NZ731847B2 - Heterocyclic derivatives and use thereof - Google Patents

Heterocyclic derivatives and use thereof Download PDF

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NZ731847B2
NZ731847B2 NZ731847A NZ73184715A NZ731847B2 NZ 731847 B2 NZ731847 B2 NZ 731847B2 NZ 731847 A NZ731847 A NZ 731847A NZ 73184715 A NZ73184715 A NZ 73184715A NZ 731847 B2 NZ731847 B2 NZ 731847B2
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methylsulfonyl
chloro
thieno
pyridinyl
dihydro
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NZ731847A
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NZ731847A (en
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Junhwan Im
Byungho Kim
Hye Jung Kim
Jungsook Kim
Mi Sun Kim
Kwang Seok Ko
Minjung Kong
Sang Hwi Lee
Soon Ok Lee
Hyung Jo Moon
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C&C Research Laboratories
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Priority claimed from KR1020150128025A external-priority patent/KR20160066490A/en
Application filed by C&C Research Laboratories filed Critical C&C Research Laboratories
Priority claimed from PCT/KR2015/012926 external-priority patent/WO2016089062A2/en
Publication of NZ731847A publication Critical patent/NZ731847A/en
Publication of NZ731847B2 publication Critical patent/NZ731847B2/en

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    • A—HUMAN NECESSITIES
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

heterocyclic derivative represented by 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, is provided. ided.

Description

DESCRIPTION HETEROCYCLIC DERIVATIVES AND USE THEREOF 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 pharmaceutical 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) subtypes of STAT proteins (i.e., STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b 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, DNA binding domain, linker domain, SH2 domain and transactivation domain (TAD)). Further, X-ray crystalline structures of STAT1, STAT3, STAT4 and STAT5 have been reported since 1998 (Becker S et al., Nature, 1998, 394; Vinkemeier U et al., Science, 1998, 279; Chen X et al., Cell, 1998, 93; D. Neculai et al., J. Biol. Chem., 2005, 280). In general, receptors to which cytokines and growth factors bind are categorized into Class I and Class II. IL-2, IL-3, IL-5, IL-6, IL- 12, G-CSF, GM-CSF, LIF, thrombopoietin, etc., bind to Class I receptors, while INF-α, INF-γ, IL-10, etc., bind to Class II receptors (Schindler C et al., Annu. Rev. Biochem., 1995, 64; Novick D et al., Cell, 1994, 77; Ho AS et al., Proc. Natl. Acad. Sci., 1993, 90).
Among them, the cytokine receptors involved in the activation of STAT proteins can be classified depending on their structural forms of extracellular domains into a gp-130 family, an IL-2 family, a growth factor family, an interferon family and a receptor tyrosine kinase family. 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 ILgp-130 receptor complex. At the same time, JAK kinases (JAK1, JAK2, JAK3 and Tyk2) in the cytoplasm are recruited to a cytoplasmic region of gp130 to be phosphorylated and activated. Subsequently, latent cytoplasmic STAT 40 proteins are attracted to a receptor, phosphorylated by JAK kinases and activated.
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 and bind to a specific DNA binding promoter to promote the transcription. Through its transcription process, various proteins (Myc, Cyclin D1/D2, Bcl-xL, Mcl, survivin, VEGF, HIF-1, immune suppressors, etc.) associated with cell proliferation, survival, angiogenesis and immune evasion are produced (Stark et al., Annu. Rev. Biochem., 1997, 67; Levy et al., Nat. Rev. Mol. Cell Biol., 2002, 3).
In particular, STAT3 protein is known to play a crucial role in the acute inflammatory response and the signal transduction pathway of IL-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 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 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 tissue- specific 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 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 Th17 cells have been reported through a number of recent articles to be associated with various autoimmune diseases (Jacek Tabarkiewicz et al., Arch. Immunol. Ther. Exp., 2015, 11). Based on these reports, a control of the differentiation and function of Th17 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 Th17 cells (Xuexian O. Yang et al., J. Biol. Chem., 2007, 282; Harris T J et al., J. Immunol., 2007, 179), an inhibition of the function of STAT3 is expected to be effective in the treatment of diseases associated with Th17 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. Exp., 2015, 11).
Recently, IL-6 and IL-23 antibodies are under clinical studies on the treatment of 40 arthritis and psoriasis associated with Th17 cells and exhibit a clinical efficacy (Nishimoto 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 factors to those of STAT3, STAT1 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 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, S3I-201 (Siddiquee et al., Proc. Natl. Acad. Sci., 2007, 104), S3I- M2001 (Siddiquee et al., Chem. Biol., 2007, 2), LLL-12 (Lin et al., Neoplasia, 2010, 12), Stattic (Schust et al., Chem. Biol. 2006, 13), STA-21 (Song et al., Proc. Natl. Acad. Sci., 2005, 102), SF066 (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 of pY- 705 (STAT3) adjacent 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.
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; and/or to at least provide the public with a useful choice.
It is another object of the present invention to provide uses of the heterocyclic derivatives 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), and a pharmaceutically acceptable salt and a stereoisomer thereof: Rc (R ) (R ) A L B wherein one of X and X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -N(Rx)-, or -N(-Rx')-, and the other is –C(-Rx'')(-Rx'')-, -N(-Rx'')-, -C(=O)-or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl, haloC alkyl, C alkoxy-C alkyl, C alkylcarbonyl-C alkyl, 1-6 1-6 1-6 1-6 1-6 1-6 C alkenyl, amino, or aminoC alkyl; 2-7 1-6 Rx' is haloC alkyl, C alkoxycarbonyl, cyano, nitro, azido, amino, or a 3-6 1-6 1-4 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 O and unsubstituted or substituted with oxo; Rx'' is each independently hydrogen, halogen, nitro, amino, C alkyl, C alkoxy, 1-6 1-6 haloC alkoxy, carbamoylC alkyl, C alkylamino-C alkyl, C alkoxycarbonyl, or diC 1-6 1-6 1-6 1-6 1-4 1- alkylamino-C alkyl; 6 1-6 one of Y and Z is -S- or -NH-, and the other is -CH= or -N=; Lx is a saturated or unsaturated C 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; A and B are each independently a monocyclic- or bicyclic-saturated or unsaturated C carbocycle or 5- to 12-membered heterocycle; 3-10 Rc is =O, =NH, =N(-C alkyl), or =N(-OH); R is hydrogen or C alkyl; N 1-6 L is -[C(-R )(-R ')] -, -[C(-R )(-R ')] -O-, -O-, -NH-, -N(C alkyl)-, -S(=O) -, - B L L m L L n 1-6 2 C(=O)-, or -C(=CH )-, wherein m is an integer of 0 to 3, n is an integer of 1 to 3, R and R ' are each independently hydrogen, hydroxy, halogen or C alkyl, or R and R ' are L 1-6 L L linked together to form C alkylene; R is hydrogen, halogen, cyano, C alkyl, haloC alkyl, cyanoC alkyl, C A 1-6 1-6 1-6 1- alkylcarbonyl, C alkoxy, haloC alkoxy, cyanoC alkoxy, C alkylamino, diC 6 1-6 1-6 1-6 1-6 1- alkylamino, C alkylthio, C alkylaminocarbonyl, diC alkylaminocarbonyl, C 6 1-6 1-6 1-6 2- alkynyl, C alkoxycarbonylamino-C alkoxy, aminoC alkoxy, or 3- to 6-membered 8 1-6 1-6 1-6 heterocyclyl; R is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C alkylamino, C alkyl, haloC alkyl, cyanoC alkyl, C alkoxy, 1-6 1-6 1-6 1-6 1-6 haloC alkoxy, cyanoC alkoxy, C cycloalkyloxy, C alkenyl, C alkenyloxy, C 1-6 1-6 3-8 2-8 2-8 2- alkynyl, C alkynyloxy, C alkylamino-C alkoxy, diC alkylamino-C alkoxy, C 8 2-8 1-6 1-6 1-6 1-6 1- alkoxy-carbonyl, carbamoyl, carbamoyl-C alkoxy, C alkylthio, C alkylsulfinyl, C 6 1-6 1-6 1-6 1- 6alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C1-6alkyl, 5- to 10-membered heterocyclyl-C alkoxy, or 5- to 10-membered heterocyclyl-oxy; p is an integer of 0 to 4, and, when p is 2 or higher, R moieties are the same as or different from each other; q is an integer of 0 to 4, and, when q is 2 or higher, R moieties are the same as or different from each other; and each of said heterocycle, 3- to 6-membered heterocyclyl, and 5- to 10-membered heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S(=O) -.
In accordance with another aspect of the present invention, provided is a pharmaceutical composition for preventing or treating diseases associated with the activation of STAT3 protein, comprising the compound according to the invention as an active ingredient.
In accordance with a further aspect of the present invention, provided is a use of the compound according to the invention for the manufacture of a medicament for preventing or treating diseases associated with the activation of STAT3 protein.
In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.
Also described is a compound selected from the group consisting of a heterocyclic derivative represented by formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof: 1 (R ) (R ) N A L B wherein X and X are each independently -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -C(-Rx'')(- Rx'')-, -C(=O)-, -N(Rx)-, -N(-Rx')-, -N(-Rx'')-, or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl, haloC alkyl, C alkoxy-C alkyl, C alkylcarbonyl-C alkyl, 1-6 1-6 1-6 1-6 1-6 1-6 C alkenyl, amino, or aminoC alkyl; 2-7 1-6 Rx' is haloC1-6alkyl, C1-4alkoxycarbonyl, cyano, nitro, azido, amino, or a 3- to 6- membered heterocyclyl unsubstituted or substituted with Rx''; Rx'' is each independently hydrogen, halogen, nitro, amino, C alkyl, C alkoxy, 1-6 1-6 haloC alkoxy, carbamoylC alkyl, C alkylamino-C alkyl, or diC alkylamino-C 1-6 1-6 1-6 1-6 1-6 1- alkyl; one of Y and Z is -S- or -NH-, and the other is -CH= or -N=; Lx is a saturated or unsaturated C 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) - in the chain, and unsubstituted or substituted with at least one Rx'' moiety; A and B are each independently a monocyclic- or bicyclic-saturated or unsaturated C carbocycle or 5- to 12-membered heterocycle; 3-10 Rc is =O, =NH, =N(-C alkyl), or =N(-OH); R is hydrogen or C alkyl; N 1-6 L is -[C(-R )(-R ')] -, -[C(-R )(-R ')] -O-, -O-, -NH-, -N(C alkyl)-, -S(=O) -, - B L L m L L n 1-6 2 C(=O)-, or -C(=CH )-, wherein m is an integer of 0 to 3, n is an integer of 1 to 3, R and RL' are each independently hydrogen, hydroxy, halogen or C1-6alkyl, or RL and RL' are linked together to form C alkylene; R is hydrogen, halogen, cyano, C alkyl, haloC alkyl, cyanoC alkyl, C A 1-6 1-6 1-6 1- alkylcarbonyl, C alkoxy, haloC alkoxy, cyanoC alkoxy, C alkylamino, diC 6 1-6 1-6 1-6 1-6 1- alkylamino, C alkylthio, C alkylaminocarbonyl, diC alkylaminocarbonyl, C 6 1-6 1-6 1-6 2- alkynyl, C alkoxycarbonylamino-C alkoxy, aminoC alkoxy, or 3- to 6-membered 8 1-6 1-6 1-6 heterocyclyl; R is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C alkylamino, C alkyl, haloC alkyl, cyanoC alkyl, C alkoxy, 1-6 1-6 1-6 1-6 1-6 haloC alkoxy, cyanoC alkoxy, C cycloalkyloxy, C alkenyl, C alkenyloxy, C 1-6 1-6 3-8 2-8 2-8 2- alkynyl, C alkynyloxy, C alkylamino-C alkoxy, diC alkylamino-C alkoxy, C 8 2-8 1-6 1-6 1-6 1-6 1- alkoxy-carbonyl, carbamoyl, carbamoyl-C alkoxy, C alkylthio, C alkylsulfinyl, C 6 1-6 1-6 1-6 1- alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C alkyl, 6 1-6 - to 10-membered heterocyclyl-C alkoxy, or 5- to 10-membered heterocyclyl-oxy; p is an integer of 0 to 4, and, when p is 2 or higher, R moieties are the same as or different from each other; q is an integer of 0 to 4, and, when q is 2 or higher, R moieties are the same as or different from each other; and each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and - 40 S(=O) -.
