s buff er was added to each well. After shaking the plate for 30 minutes, luciferase activities of each well were measured in a PHERAstar™ microplate reader (BMG LABTECH) using a luciferase assay system (Cat No. El501, Promega). For the cell viability 30 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 cytotoxicity caused by the compounds listed in Examples with a PHERAstar™ microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulation were used as a negative control and wells with 0.1 % DMSO and stimulation were used as a positive control. 64 Date Re9ue / Date Received 2022-06-13 5 The results of evaluation on the inhibitory effect of the compounds listed in the Examples on the dimerization of STAT3 and STAT I obtained via the STAT3 and STAT I reporter gene assays are shown in Table 6 below. [Table 6] Ex. IC50 (p.M) ICso(μM) Ex. ICso(μM) IC50 (pM) pSTAT3 pSTATl pSTAT3 pSTATl 1 0.0026 >50 2 0.17 >50 64a Date Re9ue / Date Received 2022-06-13 5 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 3 0.01 >50 4 0.93 >50 5 0.76 >50 6 0.0030 >50 7 0.012 >50 8 0.024 >50 9 0.029 >50 10 0.0026 >50 11 0.0060 >50 12 0.0030 >50 13 0.0081 >50 14 0.029 >50 15 0.018 >50 16 0.0051 >50 17 0.0039 >50 18 0.015 >50 19 0.0084 >50 20 0.010 >50 21 0.011 >50 22 0.030 >50 23 0.0063 >50 ·24 0.0062 >50 25 0.011 >50 26 0.0073 >50 27 0.0078 >50 28 0.0051 >50 29 0.0059 >50 30 0.02 >50 31 0.008 >50 32 0.016 >50 33 0.0098 >50 34 0.0064 >SO 35 0.010 >50 36 0.014 >50 37 0.0062 >50 38 0.0088 >50 39 0.014 >50 40 0.0087 >50 41 0.011 >50 42 0.023 >50 43 0.018 >50 44 1.5 >50 45 0.0039 >50 46 0.14 >50 47 0.0045 >SO 48 0.15 >50 49 0.0066 >50 50 0.0082 >50 51 0.10 >50 52 0.10 >50 53 5.2 >50 54 0.18 16.6 55 0.039 17.9 56 0.0028 >50 As shown in Table 6, the compounds according to the present invention exhibited excellent inhibitory effects against the activity of STAT3 protein but showed almost no inhibitory effect against the activity ofSTATl protein. Experimental Example 2) Cell growth inhibition assay The inhibitory effects of the compounds of the present invention against the growth of cancer cells were evaluated as shown below. The cancer cell lines including stomach 10 cancer cell line (NCI-N87) and breast cancer cell line (MDA-MB-468) were cultured under the protocol provided by each supplier. Each type of cells to be used in experiments was 65 CA 02966742 2017-05•03 WO 2016 / 089062 PCT / KR2015 / 012926 sub-cultured in a 96-well plate by counting the exact nwnber of cells using Tali™ hnagebased Cytometer {Life Technologies). In a 96-well plate, NCI-N87 was employed with 5,000 ceils / well; and MDA-MB-468 was employed with 10,000 cells / well. The cells were treated with the compounds listed in Examples which were diluted in various S concentrations. Upon completion of the compounds treatment, NCI-N87 cells were cultured at 37°C under 5% COi for 96 hours, and MDA-MB~468 cells were cultured at 37°C in air for 96 hours. Subsequently, the cells were observed under microscope and drug precipitation and particular :findings were investigated and recorded. And then, the 96- well plate was placed at room temperature for 30 minutes, added with 20 μL / well of 10 CellTiter-Glo solution (Cat No. 07573, Promega) and shaken for 10 minutes, followed by being subjected to the measurement usmg PHERAstar™ microplate reader (BMG LABTECH) according to the supplier's general luminometer protocol. Wells where only culture liquid 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 Examples 15 were used as a positive control. The results of th_e inhibitory effects of the compounds prepared in. Examples against the growth of cancer cells are shown in Tables 7 to 8 below. 20 [Table7] ICso ICso ICso(p.M) ICso Ex. (μM) Ex. (p.M) Ex. Ex. (p.M) NCI-N87 NCI-N87 NCI-N87 NCI-N87 1 0.0083 2 1.2 3 0.045 4 4.1. 5 0.72 6 0.0055 7 0.027 8 0.031 9 0.067 10 0.0060 11 0.01 12 0.0018 13 0.025 14 0.16 15 0.035 16 0.021 17 0.011 18 0.020 19 0.0061 20 0.0094 21 O.o18 22 0.071 23 0.0056 24 0.0038 25 0.010 26 0.0072 27 0.0049 28 0.0056 29 0.0046 30 0.025 31 0.009 · 32 0.031 33 0.024 34 0.0092 37 0.0095 40 0.023 41 0.021 42 0.024 43 0.015 44 1.8 45 0.0056 46 0.56 47 0.0064 48 0.79 49 0.018 ·so 0.0091 51 0.20 52 0.40 53 4.4 S4 0.32 55 1.2 56 0.019 [Table 8] Ex. IC50(JlM) EL ICso(,aM) Ex. ICso(p.M) Ex. ICso(,iM) MDA-MB-468 MDA-MB-468 MDA-MB-468 MDA-.MB-468 66 CA 02966'142 201'1-05-03 WO 2016 / 089062 PCT / KR2015 / 012926 7 0.0065 8 0.0032 9 0.023 10 0.0019 11 0.0052 12 0.0028 13 0.0066 14 0.026 15 0.0089 16 0.0039 17 0.0023 18 0.0043 19 0.0025 20 0.0024 11 0.0051 22 0.017 23 0.0028 24 0.0024 25 0.0049 26 0.0046 27 0.0029 28 0.0020 29 0.0029 30 0.0085 31 0.0022 32 0.0089 33 0.0093 34 0.0023 37 0.0047 40 0.0086 41 0.012 42 0.0078 43 0.0029 44 0.086 45 0.0025 46 >0.10 47 0.0017 48 >0:10 49 0.0059 51 0.050 52 0.12 53 0.71 54 0.075 55 0.078 As shown in Tables 7 to 8, the compounds according to the present invention exhibited excellent inhibitory effects against the growth of varipus kinds of cancer cells. 67