Also described is 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 protein.
Also described is 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 active ingredients.
Also described is a 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 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 STAT3 protein, and thus it can be used for the prevention or treatment of diseases associated with the activation of STAT3 protein.
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.
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 “carbocyclyl” refers to a radical of “carbocycle”, and is used as a term inclusive of “cycloalkyl” and “aryl”. The term “cycloalkyl” refers to a saturated hydrocarbon radical, which may be monocyclic or polycyclic. The term “aryl” refers to an aromatic 40 hydrocarbon ring, which may be monocyclic or polycyclic.
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 “C carbocycle”, “C carbocyclyl”, “C cycloalkyl”, and “C aryl”, respectively. 3-20 3-20 3-20 3-20 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.
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 heteroatom, which may be monocyclic or polycyclic. The term “heteroaryl” refers to an aromatic ring radical having at least one heteroatom, which may be monocyclic or polycyclic.
The term “heteroatom” may be selected from N, O and S.
The terms “heterocycle", "heterocyclyl", "heterocycloalkyl” and “heteroaryl” may refer to, for example, a mono- or polycycle having 3 to 20 heteroatoms and/or carbon atoms, and will be indicated as “3- to 20-membered heterocycle”, “3- to 20-membered heterocyclyl”, “3- to 20-membered heterocycloalkyl”, and “3- to 20-membered heteroaryl”.
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 - CH -CH=CH-; or a saturated or unsaturated C hydrocarbon chain containing at least one 2 2-10 heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and - S(=O) - in the chain, for example, -CH -O-CH -, -CH -O-CH -O-CH -, -CH -CH=CH- 2 2 2 2 2 2 2 NH- and -CH -CH -S(=O) -CH -O-, unless specified otherwise. The chain may be 2 2 2 2 substituted with at least one selected from the group consisting of halogen, C alkyl and C alkoxy.
The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprises” are to be interpreted in similar manner.
Described herein is a compound selected from the group consisting of a heterocyclic derivative represented by formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof: Rc (R ) (R ) A L B wherein X and X are each independently -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -C(-Rx'')(- Rx'')-, -C(=O)-, -N(Rx)-, -N(-Rx')-, -N(-Rx'')-, or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl, haloC alkyl, C alkoxy-C alkyl, C alkylcarbonyl-C alkyl, 1-6 1-6 1-6 1-6 1-6 1-6 C alkenyl, amino, or aminoC alkyl; 2-7 1-6 Rx' is haloC alkyl, C alkoxycarbonyl, cyano, nitro, azido, amino, or a 3- to 6- 1-6 1-4 membered heterocyclyl unsubstituted or substituted with Rx''; Rx'' is each independently hydrogen, halogen, nitro, amino, C alkyl, C alkoxy, 1-6 1-6 haloC alkoxy, carbamoylC alkyl, C alkylamino-C alkyl, or diC alkylamino-C 1-6 1-6 1-6 1-6 1-6 1- alkyl; one of Y and Z is -S- or -NH-, and the other is -CH= or -N=; Lx is a saturated or unsaturated C 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) - in the chain, and unsubstituted or substituted with at least one Rx'' moiety; A and B are each independently a monocyclic- or bicyclic-saturated or unsaturated C carbocycle or 5- to 12-membered heterocycle; 3-10 Rc is =O, =NH, =N(-C alkyl), or =N(-OH); R is hydrogen or C alkyl; N 1-6 L is -[C(-R )(-R ')] -, -[C(-R )(-R ')] -O-, -O-, -NH-, -N(C alkyl)-, -S(=O) -, - B L L m L L n 1-6 2 C(=O)-, or -C(=CH )-, wherein m is an integer of 0 to 3, n is an integer of 1 to 3, R and R ' are each independently hydrogen, hydroxy, halogen or C alkyl, or R and R ' are L 1-6 L L linked together to form C alkylene; R is hydrogen, halogen, cyano, C alkyl, haloC alkyl, cyanoC alkyl, C A 1-6 1-6 1-6 1- alkylcarbonyl, C alkoxy, haloC alkoxy, cyanoC alkoxy, C alkylamino, diC 6 1-6 1-6 1-6 1-6 1- alkylamino, C alkylthio, C alkylaminocarbonyl, diC alkylaminocarbonyl, C 6 1-6 1-6 1-6 2- alkynyl, C alkoxycarbonylamino-C alkoxy, aminoC alkoxy, or 3- to 6-membered 8 1-6 1-6 1-6 heterocyclyl; R is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C alkylamino, C alkyl, haloC alkyl, cyanoC alkyl, C alkoxy, 1-6 1-6 1-6 1-6 1-6 haloC alkoxy, cyanoC alkoxy, C cycloalkyloxy, C alkenyl, C alkenyloxy, C 1-6 1-6 3-8 2-8 2-8 2- alkynyl, C alkynyloxy, C alkylamino-C alkoxy, diC alkylamino-C alkoxy, C 8 2-8 1-6 1-6 1-6 1-6 1- alkoxy-carbonyl, carbamoyl, carbamoyl-C alkoxy, C alkylthio, C alkylsulfinyl, C 6 1-6 1-6 1-6 1- alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C alkyl, 6 1-6 - to 10-membered heterocyclyl-C alkoxy, or 5- to 10-membered heterocyclyl-oxy; p is an integer of 0 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 0 to 4, and, when q is 2 or higher, R moieties are the same as or different from each other; and each of said heterocycle and heterocyclyl moieties independently contains at least one heterogroup selected from the group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and - S(=O) -.
In a preferred embodiment of the compound of formula (I), one of Y and Z is -S- or -NH-, and the other is -CH=; Lx is a saturated C hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of O, N and S in the chain, and unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C alkyl and C alkoxy; 1-6 1-6 one of X and X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -C(=O)-, -N(Rx)- or -N(- Rx')-, and the other is -C(-Rx'')(-Rx'')-, -N(-Rx'')- or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl or haloC alkyl; 1-6 1-6 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 of N, S and O and unsubstituted or substituted with oxo; Rx'' is hydrogen, halogen, C alkyl, or C alkoxycarbonyl; and 1-6 1-4 Rc, R , A, B, L , R , R , p and q are the same as defined above in formula (I).
N B A B In a preferred embodiment of the compound of formula (I), Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is a saturated C 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, C alkyl and C alkoxy; 1-6 1-6 X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, or -N(Rx)-; X is -C(-Rx'')(-Rx'')-, -C(=O)-, -N(-Rx'')-, or -O-; H C S Rx is ; Xs is =O or =NH; Rx' is haloC alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from N and O and unsubstituted or substituted with oxo; Rx'' is hydrogen, halogen, C alkyl, or C alkoxycarbonyl; and 1-6 1-4 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), Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is a saturated C 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, C alkyl and C alkoxy; 1-6 1-6 X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, or -N(Rx)-; X is -C(-Rx'')(-Rx'')-, -C(=O)-, -N(-Rx'')-, or -O-; H C S Rx is ; Xs is =O or =NH; Rx' is haloC alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from N and O and unsubstituted or substituted with oxo; Rx'' is hydrogen, halogen, C1-6alkyl, or C1-4alkoxycarbonyl; 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 C carbocycle or 5- to 10- 6-10 membered heterocycle; L is -[C(-R )(-R ')] -, -O-, -NH- or -N(C alkyl)-, wherein m is 0 or 1, R and B L L m 1-6 L R ' are each independently hydrogen, hydroxy, halogen or C alkyl, or R and R ' are L 1-6 L L linked together to form C alkylene; R is halogen, C alkoxycarbonylamino-C alkoxy, aminoC alkoxy, or 3- to 6- A 1-6 1-6 1-6 membered heterocyclyl; R is halogen, C alkyl, C alkoxy, haloC alkyloxy, C alkenyloxy, C B 1-6 1-6 1-6 2-6 3- carbocyclyl-oxy, or 3- to 10-membered heterocyclyl-C alkoxy; and 1-3 each of said heteroaryl, heterocycle and heterocyclyl moieties independently contains 1 to 3 heteroatoms selected from the group consisting of O, N and S.
In a preferred embodiment of the compound of formula (I), X is -N(-Rx)-; X2 is -C(-Rx'')(-Rx'')- or -N(-Rx'')-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene substituted with one or two Rx'' moieties, Rs S Rx is ; Xs is =O; Rs is methyl; Rx'' is the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -CH(-Rx)-; X is -N(-Rx'')-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S Rx is ; Xs is =O; Rs is methyl; Rx'' is the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -C(-Rx)(-Rx'')-; X is -O-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S Rx is ; Xs is =O; Rs is methyl; Rx'' is the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -C(-Rx')(-Rx'')-; X is -O-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rx' and Rx'' are the same defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -CH(-Rx)-; X is -C(-Rx'')(-Rx'')- or -C(=O)-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S Rx is ; Xs is =O; Rs is methyl; Rx'' is the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -CH(-Rx)-; X is -C(-Rx'')(-Rx'')-; Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is -CH2-O-; Rs S Rx is ; Xs is =O; Rs is methyl; Rx'' is the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B In a preferred embodiment of the compound of formula (I), X is -C(-Rx)(-Rx'')- or -N(Rx)-; X is -O-; Y is -NH-; Z is -CH=; Rc is =O; R is hydrogen; Lx is propylene; Rx and Rx'' are the same as defined above in formula (I); and A, B, L , R , R , p and q are the same as defined above in formula (I).
B A B 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: 1) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-2,3-dihydro- 1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide; 2) N-(2-chloro(4-chlorophenoxy)pyridinyl)-3,3-dimethyl (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide; 3) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-1,2,3,4- tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazepinecarboxamide; 4) N-(2-chloro(4-chlorophenoxy)pyridinyl)-8,8-dimethyl (methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxamide; ) tert-butyl 7-((2-chloro(4-chlorophenoxy)pyridinyl)carbamoyl) (methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate; 6) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3-g]quinolinecarboxamide; 7) N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl(methylsulfonyl)- 1,2,3,4-tetrahydrothieno[2,3-g]quinoxalinecarboxamide; 8) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro- 2H-thieno[3,2-g]chromenecarboxamide; 9) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-2,3,4,5- tetrahydrothieno[3',2':4,5]benzo[1,2-b]oxepinecarboxamide; 10) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3-b]thiophenecarboxamide; 11) N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 12) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,8- dihydro-6H-thieno[3,2-g]isochromenecarboxamide; 13) N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 14) N-(2-chloro(4-chlorophenoxy)pyridinyl)-8,8-difluoro (methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxamide; 15) N-(2-chloro(p-tolyloxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 16) N-(2-chloro(3-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 17) N-(2-chloro(4-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 18) N-(2-chloro(3,5-dichlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 19) N-(2-chloro(4-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 20) N-(2-chloro(4-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 21) N-(2-chloro(4-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 22) N-(2-chloro(4-methoxyphenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 23) N-(2-chloro(4-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 24) N-(2-chloro(3,4-dichlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 25) N-(2-chloro(3-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 26) N-(2-chloro(4-fluorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro- 2H-thieno[3,2-g]chromenecarboxamide; 27) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 40 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 28) N-(2-chloro(4-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 29) N-(2-chloro(3-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 30) N-(2-chloro(3-chloromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 31) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 32) N-(2-chloro(3-fluoromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 33) N-(2-chloro(m-tolyloxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 34) N-(2-chloro(3,4-difluorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 35) N-(2-chloro(5-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 36) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 37) N-(2-chloro(5-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 38) N-(2-chloro(3-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 39) N-(2-chloro(2-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 40) N-(2-chloro(2-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 41) N-(2-chloro(2-fluoromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 42) N-(2-chloro(4-chloromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 43) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 44) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 45) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 46) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 47) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl 40 (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 48) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 49) (S)-N-(2-chloro(3-chloromethoxyphenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 50) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxamide; 51) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)oxo- ,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxamide; 52) N-(2-chloro(4-chlorophenoxy)pyridinyl)(1H-pyrazolyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 53) N-(2-chloro(4-chlorophenoxy)pyridinyl)(2-oxopyrrolidinyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 54) N-(2-chloro(4-chlorophenoxy)pyridinyl)cyano-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 55) 4-azido-N-(2-chloro(4-chlorophenoxy)pyridinyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; and 56) N-(3-chloro(2-(4-chlorophenyl)propanyl)phenyl)(methylsulfonyl)- 2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide.
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 PerkinElmer.
The present invention provides a pharmaceutically acceptable salt of a heterocyclic derivative represented by formula (I) above. The pharmaceutically acceptable salt should have low toxicity to humans, and should not have any negative impact on the biological activities and physicochemical properties of parent compounds. Examples of the pharmaceutically acceptable salt may include an acid addition salt between a pharmaceutically usable free acid and a basic compound represented by formula (I), 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 formula (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, methanesulfonic acid, ethanesulfonic acid, p- 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 40 may be used for the preparation of the organic base addition salt may include tris(hydroxymethyl)methylamine, dicyclohexylamine, etc. Amino acids which may be 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 formula (I) in a water- miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, adding a free acid or a free base, and then crystallizing the resultant thereafter.
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 belong to the scope of the present invention.
Additionally, the compounds of the present invention may also include a hydrate or solvate of the heterocyclic derivative represented by formula (I). The hydrate or solvate may be prepared using a known method, and they are preferred to be non-toxic and water- soluble, and in particular, they are preferably water or a hydrate or solvate having 1-5 molecules of alcoholic solvent (especially ethanol, etc.) bound thereto.
Also described is 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 protein.
Also described is a 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 stereoisomer thereof to the mammal.
Also described is 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 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, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological 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 leukemia, multiple myeloma, B- or T-cell lymphoma, non-Hodgkin's lymphoma, auto- 40 immune diseases comprising rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.
In particular, a 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 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 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, 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, 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, orange essence, strawberry essence, vanilla flavor, etc.
The pharmaceutical composition of the present invention may be formulated into a preparation for oral administration by adding additives to active ingredients, wherein the additives may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, 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, 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 divided doses. The dosage of the compound of the present invention may vary depending on the health conditions, age, body weight, sex of the subject, 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 not limited thereto.
The definition of the abbreviations used in the following examples is as follows.
[Table 1] Abbreviation Full name AlCl Aluminum chloride ACN Acetonitrile AcOH Acetic acid AIBN 2,2'-Azobis(2-methylpropionitrile) BH -THF complex Borane tetrahydrofuran complex BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BBr Boron tribromide Boc2O Di-tert-butyl dicarbonate Brine is water saturated or nearly saturated with a brine salt (generally, Brine sodium chloride) CH CN Acetonitrile CDCl Deuterated chloroform CH Cl Dichloromethane CH I Methyl iodide CH SO Cl Methanesulfonyl chloride (COCl) Oxalyl chloride Cs CO Cesium carbonate Cu O Copper (I) oxide DAST (Diethylamino)sulfur trifluride DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DME 1,2-Dimethoxyethane DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DMSO-d Dimethylsulfoxide-d EtOAc Ethyl acetate EtOH Ethyl alcohol Et O Diethyl ether HBr Hydrogen bromide HCl Hydrogen chloride H SO Sulfuric acid n-Hex n-Hexane HNO Nitric acid H O Water K CO Potassium carbonate LDA Lithium diisopropylamide LiOHH O Lithium hydroxide, monohydrate MeOH Methyl alcohol NaBH Sodium borohydride NaCN Sodium cyanide Na CO Sodium carbonate Na SO Sodium sulfate NaH Sodium hydride NaHCO Sodium bicarbonate NaOH Sodium hydroxide NH Cl Ammonium chloride NFS N-fluorobenzenesulfonimide Oxone Potassium peroxymonosulfate Pd(PPh ) Tetrakis(triphenylphosphine)palladium(0) Pd(OAc) Palladium(II) acetate PBr Phosphorus tribromide PPh Triphenylphosphine SOCl Thionyl chloride THF Tetrahydrofuran TFA Trifluoroacetic acid Zn Zinc Intermediate 1) Synthesis of 1-(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxylic acid (a) Synthesis of 2-fluoromethoxynitrobenzaldehyde 2-Fluoromethoxybenzaldehyde (1.0 g, 6.49 mmol) was dissolved in conc.
H SO (6.0 mL), and 70% HNO aqueous solution (0.8 mL, 6.49 mmol) and conc. H SO 2 4 3 2 4 (0.8 mL, 14.92 mmol) were slowly added at -15°C. The reaction mixture was stirred at - °C for 2 hours and poured into ice water. The precipitate was filtered and dissolved in CH Cl and neutralized with sat. NaHCO aqueous solution. The organic extract was 2 2 3 dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : CH2Cl2 = 3 : 1) to obtain 2- fluoromethoxynitrobenzaldehyde (1.2 g, 91%) as a white solid.
H-NMR (400MHz, CDCl ): δ 10.21 (s, 1H), 8.46 (d, 1H, J=7.2Hz), 6.88 (d, 1H, J=11.6Hz), 4.06 (s, 3H) (b) Synthesis of methyl 6-methoxynitrobenzo[b]thiophenecarboxylate 2-Fluoromethoxynitrobenzaldehyde (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 K CO (1.8 g, 12.80 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure to obtain methyl 6-methoxynitrobenzo[b]thiophenecarboxylate (1.5 g) as a yellow solid without purification.
H-NMR (400MHz, CDCl ): δ 8.34 (s, 1H), 8.03 (s, 1H), 7.47 (s, 1H), 4.04 (s, 3H), 3.96 (s, 3H) (c) Synthesis of methyl 5-aminomethoxybenzo[b]thiophenecarboxylate Methyl 6-methoxynitrobenzo[b]thiophenecarboxylate (1.3 g, 4.83 mmol) was dissolved in a mixture of MeOH/H O (44.0 mL, 10/1 v/v), and Zn (3.1 g, 65.30 mmol) and NH Cl (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. The residue was purified by flash column chromatography (amine silica gel, n-Hex : EtOAc = 4 : 1) to obtain methylamino methoxybenzo[b]thiophenecarboxylate (1.1 g, 93%) as a yellow solid.
H-NMR (400MHz, CDCl ): δ 7.84 (s, 1H), 7.17 (s, 1H), 7.12 (s, 1H), 3.94-3.96 (m, 5H), 3.91 (s, 3H) (d) Synthesis of methyl 5-aminohydroxybenzo[b]thiophenecarboxylate Methyl 5-aminomethoxybenzo[b]thiophenecarboxylate (500.0 mg, 4.83 mmol) was dissolved in CH Cl (40.0 mL), and 1M solution of BBr in CH Cl (6.7 mL, 2 2 3 2 2 6.74 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, H O was added, and extracted with CH Cl . The organic extract was washed 2 2 2 with brine, dried over anhydrous Na SO and concentrated under 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 H2O) to obtain methyl 5-amino hydroxybenzo[b]thiophenecarboxylate (398.0 mg, 85%) as a gray solid. 40 LC/MS ESI (+): 224 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.15 (brs, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 7.07 (s, 1H), 4.86 (brs, 2H) 3.82 (s, 3H) (e) Synthesis of methyl 2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine- 7-carboxylate Methyl 5-aminohydroxybenzo[b]thiophenecarboxylate (85.0 mg, 0.38 mmol) was dissolved in anhydrous DMF (3.8 mL), and 1,2-dibromoethane (215.0 mg, 1.14 mmol) and K CO (116.0 mg, 0.83 mmol) were added at room temperature. The reaction mixture was stirred at 75°C for 15 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate (45.2 mg, 47%) as a gray solid.
LC/MS ESI (+): 250 (M+1) H-NMR (400MHz, DMSO-d ): δ 7.89 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 6.16 (s, 1H), 4.19 (t, 2H, J= 4.6Hz), 3.82 (s, 3H), 3.30-3.32 (m, 2H) (f) Synthesis of methyl 1-(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate Methyl 2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate (69.0 mg, 0.27 mmol) was dissolved in CH Cl (2.7 mL), CH SO Cl (28.0 μL, 0.36 mmol) 2 2 3 2 was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour, H O was added, and extracted with CH Cl . The organic extract was washed with 2 2 2 brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 1-(methylsulfonyl)-2,3- dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate (42.3 mg, 46%) as a white solid.
LC/MS ESI (+): 328 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.21 (s, 1H), 8.12 (s, 1H), 7.63 (s, 1H), 4.35 (t, 2H, J= 4.3Hz), 3.86- 3.89 (m, 5H), 3.17 (s, 3H) (g) Synthesis of 1-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using methyl 1-(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylate (42.0 mg, 0.12 mmol) to obtain 1-(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylic acid (35.1 mg, 87%) as a white 40 solid.
LC/MS ESI (-): 312 (M-1) H-NMR (400MHz, DMSO-d ): δ 13.32 (brs, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.60 (s, 1H), 4.36 (t, 2H, J= 4.7Hz), 3.89 (t, 2H, J=4.7Hz), 3.18 (s, 3H) Intermediate 2) Synthesis of 3,3-dimethyl(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxylic acid (a) Synthesis of methyl 5-(2-bromomethylpropanamido) hydroxybenzo[b]thiophenecarboxylate Methyl 5-aminohydroxybenzo[b]thiophenecarboxylate (110.0 mg, 0.49 mmol) was dissolved in DMA (5.0 mL), and 2-bromomethyl propanoyl bromide (73.0 μL, 0.59 mmol) and DIPEA (258.0 μL, 1.47 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, H O was added, and extracted with EtOAc.
The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 5-(2-bromomethylpropanamido)hydroxybenzo[b]thiophene carboxylate (161.0 mg, 88%) as a white solid.
LC/MS ESI (+): 372 (M+1) H-NMR (400MHz, DMSO-d ): δ 11.15 (brs, 1H), 9.24 (s, 1H), 8.49 (s, 1H), 8.08 (s, 1H), 7.43 (s, 1H), 3.85 (s, 3H), 2.03 (s, 6H) (b) Synthesis of methyl 3,3-dimethyloxo-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate Methyl 5-(2-bromomethylpropanamido)hydroxybenzo[b]thiophene carboxylate (161.0 mg, 0.43 mmol) was dissolved in DMA (4.3 mL) and K CO (132.0 mg, 0.95 mmol) was added. The reaction mixture was stirred at 60°C for 15 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 3,3-dimethyloxo-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate (112.0 mg, 89%) as a gray solid.
LC/MS ESI (-): 290 (M-1) H-NMR (400MHz, DMSO-d ): δ 10.95 (s, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 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- b][1,4]oxazinecarboxylate 40 Methyl 3,3-dimethyloxo-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxylate (112.0 mg, 0.38 mmol) was dissolved in THF (4.0 mL), and 1M solution of BH -THF complex (1.9 mL, 1.92 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours, H O 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 (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 3,3-dimethyl-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylate (80.0 mg, 75%) as a gray solid.