Claims

5 WHAT IS CLAIMED IS:

1. A compound selected from the group consisting of a heterocyclic derivative represented by formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof: wherein one of X1 and X2 is -C(-Rx)(-Rx")-, -C(-Rx')(-Rx")-, -N(Rx)-, or -N(-Rx')-, and the other is -C(-Rx")(-Rx")-, -N(-Rx")-, -C(=O)- or -0-; 0 Rs-g-~ II ~ Rx is Xs Xs is =O or =NH; Rs is C1-6alkyl, haloC1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C2- 1alkenyl, amino, or aminoC1-6alkyl; Rx' is haloC1-6alkyl, C1-4alkoxycarbonyl, cyano, nitro, azido, amino, a 3- to 6-membered 15 heterocyclyl unsubstituted or substituted with Rx", or a 5- to 6-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N, S and 0, unsubstituted or substituted with oxo; Rx" is each independently hydrogen, halogen, nitro, amino, C1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, carbamoylC1-6alkyl, C1-6alkylamino-C1-6alkyl, C1-4alkoxycarbonyl, or diC1-6alkylamino- 20 C1-6alkyl; 25 Y is -CH= and Z is -S-; Lx is a saturated or unsaturated Ci-4 hydrocarbon chain not containing or containing 1 to 3 heterogroups selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and-S(=O)2- in the chain, unsubstituted or substituted with at least one Rx" moiety; A is benzene or a 6- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; 68 Date Re9ue / Date Received 2023-11-29 B is a monocyclic- saturated or unsaturated C6carbocycle; Re is =O, =NH, =N(-C1-6alkyl), or =N(-OH); RN is hydrogen or C1-6alkyl; Ls is -[C(-RL)(-RL')]m-, -[C(-RL)(-RL')]n-O-, -0-, -C(=O)-, or -C(=CH2)-, wherein mis an 5 integer of Oto 3, n is an integer of 1 to 3, RL andRL' are each independently hydrogen, or C1-6alkyl, or RL and RL' are linked together to form C1-6alkylene; RA is hydrogen, halogen, cyano, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, C1- Galkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1-6alkoxy, C1-6alkylamino, diC1-6alkylamino, C1-6alkylthio, C1-6alkylaminocarbonyl, diC1-6alkylaminocarbonyl, C2-salkynyl, Ci- 10 6alkoxycarbonylamino-C1-6alkoxy, aminoC1-6alkoxy, or 3- to 6-membered heterocyclyl; Rs is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C1-6alkylamino, C1-6alkyl, haloC1-6alkyl, cyanoC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, cyanoC1- 6alkoxy, C3.scycloalkyloxy, C2-salkenyl, C2-salkenyloxy, C2-salkynyl, C2-salkynyloxy, C1. 6alkylamino-C1-6alkoxy, diC1-6alkylamino-C1-6alkoxy, C1-6alkoxy-carbonyl, carbamoyl, 15 carbamoyl-C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, 5- to IO-membered heterocyclyl, 5- to IO-membered heterocyclyl-C1-6alkyl, 5- to IO-membered heterocyclyl-C1. 6alkoxy, or 5- to IO-membered heterocyclyl-oxy; pis an integer of Oto 4, and, when pis 2 to 4, RA moieties are the same as or different from each other; 20 q is an integer of Oto 4, and, when q is 2 to 4, Rs moieties are the same as or different from 25 each other; and each of said 5- to IO-membered heterocycle, 3- to 6-membered heterocyclyl, and 5- to IOmembered heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-.