LC/MS ESI (+): 278 (M+1) H-NMR (400MHz, DMSO-d ): δ 7.90 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 6.26 (brs, 1H), 3.83 (s, 3H) 3.06 (d, 2H, J=2.3Hz), 1.29 (s, 6H) (d) Synthesis of methyl 3,3-dimethyl(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylate Methyl 3,3-dimethyl-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylate (65.0 mg, 0.88 mmol) was dissolved in pyridine (2.3 mL) and CH SO Cl (95.0 μL, 1.06 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 15 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18- silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 3,3- dimethyl(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylate (52.2 mg, 63%) as a white solid.
LC/MS ESI (+): 356 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.20 (s, 1H), 8.11 (s, 1H), 7.56 (s, 1H), 3.87 (s, 3H), 3.67 (s, 2H), 3.37 (s, 3H), 1.36 (s, 6H) (e) Synthesis of 3,3-dimethyl(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using methyl 3,3-dimethyl(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxylate (52.0 mg, 0.14 mmol) as a starting material to obtain 3,3- dimethyl(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylic acid (45.0 mg, 90%).
LC/MS ESI (+): 342 (M+1) H-NMR (400MHz, DMSO-d ): δ 13.30 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.53 (s, 1H), 3.66 (s, 2H), 3.34 (s, 3H), 1.36 (s, 6H) 40 Intermediate 3) Synthesis of 1-(methylsulfonyl)-1,2,3,4- tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazephinecarboxylic acid (a) Synthesis of methyl 6-hydroxy(methylsulfonamido)benzo[b]thiophene carboxylate Methyl 5-aminohydroxybenzo[b]thiophenecarboxylate (126.0 mg, 0.56 mmol) was dissolved in pyridine (2.8 mL), and CH SO Cl (50.6 μL, 0.64 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 6-hydroxy (methylsulfonamido)benzo[b]thiophenecarboxylate (131.0 mg, 77%) as a white solid.
LC/MS ESI (-): 300 (M-1) H-NMR (400MHz, DMSO-d ): δ 9.92 (brs, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 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]oxazephinecarboxylate Methyl 6-hydroxy(methylsulfonamido)benzo[b]thiophenecarboxylate (5.0 mg, 0.02 mmol) as a starting material was dissolved in DMA (160.0 μL), and 1,3- dibromopropane (16.7 mg, 0.08 mmol) and K CO (116.0 mg, 0.83 mmol) were added.
The reaction mixture was stirred at room temperature for 15 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO 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)-1,2,3,4-tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazephine carboxylate (1.2 mg, 21%) as a white solid.
LC/MS ESI (+): 342 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.20 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 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 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[3',2':4,5]benzo[1,2- b][1,4]oxazephinecarboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using methyl 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazephine carboxylate (42.0 mg, 0.12 mmol) as a starting material to obtain 1-(methylsulfonyl)- 1,2,3,4-tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazephinecarboxylic acid (22.3 mg, 55%).
LC/MS ESI (+): 328 (M+1) 40 H-NMR (400MHz, DMSO-d ): δ 13.52 (brs, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 4.12-4.14 (m, 2H), 3.73-3.75 (m, 2H), 3.09 (s, 3H), 1.99-2.07 (m, 2H) Intermediate 4) Synthesis of 8,8-dimethyl(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3- g]quinolinecarboxylic acid (a) Synthesis of ethyl 5-(3-methylbutenamido)benzo[b]thiophenecarboxylate Ethyl 5-aminobenzo[b]thiophenecarboxylate (1.5 g, 6.78 mmol) was dissolved in pyridine (33.9 mL), and 3-methylbutenoyl chloride (755.0 μL, 6.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO 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- methylbutenamido)benzo[b]thiophenecarboxylate (1.3 g, 63%) as a colorless liquid.
H-NMR (400MHz, CDCl ): δ 8.29 (s, 1H), 7.99 (s, 1H), 7.77 (d, 1H, J=8.7Hz), 7.44 (d, 1H, J=8.6Hz), 7.17 (s, 1H), 5.74 (s, 1H), 4.40 (q, 2H, J=7.1Hz), 2.26 (s, 3H), 1.93 (s, 3H), 1.41 (t, 3H, J=7.1Hz) (b) Synthesis of ethyl 8,8-dimethyloxo-5,6,7,8-tetrahydrothieno[2,3- g]quinolinecarboxylate Ethyl 5-(3-methylbutenamido)benzo[b]thiophenecarboxylate (1.3 g, 4.29 mmol) was dissolved in CH Cl (42.9 mL), and AlCl (1.7 g, 12.86 mmol) was added at 2 2 3 0°C. The reaction mixture was stirred at room temperature for 2 hours, H O was added, and extracted with CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain ethyl 8,8-dimethyloxo-5,6,7,8-tetrahydrothieno[2,3- g]quinolinecarboxylate (250.0 mg, 19%) as a yellow solid.
H-NMR (400MHz, CDCl ): δ 8.44 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 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 carboxylate The synthesis procedure of Intermediate 15-c was repeated except for using ethyl 8,8-dimethyloxo-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate (217.0 mg, 0.72 mmol) as a starting material to obtain ethyl 8,8-dimethyl-5,6,7,8-tetrahydrothieno[2,3- g]quinolinecarboxylate (56.0 mg, 27%).
H-NMR (400MHz, CDCl3): δ 7.78 (s, 1H), 7.63 (s, 1H), 6.88 (s, 1H), 4.37 (q, 2H, J=7.1Hz), 3.37 (t, 2H, J=5.8Hz), 1.78 (t, 2H, J=5.8Hz), 1.37-1.41 (m, 9H) (d) Synthesis of ethyl 8,8-dimethyl(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3-g]quinolinecarboxylate The synthesis procedure of Intermediate 16-f was repeated except for using ethyl 8,8-dimethyl-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate (56.0 mg, 0.19 mmol) as a starting material to obtain ethyl 8,8-dimethyl(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3-g]quinolinecarboxylate (57.0 mg, 80%).
H-NMR (400MHz, CDCl ): δ 8.21 (s, 1H), 7.97 (s, 1H), 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=5.8Hz), 1.39-1.43 (m, 9H) (e) Synthesis of 8,8-dimethyl(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3- g]quinolinecarboxylic acid The synthesis procedure of Intermediate 1-g was repeated except for using ethyl 8,8-dimethyl(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate (57.0 mg, 0.16 mmol) as a starting material to obtain 8,8-dimethyl(methylsulfonyl)- 5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylic acid (52.0 mg, 80%).
LC/MS ESI (+): 340 (M+1) H-NMR (400MHz, CDCl ): δ 8.25 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 3.91 (t, 2H, J=5.8Hz), 2.94 (s, 3H), 1.89 (t, 2H, J=5.8Hz), 1.43 (s, 6H) Intermediate 5) Synthesis of 4-(tert-butoxycarbonyl)(methylsulfonyl)- 1,2,3,4-tetrahydrothieno[2,3-g]quinoxalinecarboxylic acid (a) Synthesis of 4-bromofluoronitrobenzaldehyde 4-bromofluorobenzaldehyde (2.0 g, 9.85 mmol) was dissolved in conc. H SO (5.2 mL, 98.50 mmol), and 60% HNO (1.0 mL, 12.80 mmol) was added at 0 C. The reaction mixture was stirred for 4 hours, and extracted with CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was recrystallized using i-Pr O to obtain 4-bromofluoro nitrobenzaldehyde (900.0 mg, 37%) as a white solid.
H-NMR (400MHz, CDCl ): δ 10.31 (s, 1H), 8.42 (d, 1H, J=6.4Hz), 7.67 (d, 1H, J=9.0Hz). (b) Synthesis of methyl 6-bromonitrobenzo[b]thiophenecarboxylate 4-bromofluoronitrobenzaldehyde (5.0 g, 20.10 mmol) was dissolved in anhydrous DMF (50.0 mL), and methyl 2-mercaptoacetate (2.1 g, 20.10 mmol) and K CO (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 was washed with brine, dried over anhydrous Na SO , concentrated under reduced 40 pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 6-bromo nitrobenzo[b]thiophenecarboxylate (3.4 g, 53%) as a yellow solid.
H-NMR (400MHz, DMSO-d ): δ 8.38 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 3.98 (s, 3H) (c) Synthesis of methyl 6-aminonitrobenzo[b]thiophenecarboxylate 6-bromonitrobenzo[b]thiophenecarboxylate (3.0 g, 9.49 mmol) was dissolved in DMSO (10.0 ml) and Cu O (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 hour and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 6-aminonitrobenzo[b]thiophenecarboxylate (1.6 g, 66%).as an off-white solid.
LC/MS ESI (+): 253 (M+1) H-NMR(400MHz, CDCl ): δ 8.77 (s, 1H), 8.11 (s, 1H), 7.44 (s, 1H), 7.39 (s, 2H), 3.33 (s, 3H) (d) Synthesis of methyl 6-((tert-butoxycarbonyl)amino)nitrobenzo[b]thiophene- 2-carboxylate Methyl 6-aminonitrobenzo[b]thiophenecarboxylate (800.0 mg, 3.17 mmol) was dissolved in DMA (10.0 mL) and Boc O (831.0 mg, 3.81 mmol), DIPEA (1.6 mL, 9.51 mmol) were added at room temperature. The mixture was stirred at 100 °C for 2 hours and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 6-((tert-butoxycarbonyl)amino) nitrobenzo[b]thiophenecarboxylate (663.0 mg, 59%), as an off-white solid.
H-NMR(400MHz, CDCl ): δ 9.59 (s, 1H), 8.74 (s, 1H), 8.32 (s, 1H), 8.31 (s, 1H), 3.91 (s, 3H), 1.46 (s, 9H) (e) Synthesis of methyl 5-amino((tert- butoxycarbonyl)amino)benzo[b]thiophenecarboxylate Methyl 6-((tert-butoxycarbonyl)amino)nitrobenzo[b]thiophenecarboxylate (662.0 mg, 1.87 mmol) was dissolved in a mixture solvent of MeOH/H O (20.0 mL, 9/1 v/v), and Zn (18.7 g, 18.70 mmol) and NH Cl (1.0 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: 0.1% formic acid in H O) to obtain methyl 5-amino((tert-butoxycarbonyl) amino) benzo 40 [b]thiophenecarboxylate (633.0 mg, 104%) as an off-white solid.
LC/MS ESI (+): 323 (M+1) H-NMR(400MHz, CDCl ): δ 8.56 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.21 (s, 1H), .14 (s, 2H), 3.85 (s, 3H), 1.50 (s, 9H) (f) Synthesis of methyl 6-((tert-butoxycarbonyl)amino)(methylsulfonamido) benzo[b]thiophenecarboxylate Methyl 5-amino((tert-butoxycarbonyl) amino) benzo [b]thiophene carboxylate (633.0 mg, 1.96 mmol) was dissolved in pyridine (9.8 mL), and methanesulfonyl chloride (168.0 μL, 2.16 mmol) was slowly added thereto at 0°C. The reaction mixture was warmed to room temperature, followed by stirred for 3 hours and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed- phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 6-((tert-butoxycarbonyl)amino) (methylsulfonamido)benzo[b]thiophenecarboxylate (694.0 mg, 88%), as an off-white solid.
LC/MS ESI (-): 399 (M-1) H-NMR (400MHz, DMSO-d ): δ 9.28 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 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)(methylsulfonamido) benzo[b]thiophenecarboxylate (684.0 mg, 1.70 mmol) was dissolved in DMA (17.1 mL), and 1,2-dibromoethane (963.0 mg, 5.12 mmol) and K CO (472.0 mg, 3.42 mmol) were slowly added at room temperature. The mixture was stirred for 1 hour, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 4-(tert-butyl) 7-methyl 1-(methylsulfonyl)-2,3- dihydrothieno[2,3-g]quinoxaline-4,7(1H)-dicarboxylate (495.0 mg, 68%), as an off-white solid.