2. The compound according to claim 1, wherein Y is -CH= and Z is -S-; Lx is a saturated C 1-3 hydrocarbon chain not containing or containing 1 to 3 heterogroups selected from the group consisting of -0-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2- in the chain, 69 Date Re9ue / Date Received 2023-11-29 5 unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C1-6alkyl and C1-6alkoxy; one of X1 and X2 is -C(-Rx)(-Rx")-, -C(-Rx')(-Rx")-, -N(Rx)- or -N(-Rx')-, and the other is -C(-Rx")(-Rx")-, -C(=O)-, -N(-Rx")- or -0-; 0 Rs-~-~ II ~ Rx is Xs Xs is =O or =NH; Rs is C1-6alkyl or haloC1-6alkyl; Rx' is haloC1-6alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl containing at least one heteroatom selected from the group consisting ofN, Sand 0, unsubstituted 10 or substituted with oxo; and 15 Rx" is hydrogen, halogen, C1-6alkyl, or C1-4alkoxycarbonyl.

3. The compound according to claim 2, wherein Yis-CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is a saturated C1-3 hydrocarbon chain not containing or containing 1 to 3 heterogroups selected from the group consisting of -0-, -S(=O)- and -S(=O)2- in the chain, unsubstituted or 20 substituted with at least one substituent selected from the group consisting of halogen, C 1-6alkyl 25 and C1-6alkoxy; X1 is -C(-Rx)(-Rx")-, -C(-Rx')(-Rx")-, or -N(Rx)-; X2 is -C(-Rx")(-Rx")-, -C(=O)-, -N(-Rx")-, or -0-; 0 II I H3C-S- 11 Rx is Xs Xs is =O or =NH; Rx' is haloC1-6alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl 70 Date Re9ue / Date Received 2023-11-29 5 containing 1 to 2 heteroatoms selected from N and 0, unsubstituted or substituted with oxo; and Rx" is hydrogen, halogen, C1-6alkyl, or C1-4alkoxycarbonyl.

4. The compound according to claim 3, wherein A is benzene or a 6- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms; B is a monocyclic- saturated or unsaturated C6carbocycle; LB is -[C(-RL)(-RL')]m-, or -0-, wherein mis 0 or 1, RL and RL' are each independently hydrogen, or C1-6alkyl, or RL and RL' are linked together to form C2-salkylene; RA is halogen, C1-6alkoxycarbonylamino-C1-6alkoxy, aminoC1-6alkoxy, or 3- to 6- 10 membered heterocyclyl; 15 20 25 RB is halogen, C1-6alkyl, C1-6alkoxy, haloC1-6alkyloxy, C2-6alkenyloxy, 5- to IO-membered heterocyclyl-oxy, or 5- to IO-membered heterocyclyl-C1-Jalkoxy.

5.

6. The compound according to claim 1, wherein X1 is -N(-Rx)-; X2 is -C(-Rx")(-Rx")- or -N(-Rx")-; Y is -CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is ethylene substituted with one or two Rx" moieties, 0 II I Rs-SIi Rx is Xs Xs is =O; Rs is methyl; and Rx" is the same as defined in claim 1. The compound according to claim 1, wherein X1 is -CH(-Rx)-; 71 Date Re9ue / Date Received 2023-11-29 5 15 20 25 7.

8. X2 is -N(-Rx")-; Y is -CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is ethylene; 0 II I Rs-SIi Rx is Xs Xs is =O; Rs is methyl; and Rx" is the same as defined in claim 1. The compound according to claim 1, wherein X1 is -C(-Rx)(-Rx")-; Yis-CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is ethylene; 0 II I Rs-SIi Rx is Xs Xs is =O; Rs is methyl; and Rx" is the same as defined in claim 1. The compound according to claim 1, wherein X1 is -C(-Rx')(-Rx")-; 72 Date Re9ue / Date Received 2023-11-29 5 15 20 25 9.

10. X2 is -0-; Y is -CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is ethylene; and Rx' and Rx" are the same as defined in claim 1. The compound according to claim 1, wherein X1 is -CH(-Rx)-; X2 is -C(-Rx")(-Rx")-; Yis-CH=; Z is -S-; Re is =O; RN is hydrogen; Lx is ethylene; 0 II I Rs-SIi Rx is Xs Xs is =O; Rs is methyl; and Rx" is the same as defined in claim 1. The compound according to claim 1, wherein X1 is -CH(-Rx)-; X2 is -C(-Rx")(-Rx")-; Yis-CH=; Z is -S-; Re is =O; RN is hydrogen; 73 Date Re9ue / Date Received 2023-11-29 5 11. Lx is -CH2-O-; 0 Rs-g-~ II ~ Rx is Xs Xs is =O; Rs is methyl; and Rx" is the same as defined in claim 1. The compound according to claim 1, which is selected from the group consisting of: 1) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-1-(methylsulfonyl)-2,3-dihydro-1Hthieno[ 3',2':4,5]benzo[l ,2-b ][1,4]oxazine-7-carboxamide; 10 2) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-3,3-dimethyl-1-(methylsulfonyl)-2,3- dihydro-1H-thieno[3',2':4,5]benzo[l,2-b][l,4]oxazine-7-carboxamide; 3) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-l-(methylsulfonyl)-1,2,3,4- tetrahydrothieno[3' ,2':4,5]benzo[l ,2-b ][1,4 ]oxazepine-8-carboxamide; 4) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-8,8-dimethyl-5-(methylsulfonyl)- 15 5 ,6, 7,8-tetrahydrothieno[2,3-g]quinoline-2-carboxamide; 5) tert-butyl 7-((2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)carbamoyl)-1- (methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate; 6) N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-5-(methylsulfonyl)-5 ,6, 7 ,8- tetrahydrothieno[2,3-g]quinoline-2-carboxamide; 20 7) N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-4-methyl-1-(methylsulfony 1)-1,2,3 ,4- tetrahydrothieno[2,3-g]quinoxaline-7-carboxamide; 8) N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl )-4-(methylsulfony 1)-3, 4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 9) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonyl)-2,3,4,5- 25 tetrahydrothieno[3' ,2' :4,5]benzo[l ,2-b ]oxepine-8-carboxamide; 10) N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-5-(methylsulfonyl)-5 ,6, 7 ,8- tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide; 11) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-methyl-4-(methylsulfonyl)-3,4- 74 Date Re9ue / Date Received 2023-11-29 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 12) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonyl)-5,8-dihydro-6Hthieno[ 3,2-g]isochromene-2-carboxamide; 13) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-fluoro-4-(methylsulfonyl)-3,4- 5 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 14) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-8,8-difluoro-5-(methylsulfonyl)- 5 ,6, 7,8-tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide; 15) N-(2-chloro-6-(p-tolyloxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 10 16) N-(2-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 17) N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 18) N-(2-chloro-6-(3 ,5-dichlorophenoxy )pyridin-4-yl )-4-(methylsulfony 1)-3, 4-dihydro- 15 2H-thieno[3 ,2-g]chromene-7-carboxamide; 19) N-(2-chloro-6-(4-chloro-3-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 20) N-(2-chloro-6-( 4-chloro-3-methylphenoxy )pyridin-4-y 1)-4-(methylsulfonyl)-3 ,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 20 21) N-(2-chloro-6-(4-chloro-2-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 22) N-(2-chloro-6-( 4-methoxyphenoxy )pyridin-4-y 1 )-4-(methylsulfony 1)-3, 4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 