H-NMR (400MHz, DMSO-d ): δ 8.42 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 3.85- 3.92 (m, 4H), 3.89 (s, 3H), 3.12 (s, 3H), 1.51 (s, 9H) (h) Synthesis of 4-(tert-butoxycarbonyl)(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxylic acid 4-(tert-butyl) 7-methyl 1-(methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline- 4,7(1H)-dicarboxylate (495.0 mg, 1.16 mmol) was dissolved in THF/H O (10.0 mL, 3/1 40 v/v), and LiOH·H O (146.0 mg, 3.48 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 H O (1.0 mL), and acidified with 1N HCl (pH 1-2). The precipitate was filtered to obtain 4-(tert-butoxycarbonyl)(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxylic acid (422.0 mg, 88%) as a white solid.
LC/MS ESI (-): 411 (M-1) H-NMR (400MHz, DMSO-d ): δ 13.47 (brs, 1H), 8.37 (s, 1H), 8.09 (s, 1H), ,8.05 (s, 1H), 3.83 ~ 3.92 (m, 4H), 3.11 (s, 3H), 1.50 (s, 9H) Intermediate 6) Synthesis of 5-(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3- g]quinolinecarboxylic acid (a) Synthesis of methyl (E)(3-methoxyoxopropenyl) nitrobenzo[b]thiophenecarboxylate Methyl 6-bromonitrobenzo[b]thiophenecarboxylate (0.4 g, 1.26 mmol) was dissolved in anhydrous DMF(12.6 ml), and Pd(OAc) (28.0 mg, 0.13 mmol), PPh (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 Na SO and concentrated under reduced pressure. The residue was recrystallized with diethyl ether to obtain methyl (E)(3-methoxyoxopropenyl)nitrobenzo[b]thiophenecarboxylate as a white solid.
LC/MS ESI (+): 322 (M+1) H-NMR (400MHz, CDCl ): δ 8.62 (s, 1H), 8.16-8.22 (m, 2H), 8.09 (s, 1H), 6.43 (d, 1H, J=16.0Hz), 4.00 (s, 3H), 3.85 (s, 3H) (b) Synthesis of methyl 6-oxo-5,6,7,8-tetrahydrothieno[2,3-g]quinoline carboxylate (E)-methyl 6-(3-methoxyoxopropenyl)nitrobenzo[b]thiophene carboxylate (0.2 g, 0.62 mmol) was dissolved in anhydrous MeOH(15.6 mL), and 5% Pd-C (20.0 mg, 0.19 mmol) was added. The reaction mixture was charged with H gas and stirred at 25°C for 4 days. The residue was filtered through Celite and concentrated under reduced pressure to obtain methyl 6-oxo-5,6,7,8-tetrahydrothieno[2,3-g]quinoline carboxylate (100.0 mg, 61%) as a white solid without purification.
LC/MS ESI (+): 262 (M+1) H-NMR (400MHz, CDCl ): δ 7.95 (s, 1H), 7.80 (brs, 1H), 7.66 (s, 1H), 7.21 (s, 1H), 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]quinolinecarboxylate Methyl 6-oxo-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate (100.0 mg, 40 0.38 mmol) was dissolved in THF (4.0 mL), and 1M solution of BH -THF complex (1.9 mL, 1.91 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 5,6,7,8- tetrahydrothieno[2,3-g]quinolinecarboxylate (65.0 mg, 69%) as a gray solid.
LC/MS ESI (+): 248 (M+1) H-NMR (400MHz, CDCl ): δ 7.80 (s, 1H), 7.40 (s, 1H), 6.89 (s, 1H), 3.91 (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]quinolinecarboxylate Methyl 5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylatee (50.0 mg, 0.20 mmol) was dissolved in CH Cl (2.0 mL), and CH SO Cl (23.6 μL, 0.30 mmol) and 2 2 3 2 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 Na SO and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 2 : 1) to obtain methyl 5- (methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate (57.0 mg, 87%) as a white solid.
LC/MS ESI (+): 326 (M+1) H-NMR (400MHz, CDCl ): δ 8.21 (s, 1H), 7.99 (s, 1H), 7.63 (s, 1H), 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)-5,6,7,8-tetrahydrothieno[2,3-g]quinoline carboxylic acid The synthesis procedure of Intermediate 5-h was repeated except for using methyl -(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylate(60.0 mg, 0.18 mmol) to obtain 5-(methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxylic acid (450.0 mg, 87 %), as a white solid.
LC/MS ESI (+): 312 (M+1) Intermediate 7) Synthesis of 4-methyl(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxylic acid (a) Synthesis of methyl 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxalinecarboxylate Unpurified tert-butyl 7-(chlorocarbonyl)(methylsulfonyl)-2,3- dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate (40.0 mg, 0.09 mmol) was dissolved 40 in CH Cl /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 (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 1- (methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3-g]quinoxalinecarboxylate (21.0 mg, 69%) as a white solid.
LC/MS ESI (+): 327 (M+1) H-NMR (400MHz, DMSO-d ): δ 7.97 (s, 1H), 7.90 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 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(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxylate Methyl 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3-g]quinoxaline carboxylate (63.0 mg, 0.19 mmol) was dissolved in MeOH (1.9 mL), and formaldehyde (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 Na SO , filtered and concentrated under a reduced pressure. The residue was separated on reversed-phase silica by column chromatography (0.1% formic acid in CH CN : 0.1% formic acid in H O = 70 : 30), and fractions including the product were combined and evaporated to obtain methyl 4-methyl- 1-(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3-g]quinoxalinecarboxylate (51.0 mg, 78%) as a white solid.
LC/MS ESI (+): 341 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.00 (s, 1H), 7.90 (s, 1H), 7.28 (s, 1H), 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(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxalinecarboxylic acid Methyl 4-methyl(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3-g]quinoxaline- 7-carboxylate (50.0 mg, 0.14 mmol) was dissolved in THF/H O (1.5 mL, 3/1 v/v), and LiOH·H O (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 H O (1.0 mL), and acidified with 1N HCl (pH 1-2). The precipitate was filtered to obtain 4-methyl(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxalinecarboxylic acid (42.0 mg, 88%) as a white solid.
LC/MS ESI (+): 327 (M+1) H-NMR (400MHz, DMSO-d ): δ 13.02 (brs, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 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) 40 Intermediate 8) Synthesis of 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid (a) Synthesis of 2-chloro(3,3-diethoxypropoxy)methylbenzene 3-Chloromethylphenol (3.0 g, 21.04 mmol) was dissolved in anhydrous DMF (105.0 mL), and 3-chloro-1,1-diethoxypropane (4.2 g, 25.20 mmol) and K CO (8.7 g, 63.10 mmol) were added. The reaction mixture was stirred at 80°C for 15 hours, H O was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 95 : 5) to obtain 2-chloro (3,3-diethoxypropoxy)methylbenzene (4.0 g, 69%) as a colorless liquid.
H-NMR (400MHz, CDCl ): δ 7.16 (d, 1H, J=8.4Hz), 6.91 (d, 1H, J=2.6Hz), 6.71 (dd, 1H, J=8.4Hz, 2.6Hz), 4.75 (t, 1H, 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 (t, 6H, J=7.1Hz). (b) Synthesis of 7-chloromethyl(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(3,3-diethxypropoxy) methylbenzene (4.0 g, 14.66 mmol) in CH Cl (12.2 mL) was added to the reaction mixture for a period of 1 hour, and stirred at room temperature for 30 minutes. The reaction mixture was basified with sat. NaHCO3 aqueous solution (pH=9-10), and extracted with CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO and 2 2 2 4 concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 1 : 2) to obtain 7-chloromethyl (methylsulfonyl)chromane (2.3 g, 60%) as an off-white solid.
H-NMR (400MHz, CDCl ): δ 7.36 (s, 1H), 6.95 (s, 1H), 4.40-4.46 (m, 1H), 4.17- 4.25 (m, 2H), 2.83 (s, 3H), 2.55-2.62 (m, 1H), 2.32-2.42 (m, 1H), 2.31 (s, 3H). (c) Synthesis of 6-(bromomethyl)chloro(methylsulfonyl)chromane 7-Chloromethyl(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, H O was added, and extracted with CH Cl . The 2 2 2 organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 4 : 1) to obtain 6-(bromomethyl)chloro (methylsulfonyl)chromane (2.5 g, 85%) as a yellow solid.
H-NMR (400MHz, CDCl ): δ 7.59 (s, 1H), 7.00 (s, 1H), 4.47-4.62 (m, 3H), 4.25- 4.31 (m, 1H), 4.19-4.22 (m, 1H), 2.87 (s, 3H), 2.56-2.62 (m, 1H), 2.34-2.43 (m, 1H). 40 (d) Synthesis of 7-chloro(methylsulfonyl)chromanecarbaldehyde 6-(Bromomethyl)chloro(methylsulfonyl)chromane (2.5 g, 7.36 mmol) was dissolved in anhydrous CH CN (73.6 mL) , and 4-methylmorpholine N-oxide (1.7 g, 14.72 mmol) and a molecular sieve (3.0 g) were added. The reaction mixture was stirred at room temperature for 2 hours, H2O was added to the reaction mixture, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was recrystallized with Et O to obtain 7- chloro(methylsulfonyl)chromanecarbaldehyde (1.3 g, 64%) as a pale yellow solid.
LC/MS ESI (+): 275 (M+1).
H-NMR (400MHz, CDCl ): δ 10.32 (s, 1H), 7.97 (s, 1H), 7.03 (s, 1H), 4.64-4.71 (m, 1H), 4.39-4.44 (m, 1H), 4.23 (m, 1H), 2.99 (s, 3H), 2.73-2.78 (m, 1H), 2.30-2.34 (m, 1H). (e) Synthesis of methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate 7-Chloro(methylsulfonyl)chromanecarbaldehyde (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 Cs CO (1.1 g, 3.28 mmol) were added. The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, H O was added, and extracted with EtOAc.
The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was recrystallized with CH2Cl2 and Et2O to obtain methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (200.0 mg, 56%) as a white solid.
H-NMR (400MHz, DMSO-d ): δ 8.17 (s, 1H), 8.09 (s, 1H), 7.57 (s, 1H), 4.82 (m, 1H), 4.45-4.50 (m, 1H), 4.31-4.35 (m, 1H), 3.88 (s, 3H), 3.17 (s, 3H), 2.59-2.69 (m, 1H), 2.26-2.37 (m, 1H).
LC/MS ESI (+): 327 (M+1). (f) Synthesis of 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylic acid Methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (200.0 mg, 0.61 mmol) was dissolved in THF (4.0 mL)/H O (2.0 mL), and LiOH·H O (257.0 mg, 6.13 mmol) was added. The reaction mixture was stirred at 60°C for 15 hours, 1N HCl (3.0 mL) was added, and extracted with CH Cl and MeOH. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure to obtain 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylic acid (140.0 mg, 73%) as an off-white solid.
LC/MS ESI (-): 311 (M-1).
H-NMR (400MHz, DMSO-d6): δ 13.34 (bs, 1H), 8.06 (s, 2H), 7.54 (s, 1H), 4.82 (m, 1H), 4.45-4.54 (m, 1H), 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.60-2.74 (m, 1H), 2.28-2.39 40 (m, 1H).
Intermediate 9) Synthesis of 5-(methylsulfonyl)-2,3,4,5- tetrahydrothieno[3',2':4,5]benzo[1,2- b]oxepinecarboxylic acid (a) Synthesis of 2-chloro(4,4-diethoxybutoxy)methylbenzene The synthesis procedure of Intermediate 8-a was repeated except for using 3- chloromethylphenol (1.0 g, 7.01 mmol) to obtain 2-chloro(4,4-diethoxybutoxy) methylbenzene (1.8 g, 89 %) as a colorless liquid.