23) N-(2-chloro-6-(4-chloro-2-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 25 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 24) N-(2-chloro-6-(3,4-dichlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro- 2H-thieno[3 ,2-g]chromene-7-carboxamide; 25) N-(2-chloro-6-(3-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 75 Date Re9ue / Date Received 2023-11-29 26) N-(2-chloro-6-(4-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 2 7) N-(2-chloro-6-(3-chloro-4-fluorophenoxy )pyridin-4-y 1 )-4-(methy lsulfonyl )-3, 4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 5 28) N-(2-chloro-6-(4-(trifluoromethoxy)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 29) N-(2-chloro-6-(3-(trifluoromethoxy)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 30) N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 10 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 31) N-(2-chloro-6-(3-chloro-5-fluorophenoxy )pyridin-4-yl)-4-(methylsulfonyl)-3 ,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 3 2) N-(2-chloro-6-(3-fluoro-5-methoxyphenoxy )pyridin-4-y 1 )-4-(methy lsulfonyl )-3, 4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 15 33) N-(2-chloro-6-(m-tolyloxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2Hthieno[ 3 ,2-g]chromene-7-carboxamide; 34) N-(2-chloro-6-(3, 4-difluorophenoxy )pyridin-4-yl )-4-(methylsulfony 1)-3, 4-dihydro- 2H-thi eno[3 ,2-g]chromene-7-carboxamide; 35) N-(2-chloro-6-(5-chloro-2-fluorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 20 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 36) N-(2-chloro-6-(3-chloro-2-fluorophenoxy )pyri din-4-y 1 )-4-(methy lsulfonyl )-3, 4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 37) N-(2-chloro-6-(5-chloro-2-methylphenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 25 38) N-(2-chloro-6-(3-chloro-4-methylphenoxy )pyridin-4-y 1)-4-(methylsulfonyl)-3 ,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 39) N-(2-chloro-6-(2-(trifluoromethyl)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 40) N-(2-chloro-6-(2-(trifluoromethoxy)phenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 76 Date Re9ue / Date Received 2023-11-29 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 41) N-(2-chloro-6-(2-fluoro-3-methylphenoxy )pyridin-4-yl)-4-(methylsulfonyl)-3 ,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 42) N-(2-chloro-6-(4-chloro-2-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4- 5 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 43) (S)-N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl )-4-(methylsulfony 1)-3, 4-dihydro- 2H-thieno[3 ,2-g]chromene-7-carboxamide; 44) (R)-N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl )-4-(methylsulfony 1)-3, 4-dihydro- 2H-thieno[3 ,2-g]chromene-7-carboxamide; 10 45) (S)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-fluoro-4-(methylsulfonyl)-3,4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 46) (R)-N-(2-chloro-6-( 4-chlorophenoxy )pyri din-4-yl)-4-fluoro-4-(methy lsulfonyl )-3, 4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 4 7) (5)-N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-4-methyl-4-(methylsulfonyl )-3 ,4- 15 dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 48) (R)-N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-4-methy 1-4-( methy lsulfonyl )-3, 4- dihydro-2H-thieno[3 ,2-g]chromene-7-carboxamide; 49) (S)-N-(2-chloro-6-(3-chloro-5-methoxyphenoxy)pyridin-4-yl)-4-(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide; 20 50) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-1-(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxaline-7-carboxamide; 51) N-(2-chloro-6-( 4-chlorophenoxy )pyridin-4-yl)-5-(methylsulfonyl)-8-oxo-5,6, 7 ,8- tetrahydronaphtho[2,3-b ]thiophene-2-carboxamide; 52) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(1H-pyrazol-1-yl)-3,4-dihydro-2H- 25 thieno[3 ,2-g]chromene-7-carboxamide; 53) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(2-oxopyrrolidin-1-yl)-3,4-dihydro- 2H-thieno[3 ,2-g]chromene-7-carboxamide; 54) N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-cyano-3,4-dihydro-2H-thieno[3,2- g]chromene-7-carboxamide; 77 Date Re9ue / Date Received 2023-11-29 5 5 5) 4-azido-N-(2-chloro-6-( 4-chlorophenoxy )pyri din-4-yl)-3, 4-dihydro-2H-thieno[3 ,2- g]chromene-7-carboxami de; 56) N-(3-chloro-5-(2-( 4-chlorophenyl)propan-2-yl)phenyl)-1-(methylsulfonyl )-2,3- dihydro-1H-thieno[3 ',2': 4 ,5]benzo[ 1,2-b] [ 1, 4 ]oxazine-7-carboxamide; a pharmaceutically acceptable salt thereof and a stereoisomer thereof.

12. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 11 and a pharmaceutically acceptable additive. 10 13. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 11 and a pharmaceutically acceptable additive, and wherein the pharmaceutical composition is for preventing or treating a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection, tuberculosis, breast cancer, lung 15 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 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, nonHodgkin's lymphoma, hepatitis or auto-immune disease. 20 14. The pharmaceutical composition according to claim 13, wherein the disease is selected from the group consisting of solid cancer, hematological cancer, radio-resistant cancer, chemoresistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection and tuberculosis. 25 15. The pharmaceutical composition according to claim 13, wherein the disease is 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 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune disease, 78 Date Re9ue / Date Received 2023-11-29 diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.

16. The pharmaceutical composition according to claim 13 or 15, wherein the disease is autoimmune disease selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory 5 bowel disease, and Crohn's disease.

17. A use of the compound as defined in any one of claims 1 to 11 for the manufacture of a medicament for prevention or treatment of a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, 10 immunological disease, diabetes, macular degeneration, human papillomavirus infection, tuberculosis, 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 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, hepatitis or auto-immune disease. 15 18. A use of the compound as defined in any one of claims 1 to 11 for prevention or treatment of a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection, tuberculosis, breast cancer, lung cancer, stomach 20 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 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, nonHodgkin's lymphoma, or auto-immune disease. 25 19. The use according to claim 17 or 18, wherein the disease is selected from the group consisting of solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection and tuberculosis. 79 Date Re9ue / Date Received 2023-11-29 20. The use according to claim 17 or 18, wherein the disease is 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 leukemia, chronic leukemia, multiple myeloma, B-cell 5 lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.

21. The use according to claim 17, 18 or 20, wherein the disease is auto-immune disease selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, 10 and Crohn's disease.

22. The use according to any one of claims 17 to 21, for said treatment of the disease.

23. The compound as defined in any one of claims 1 to 11 for use in prevention or treatment 15 of a disease which is solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection, tuberculosis, 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 20 leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, nonHodgkin's lymphoma, hepatitis or auto-immune disease.

24. The compound for use according to claim 23, wherein the disease is selected from the group consisting of solid cancer, hematological cancer, radio-resistant cancer, chemo-resistant 25 cancer, metastatic cancer, inflammatory disease, immunological disease, diabetes, macular degeneration, human papillomavirus infection and tuberculosis.

25. The compound for use according to claim 23, wherein the disease is selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, 30 ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and 80 Date Re9ue / Date Received 2023-11-29 neck cancer, thyroid cancer, osteosarcoma, acute leukemia, chronic leukemia, multiple myeloma, B-cell lymphoma, T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis. 5 26. The compound for use according to claim 23 or 25, wherein the disease is auto-immune disease selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, and Crohn's disease.

27. The compound for use according to any one of claims 23 to 26, in said treatment of the 10 disease. 81 Date Re9ue / Date Received 2023-11-29