LC/MS ESI (+): 287 (M+1) H-NMR (400MHz, CDCl ): δ 7.09 (d, 1H, J=8.0Hz), 6.89 (d, 1H, J=2.8Hz), 6.69 (dd, 1H, J=8.6, 2.8Hz), 4.54 (t, 1H, J=1.6Hz), 3.93 (t, 2H, J=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) (b) Synthesis of 8-chloromethyl(methylsulfonyl)-2,3,4,5- tetrahydrobenzo[b]oxepine The synthesis procedure of Intermediate 8-b was repeated except for using 2- chloro(4,4-diethoxybutoxy)methylbenzene (1.8 g, 6.20 mmol) to obtain 8-chloro methyl(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine (421.0 mg, 23%) as a white solid.
LC/MS ESI (+): 275 (M+1) H-NMR (400MHz, CDCl ): δ 7.20 (s, 1H), 7.10 (s, 1H), 4.34-4.39 (m, 1H), 4.16 (t, 1H, J=1.6Hz), 3.71-3.77 (m, 1H), 2.78 (s, 3H), 2.64-2.70 (m, 1H), 2.33 (s, 3H), 2.22- 2.29 (m, 1H), 2.07-2.15 (m, 1H), 1.82-1.89 (m, 1H). (c) Synthesis of 7-(bromomethyl)chloro(methylsulfonyl)-2,3,4,5- tetrahydrobenzo[b]oxepine The synthesis procedure of Intermediate 8-c was repeated except for using 8- chloromethyl(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine (421 mg, 1.53 mmol) to obtain 7-(bromomethyl)chloro(methylsulfonyl)-2,3,4,5- tetrahydrobenzo[b]oxepine (342.0 mg, 63%) as a white solid.
LC/MS ESI (+): 353 (M+1) H-NMR (400MHz, CDCl ): δ 7.42 (s, 1H), 7.15 (s, 1H), 4.44 (m, 2H), 4.39-4.44 (m, 1H), 4.20 (t, 1H, J=1.6Hz), 3.76-3.82 (m, 1H), 2.78 (s, 3H), 2.68-2.72 (m, 1H), 2.28- 2.38 (m, 1H), 2.09-2.18 (m, 1H), 1.86-1.94 (m, 1H) (d) Synthesis of 8-chloro(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine carbaldehyde The synthesis procedure of Intermediate 8-d was repeated except for using 7- (bromomethyl)chloro(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine (342.0mg, 0.97 mmol) to obtain 8-chloro(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepine carbaldehyde (164.0 mg, 57%), as a white solid.
LC/MS ESI (+): 289 (M+1) H-NMR (400MHz, CDCl3): δ 10.36 (s, 1H), 7.89 (s, 1H), 7.21 (s, 1H), 4.55-4.59 (m, 1H), 4.31 (t, 1H, J=1.6Hz), 3.78-3.84 (m, 1H), 2.79-2.84 (m, 4H), 2.42-2.53 (m, 1H), 2.02-2.11 (m, 1H), 1.91-1.96 (m, 1H). (e) Synthesis of 5-(methylsulfonyl)-2,3,4,5-tetrahydrothieno[3',2':4,5]benzo[1,2- b]oxepinecarboxylic acid The synthesis procedure of Intermediate 8-e was repeated except for using 8- chloro(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[b]oxepinecarbaldehyde (164.0 mg, 0.57 mmol) to obtain 5-(methylsulfonyl)-2,3,4,5-tetrahydrothieno[3',2':4,5]benzo[1,2- b]oxepinecarboxylic acid (116.0 mg, 62 %) as a white solid.
LC/MS ESI (+): 341 (M+1) H-NMR (400MHz, DMSO-d ): δ 13.48 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 4.80 (t, 1H, J=1.2 Hz), 4.33-4.39 (m, 1H), 3.75-3.80 (m, 1H), 2.89 (s, 3H), 2.50-2.53 (m, 1H) 2.18-2.27 (m, 1H), 2.06-2.14 (m, 1H), 1.75-1.88 (m, 1H) Intermediate 10) Synthesis of 5-(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3- b]thiophenecarboxylic acid (a) Synthesis of 2-ethylhexyl 3-((5-bromoformylphenyl)thio)propanoate To a solution of 4-bromofluorobenzaldehyde (3.0 g, 14.78 mmol) in DMF (73.9 ml) were added 2-Ethylhexyl 3-mercaptopropionate (3.7 ml, 16.26 mmol). The reaction mixture was stirred at 40°C for 36hours. The reaction mixture was purified by reversed- phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 2-ethylhexyl 3-((5-bromoformylphenyl)thio)propanoate (4.2 g, 71 %) as a light brown oil.
LC/MS ESI (+): 401 (M+1) H-NMR (400MHz, CDCl ): δ 10.28 (s, 1H), 7.70 (d, 1H, J=8.2Hz), 7.57 (d, 1H, J=1.7Hz), 7.46 (dd, 1H, J=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) (hydroxymethyl)phenyl)thio)propanoate A solution of 4,4-diethoxybutene (503.0 mg, 3.49 mmol) in 9- borabicyclo(3.3.1)nonane (7.7 ml, 3.84 mmol) was stirred for 1hour and concentrated. The residue was dissolved in benzene (7.7 ml)/EtOH (3.9 ml). 2N Na CO aqueous solution (35.0 ml, 6.98 mmol) and Pd(PPh ) (202.0 mg, 0.17 mmol) were added and the reaction 40 mixture at 80°C for 90minutes. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO , filtered and concentrated. The residue was purified by normal phase column chromatography (EtOAc:n-Hex=1:15) to give 2-ethylhexyl 3-((5-(4,4-diethoxybutyl) formylphenyl)thio)propanoate (695.0 mg, 85 %) as crude. To a solution of 2-ethylhexyl 3- ((5-(4,4-diethoxybutyl)formylphenyl)thio)propanoate (610.0 mg, 1.31 mmol) in EtOH (6.5 ml) was added NaBH (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 Na SO , and concentrated. The residue was purified by normal phase column chromatography (EtOAc:n-Hex=1:3) to give 2- ethylhexyl 3-((5-(4,4-diethoxybutyl)(hydroxymethyl)phenyl)thio)propanoate (550.0 mg, 90 %) as a colorless oil.
H-NMR (400MHz, CDCl ): δ 7.31 (d, 1H, J=7.7Hz), 7.24 (d, 1H, J=1.7Hz), 7.07 (d, 1H, J=7.7Hz), 4.74 (d, 2H, J=3.3Hz ), 4.49 (t, 1H, J=5.2Hz), 4.00-4.02 (m, 2H), 3.59- 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 (brs, 1H), 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=7.1Hz), 0.89 (t, 6H, J=7.1Hz) (c) Synthesis of 2-ethylhexyl 3-((5-(methylsulfonyl)((2,2,2- trifluoroacetoxy)methyl)-5,6,7,8-tetrahydronaphthalenyl)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)(hydroxymethyl)phenyl)thio)propanoate (550.0 mg, 1.17 mmol) in CH Cl (1956.0 µl) was added dropwise and the reaction mixture was stirred at 23°C for 1hour. The reaction mixture was extracted with EtOAc, and the organic extract was washed with sat. NaHCO aqueous solution and brine, dried over anhydrous Na SO , filtered and concentrated. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 3-((5-(methylsulfonyl)((2,2,2-trifluoroacetoxy)methyl)-5,6,7,8- tetrahydronaphthalenyl)thio)propanoate (217.0 mg, 34 %) as a colorless oil.
H-NMR (400MHz, CDCl ): δ 7.63 (s, 1H), 7.26 (s, 1H), 5.45 (q, 2H, J=20.8Hz), 4.28 (t, 1H, J=5.1Hz), 4.01-4.04 (m, 2H), 3.20 (t, 2H, J=7.5Hz), 2.87-2.93 (m, 1H), 2.76- 2.81 (m, 4H), 2.65 (t, 2H, J=7.6Hz), 2.47-2.52 (m, 1H), 2.19-2.23 (m, 2H), 1.75-1.86 (m, 1H), 1.56-1.58 (m, 1H), 1.29-1.39 (m, 8H), 0.89 (t, 6H, J=7.4Hz) (d) Synthesis of tert-butyl 2-((3-(hydroxymethyl)(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenyl)thio)acetate To a solution of 2-ethylhexyl 3-((5-(methylsulfonyl)((2,2,2- trifluoroacetoxy)methyl)-5,6,7,8-tetrahydronaphthalenyl)thio)propanoate (150.0 mg, 40 0.27 mmol) in DMF (2714.0 µl) was added 1M solution of potassium-t-butoxide in THF (543.0 µl, 0.54 mmol) at -60~-50°C. The reaction mixture was stirred for 10minutes. tert- butyl 2-bromoacetate (42.1 µl, 0.29 mmol) was added at -60~-50°C and the reaction mixture was stirred at room temperature for 1hour. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH3CN: 0.1% formic acid in H O) to obtain tert-butyl 2-((3-(hydroxymethyl)(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenyl)thio)acetate (67.0 mg, 64 %) as a white amorphous.
H-NMR (400MHz, CDCl ): δ 7.60 (s, 1H), 7.26 (s, 1H), 4.77 (q, 2H, J=32.7Hz), 4.27 (t, 1H, J=5.9Hz), 3.60 (s, 2H), 2.83-2.89 (m, 1H), 2.71-2.79 (m, 4H), 2.49-2.55 (m, 1H), 2.15-2.20 (m, 2H), 1.73-1.46 (m, 1H), 1.40 (s, 9H) (e) Synthesis of tert-butyl 2-((3-formyl(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenyl)thio)acetate To a solution of tert-butyl 2-((3-(hydroxymethyl)(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenyl)thio)acetate (65.0 mg, 0.17 mmol) in CH Cl (1682.0 µl) was added Dess-Martin periodinane (107.0 mg, 0.25 mmol). The reaction mixture was stirred at 24°C for 1hour. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO , filtered and concentrated to give tert- butyl 2-((3-formyl(methylsulfonyl)-5,6,7,8-tetrahydronaphthalenyl)thio)acetate (71.0 mg, 110 %) as crude. The crude was used the next step without purification.
H-NMR (400MHz, CDCl3): δ 10.23 (s, 1H), 8.04 (s, 1H), 7.29 (s, 1H), 4.31-4.34 (m, 1H), 3.63 (s, 2H), 2.92-2.99 (m, 1H), 2.80-2.87 (m, 4H), 2.52-2.57 (m, 1H), 2.22-2.25 (m, 2H), 1.77-1.82 (m, 1H), 1.44 (s, 9H) (f) Synthesis of tert-butyl 5-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3- b]thiophenecarboxylate To a solution of tert-butyl 2-((3-formyl(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenyl)thio)acetate (67.0 mg, 0.17 mmol) in DMF (1742.0 µl) was added Cs CO (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 brine, dried over anhydrous Na SO , filtered and concentrated to give tert-butyl 5- (methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxylate (65.0 mg, 102 %) as crude. The crude was used the next step without purification.
H-NMR (400MHz, CDCl ): δ 8.11 (s, 1H), 7.93 (s, 1H), 7.66 (s, 1H), 4.43-4.46 (m, 1H), 3.00-3.08 (m, 1H), 2.90-2.98 (m, 4H), 2.53-2.59 (m, 1H), 2.31-2.35 (m, 1H), 2.17-2.19 (m, 1H), 1.71-1.83 (m, 1H), 1.61 (s, 9H) (g) Synthesis of 5-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophene carboxylic acid To a solution of tert-butyl 5-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3- 40 b]thiophenecarboxylate (65.0 mg, 0.18 mmol) in CH Cl (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 CH CN: 0.1% formic acid in H O) to obtain 5-(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3-b]thiophenecarboxylic acid (30.0 mg, 55 %) as a white amorphous.
LC/MS ESI (-): 309 (M-1) H-NMR (400MHz, DMSO-d ): δ 8.13 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 4.80- 4.82 (m, 1H), 3.05 (s, 3H), 2.91-3.02 (m, 2H), 2.48-2.51 (m, 1H), 2.19-2.23 (m, 2H), 1.67- 1.72 (m, 1H) Intermediate 11) Synthesis of 4-methyl(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylic acid (a) Synthesis of methyl 4-methyl(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate To a suspension of methyl 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate (50.0 mg, 0.15 mmol) in THF (1.0 ml)/CH CN (1.0 ml) was added NaH (30.6 mg, 0.77 mmol). After 1hour, CH I (0.1 ml, 1.53 mmol) was added and the reaction mixture was stirred for 3days. The reaction mixture was purified by reversed- phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 4-methyl(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate (29.0 mg, 56 %) as an off-white amorphous.
LC/MS ESI (+): 341 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.29 (s, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 4.49- 4.56 (m, 1H), 4.20-4.26 (m, 1H), 3.88 (s, 3H), 3.00 (s, 3H), 2.61-2.68 (m, 1H), 2.16-2.23 (m, 1H), 1.83 (s, 3H) (b) Synthesis of 4-methyl(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid To a suspension of methyl 4-methyl(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylate (27.0 mg, 0.08 mmol) in THF (529.0 µl)/H O (264.0 µl) was added LiOHH2O (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 (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 4-methyl(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid (20.0 mg, 77 %) as a white amorphous.
LC/MS ESI (-): 325 (M-1) H-NMR (400MHz, DMSO-d ): δ 8.22 (s, 1H), 7.96 (s, 1H), 7.49 (s, 1H), 4.47- 4.52 (m, 1H), 4.18-4.22 (m, 1H), 2.97 (s, 3H), 2.59-2.67 (m, 1H), 2.13-2.20 (m, 1H), 1.81 40 (s, 3H) Intermediate 12) Synthesis of 5-(methylsulfonyl)-5,8-dihydro-6H-thieno[3,2- g]isochromenecarboxylic acid (a) Synthesis of methyl 2-bromo(bromomethyl)benzoate 2-Bromomethylbenzoate (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 AIBN (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 CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO , and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 2-bromo (bromomethyl)benzoate (3.0 g, 48%) as a colorless liquid.
LC/MS ESI (+): 309 (M+1) H-NMR(400MHz, CDCl ): δ 7.78 (d, 1H, J=8.0Hz), 7.69 (d, 1H, J=1.6Hz), 7.38 (dd, 1H, J=8.0, 1.6Hz), 4.42 (s, 2H), 3.94 (s, 3H) (b) Synthesis of methyl 2-bromo((2,2-diethoxyethoxy)methyl)benzoate Glycolaldehyde diethyl acetal (1.6 ml, 12.14 mmol) was dissolved in anhydrous THF (50.0 ml), and NaH (0.5 g, 13.25 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Methyl 2-bromo(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 Na SO , and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 9 : 1) to obtain methyl 2-bromo((2,2- diethoxyethoxy)methyl)benzoate (1.7 g, 42%) as a colorless liquid.
H-NMR(400MHz, CDCl ): δ 7.78 (d, 1H, J=8.0Hz), 7.66 (d, 1H, J=1.2Hz), 7.31- 7.34 (m, 1H), 4.67 (t, 1H, J=10.4, 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)(methylthio)benzoic acid Methyl 2-bromo((2,2-diethoxyethoxy)methyl)benzoate (480.0 mg, 1.33 mmol) was dissolved in DMF (4.0 ml), and sodium methanethiolate (466 mg, 6.64 mmol) was added at room temperature. The mixture was stirred at 80°C for 15 hours, followed by cooling to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under a 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 H2O) to obtain 4-((2,2- diethoxyethoxy)methyl)(methylthio)benzoic acid (380.0 mg, 91%) as a colorless liquid 40 LC/MS ESI (-): 313 (M-1) H-NMR(400MHz, CDCl ): δ 8.10 (d, 1H, J=8.0Hz), 7.30 (s, 1H), 7.14 (dd, 1H, J=8.0, 0.8Hz), 4.70 (t, 1H, J=10.4, 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=14.0, 6.8Hz) (d) Synthesis of (4-((2,2-diethoxyethoxy)methyl)(methylthio)phenyl)methanol 4-((2,2-diethoxyethoxy)methyl)(methylthio)benzoic acid (380.0 mg, 1.21 mmol) was dissolved in THF (12.0 ml), and 1.0M solution of LiAlH4 in THF (1.2 ml, 1.20 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour and H O was added at 0°C. The reaction mixture was filtered through Celite and extracted with CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO , 2 2 2 4 and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain (4-((2,2-diethoxyethoxy)methyl)(methylthio)phenyl)methanol (280.0 mg, 77%) as a colorless liquid.
H-NMR(400MHz, CDCl ): δ 7.34 (d, 1H, J=8.0Hz), 7.26 (m, 1H), 7.12-7.14 (m, 1H), 4.75 (brs, 2H), 4.66 (t, 1H, J=10.4, 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, 1H), 1.22 (t, 6H, J=14.0, 7.2Hz) (e) Synthesis of (4-(methylsulfonyl)(methylthio)isochromanyl)methanol 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) (methylthio)phenyl)methanol (280.0 mg, 0.93 mmol) in CH Cl (1.5 ml) 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 Na SO and concentrated under a reduced pressure. The mixture was dissolved in THF (4.0 ml)/MeOH (1.0 ml)/H O (1.0 ml) and LiOHH O (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 Na SO , filtered and concentrated to obtain (4-(methylsulfonyl) (methylthio)isochromanyl)methanol (208.0 mg, 77%)%) as a colorless liquid.
LC/MS ESI (-): 287 (M-1) H-NMR(400MHz, CDCl ): δ 7.66 (s, 1H), 6.91 (s, 1H), 4.86-4.91 (m, 2H), 4.70- 4.80 (m, 3H), 3.97-4.01 (m, 1H), 3.87-3.88 (m, 1H), 2.67 (s, 3H), 2.50 (s, 3H) (f) Synthesis of 4-(methylsulfonyl)(methylthio)isochromanecarbaldehyde (4-(Methylsulfonyl)(methylthio)isochromanyl)methanol (208.0 mg, 0.72 mmol) was dissolved in CH Cl (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 CH Cl . The organic extract was washed with brine, dried over 40 anhydrous Na SO and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 1 : 1) to obtain 4- (methylsulfonyl)(methylthio)isochromanecarbaldehyde (150.0 mg, 72%) as a colorless liquid.
LC/MS ESI (+): 287 (M+1) H-NMR(400MHz, CDCl ): δ 10.16 (s, 1H), 8.10 (s, 1H), 7.00 (s, 1H), 4.93-4.97 (m, 2H), 4.80-4.84 (m, 1H), 4.02-4.06 (m, 1H), 3.94-3.95 (m, 1H), 2.69 (s, 3H), 2.48 (s, (g) Synthesis of 5-(methylsulfonyl)-5,8-dihydro-6H-thieno[3,2-g]isochromene carboxylic acid A mixture of 4-(Methylsulfonyl)(methylthio)isochromancarbaldehyde (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 Na SO , and concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 5- (methylsulfonyl)-5,8-dihydro-6H-thieno[3,2-g]isochromenecarboxylic acid (50.0 mg, %) as a white solid.
LC/MS ESI (-): 311 (M-1) H-NMR(400MHz, CDCl3): δ 8.26 (s, 1H), 8.14 (s, 1H), 7.64 (s, 1H), 4.91-5.08 (m, 3H), 4.07-4.11 (m, 2H), 2.66 (s, 3H) Intermediate 13) Synthesis of 4-fluoro(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylic acid (a) Synthesis of 7-chlorofluoromethyl(methylsulfonyl)chromane 7-chloromethyl(methylsulfonyl)chromane (850.0 mg, 3.26 mmol) was dissolved in THF (30.0 mL), and LDA (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 for 3 hours. The reaction was quenched with H O, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO , and concentrated under a reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 85 : 15) to obtain 7-chlorofluoro methyl(methylsulfonyl)chromane (600.0 mg, 66%) as a a white solid H-NMR (400MHz, DMSO-d ): δ 7.53 (s, 1H), 6.97 (s, 1H), 4.59-4.65 (m, 1H), 4.28-4.35 (m, 1H), 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)chlorofluoro(methylsulfonyl)chromane The synthesis procedure of Intermediate 8-c was repeated except for using 7- 40 chlorofluoromethyl(methylsulfonyl)chromane (500.0 mg, 1.79 mmol) to obtain 6- (bromomethyl)chlorofluoro(methylsulfonyl)chromane (520.0 mg, 81%).
H-NMR (400MHz, DMSO-d ): δ 7.75 (s, 1H), 7.01 (s, 1H), 4.67-4.68 (m, 1H), 4.56 (q, 2H, J=10.4, 21.1Hz), 4.35-4.41 (m, 1H), 3.06 (s, 3H), 2.74-2.82 (m, 1H), 2.49- 2.60 (m, 1H) (c) Synthesis of 6-(bromomethyl)chlorofluoro(methylsulfonyl)chromane The synthesis procedure of Intermediate 8-d was repeated except for using 6- (bromomethyl)chlorofluoro(methylsulfonyl)chromane (400.0 mg, 1.11 mmol) to obtain 7-chlorofluoro(methylsulfonyl)chromanecarbaldehyde (225.0 mg, 68%).
LC/MS ESI (+): 293 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.32 (s, 1H), 8.20 (s, 1H), 7.04 (s, 1H), 4.73- 4.80 (m, 1H), 4.49-4.55 (m, 1H), 3.09 (s, 3H), 2.86-2.93 (m, 1H), 2.47-2.59 (m, 1H) (d) Synthesis of 4-fluoro(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid 7-chlorofluoro(methylsulfonyl)chromanecarbaldehyde (210.0 mg, 0.71 mmol) was dissolved in anhydrous DMF (7.1 mL), and methyl 2-mercaptoacetate (114.0 mg, 1.07 mmol) and Cs CO (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 EtOAc. The organic extract 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% formic acid in CH CN: 0.1% formic acid in H O) to obtain 4-fluoro(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylic acid (72.0 mg, 30%) as a yellow solid LC/MS ESI (-): 329 (M-1) H-NMR (400MHz, DMSO-d ): δ 13.47 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.66 (s, 1H), 4.53-4.56 (m, 1H), 4.40-4.44 (m, 2H), 2.95-2.97 (m, 2H), 2.64-2.67 (m, 2H) Intermediate 14) Synthesis of 8,8-difluoro(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3- b]thiophenecarboxylic acid (a) Synthesis of 7-chloromethyl(methylsulfonyl)-3,4-dihydronaphthalen- 1(2H)-one To a solution of 6-chloromethyl(methylsulfonyl)-1,2,3,4- tetrahydronaphthalene (700.0 mg, 2.71 mmol) in acetic anhydride (5114.0 µl, 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 (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 7-chloromethyl(methylsulfonyl)-3,4-dihydronaphthalen-1(2H)-one (430.0 mg, 40 58 %) as a white amorphous.
LC/MS ESI (+): 273 (M+1) H-NMR (400MHz, CDCl ): δ 8.12 (s, 1H), 7.40 (s, 1H), 4.31-4.33 (m, 1H), 3.16- 3.26 (m, 1H), 2.93 (s, 3H), 2.86-2.91 (m, 1H), 2.64-2.71 (m, 1H), 2.51-2.60 (m, 1H), 2.47 (s, 3H) (b) Synthesis of 7-chloro-1,1-difluoromethyl(methylsulfonyl)-1,2,3,4- tetrahydronaphthalene A suspension of 7-chloromethyl(methylsulfonyl)-3,4-dihydronaphthalen- 1(2H)-one (430.0 mg, 1.58 mmol) in DAST (2.0 ml, 15.14 mmol) was stirred at 65°C overnight. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 7-chloro- 1,1-difluoromethyl(methylsulfonyl)-1,2,3,4-tetrahydronaphthalene (186.0 mg, 40 %) as a white amorphous.
LC/MS ESI (-): 293 (M-1) H-NMR (400MHz, CDCl ): δ 7.77 (s, 1H), 7.60 (s, 1H), 4.22-4.26 (m, 1H), 2.77 (s, 3H), 2.65-2.73 (m, 1H), 2.51-2.62 (m, 2H), 2.43 (s, 3H), 2.23-2.35 (m, 1H) (c) Synthesis of 6-(bromomethyl)chloro-1,1-difluoro(methylsulfonyl)- 1,2,3,4-tetrahydronaphthalene To a solution of 7-chloro-1,1-difluoromethyl(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 µl) 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) chloro-1,1-difluoro(methylsulfonyl)-1,2,3,4-tetrahydronaphthalene (105.0 mg, 55 %) as a white amorphous.
LC/MS ESI (-): 371 (M-1) H-NMR (400MHz, CDCl ): δ 7.85 (s, 2H), 4.55-4.64 (m, 2H), 4.25-4.29 (m, 1H), 2.82 (s, 3H), 2.68-2.73 (m, 1H), 2.56-2.59 (m, 2H), 2.27-2.34 (m, 1H) (d) Synthesis of 3-chloro-5,5-difluoro(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenecarbaldehyde A suspension of 6-(bromomethyl)chloro-1,1-difluoro(methylsulfonyl)- 1,2,3,4-tetrahydronaphthalene (105.0 mg, 0.28 mmol), N-methyl morpholine-N-oxide (49.4 mg, 0.42 mmol) and molecular sieve (4Å) in CH CN (2.8 ml) was stirred at 25°C for 1 hour. The reaction mixture was purified by reversed-phase column chromatography (C18- silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 3-chloro-5,5- difluoro(methylsulfonyl)-5,6,7,8-tetrahydronaphthalenecarbaldehyde (60.0 mg, 69 %) as a light brown amorphous. 40 LC/MS ESI (-): 307 (M-1) H-NMR (400MHz, CDCl ): δ 10.49 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 4.30-4.33 (m, 1H), 2.92 (s, 3H), 2.83-2.87 (m, 1H), 2.68-2.75 (m, 1H), 2.47-2.57 (m, 1H), 2.34-2.39 (m, 1H) (e) Synthesis of 8,8-difluoro(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3- b]thiophenecarboxylic acid To a solution of 3-chloro-5,5-difluoro(methylsulfonyl)-5,6,7,8- tetrahydronaphthalenecarbaldehyde (58.0 mg, 0.19 mmol) and Cs CO (122.0 mg, 0.38 mmol) in DMF (939.0 µl) was added methyl thioglycollate (18.5 µl, 0.21 mmol). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to 60°C and LiOHH O (79.0 mg, 1.88 mmol) was added and stirred for 1 hour. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 8,8-difluoro (methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxylic acid (33.0 mg, 51 %) as an off-white amorphous.
LC/MS ESI (-): 345 (M-1) H-NMR (400MHz, DMS-d6): δ 8.48 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 4.89-4.90 (m, 1H), 3.17 (s, 3H), 2.66-2.73 (m, 2H), 2.32-2.42 (m, 2H) Intermediate 15) Synthesis of 4-(1 H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid (a) Synthesis of 3-(3-chloromethylphenoxy)propanoic acid To a solution of 2-chloro(3,3-diethoxypropoxy)methylbenzene (3.0 g, 11.00 mmol) in THF (27.5 ml)/H O (27.5 ml) was added Oxone (10.1 g, 33.00 mmol). The reaction mixture was stirred at 25°C overnight and filtered. The filtrate was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na SO , filtered and concentrated to give 3-(3-chloromethylphenoxy)propanoic acid (2.4 g, 100 %) as a white amorphous.
LC/MS ESI (-): 213 (M-1) H-NMR (400MHz, CDCl ): δ 7.11 (d, 1H, J=8.4Hz), 6.92 (d, 1H, J=2.5Hz), 6.73 (dd, 1H, 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-chloromethylchromanone 3-(3-chloromethylphenoxy)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 Na2SO4, filtered and concentrated. The residue was purified by reversed-phase column chromatography 40 (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 7-chloro- 6-methylchromanone (795.0 mg, 37 %) as a white amorphous.
LC/MS ESI (+): 197 (M+1) H-NMR (400MHz, CDCl ): δ 7.74 (s, 1H), 7.01 (s, 1H), 4.52 (t, 2H, J=6.5Hz), 2.84 (t, 2H, J=6.5Hz), 2.32 (s, 3H) (c) Synthesis of 6-(bromomethyl)chlorochromanone The synthesis procedure of Intermediate 8-c was repeated except for using 7- chloromethylchromanone (950.0 mg, 4.83 mmol) to obtain 6-(bromomethyl) chlorochromanone (1.4 g, 87 % ) as an ivory solid.
LC/MS ESI (+): 275 (M+1) H-NMR (400MHz, CDCl ): δ 7.97 (s, 1H), 7.10 (s, 1H), 4.54-4.58 (m, 4H), 2.82 (t, 2H, J=6.5Hz) (d) Synthesis of 7-chlorooxochromanecarbaldehyde The synthesis procedure of Intermediate 8-d was repeated except for using 6- (bromomethyl)chlorochromanone (1.3 g, 4.72 mmol) to obtain 7-chloro oxochromanecarbaldehyde (660.0 mg, 66%) as a white solid.
LC/MS ESI (+): 211 (M+1) H-NMR (400MHz, CDCl ): δ 10.34 (s, 1H), 8.50 (s, 1H), 7.10 (s, 1H), 4.64 (t, 2H, 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 carboxylate The synthesis procedure of Intermediate 8-d was repeated except for using 7- chlorooxochromanecarbaldehyde (660.0 mg, 3.13 mmol) to obtain 4-oxo-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxylate (580.0 mg, 71%) as an off white solid.
LC/MS ESI (+): 263 (M+1) H-NMR (400MHz, CDCl ): δ 8.49 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 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 carboxylate To a solution of methyl 4-oxo-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate (810.0 mg, 3.09 mmol) in EtOH (15.0 ml) was added NaBH (140.0 mg, 3.71 mmol). The reaction mixture was stirred at 26°C for 2hours. H O 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+1) H-NMR (400MHz, DMSO-d ): δ 8.11 (s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 5.55 (m, 40 1H), 4.75-4.79 (m, 1H), 4.23-4.33 (m, 2H), 3.85 (s, 3H), 2.02-2.09 (m, 1H), 1.88-1.94 (m, (g) Synthesis of methyl 4-chloro-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate To a solution of methyl 4-hydroxy-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate (200.0 mg, 0.76 mmol) in toluene (3784.0 µl) was added SOCl (110.0 µl, 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]chromenecarboxylate (210.0 mg, 98%) as a white amorphous without purification.
H-NMR (400MHz, DMSO-d ): δ 8.13 (s, 1H), 8.02 (s, 1H), 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, 1H) (h) Synthesis of methyl 4-(1H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate A solution of methyl 4-chloro-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate (80.0 mg, 0.28 mmol), pyrazole (57.8 mg, 0.85 mmol) and K CO (117.0 mg, 0.85 mmol) in DMA (2829.0 µl) was stirred at 60°C for 1hour and then stirred at 80°C.
After 1hour, the reaction mixture was stirred at 100°C for 1hour. 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 methyl 4-(1H-pyrazolyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylate (26.0 mg, 29 %) as a white amorphous.
LC/MS ESI (+): 315 (M+1) H-NMR (400MHz, CDCl3): δ 7.87 (s, 1H), 7.61 (d, 1H, J=1.5Hz), 7.51 (s, 1H), 7.37 (s, 1H), 7.22 (d, 1H, J=2.1Hz), 6.25-6.26 (m, 1H), 5.72 (t, 1H, J=5.1Hz), 4.31-4.37 (m, 1H), 4.15-4.21 (m, 1H), 3.92 (s, 3H), 2.56-2.64 (m, 1H), 2.40-2.48 (m, 1H) (i) Synthesis of 4-(1H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylic acid To a suspension of methyl 4-(1H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylate (25.0 mg, 0.08 mmol) in THF (530.0 µl)/H O (265.0 µl) was added LiOHH O (33.4 mg, 0.78 mmol). The reaction mixture was stirred at 60°C for 1hour.
The reaction mixture was cooled to room temperature. 1N-HCl was added and insoluble white solid was filtered to give 4-(1H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxylic acid (17.0 mg, 71%) as a white solid.
LC/MS ESI (-): 299 (M-1) Intermediate 16) Synthesis of 4-(2-oxopyrrolidinyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylic acid 40 To a solution of 2-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]chromenecarboxylate (120.0 mg, 0.42 mmol) was added and stirred for 1hour. The reaction mixture was cooled to 80°C.
LiOHH2O (53.4 mg, 1.27 mmol) was added and stirred for 1hour. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 4-(2-oxopyrrolidinyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxylic acid (13.0 mg, 10 %) as a white amorphous.
LC/MS ESI (+): 318 (M+1) H-NMR (400MHz, DMS-d6): δ 7.93 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 5.41-5.45 (m, 1H), 4.27-4.40 (m, 2H), 3.23-3.32 (m, 1H), 2.95-3.01 (m, 1H), 2.36-2.43 (m, 2H), 2.10-2.19 (m, 1H), 1.90-2.01 (m, 3H) 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 carboxylate Methyl 4-hydroxy-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (210.0 mg, 0.79 mmol) was dissolved in CH Cl (3.9 mL), and PBr (323.0 mg, 1.19 mmol) was 2 2 3 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]chromenecarboxylate (250.0 mg. 95%).
H-NMR (400MHz, DMSO-d ): δ 8.18 (s, 1H), 8.07 (s, 1H), 7.54 (s, 1H), 6.05- 6.06 (m, 1H), 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 carboxylate Methyl 4-bromo-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (300.0 mg, 0.91 mmol) was dissolved in DMA (9.1 mL), and NaCN (90.0 mg, 1.83 mmol) was added 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 Na SO , filtered and concentrated under a reduced pressure. The residue was purified by reversed- phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate (39.0 mg, 15%) as an off-white solid.
LC/MS ESI (+): 274 (M+1) H-NMR (400MHz, DMSO-d ): δ 8.17 (s, 1H), 8.03 (s, 1H), 7.56 (s, 1H), 4.68 (t, 1H, J=6.0Hz), 4.31 (t, 2H, J=5.2Hz), 3.87 (s, 3H), 2.29-2.39 (m, 2H) 40 (c) Synthesis of 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylic acid Methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (39.0 mg, 0.14 mmol) was dissolved in THF/H O (1.5 mL, 3/1 v/v), and LiOH·H O (17.9 mg, 0.43 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was concentrated under a reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain methyl 4-cyano-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (17.0 mg, 46%) as a white solid.
LC/MS ESI (+): 260 (M+1) H-NMR (400MHz, DMSO-d ): δ 13.3 (br, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 4.60 (t, 1H, J=6.0Hz), 4.22 (t, 2H, J=5.2 Hz), 2.20-2.26 (m, 2H) Intermediate 18) Synthesis of 4-azido-3,4-dihydro-2H-thieno[3,2- g]chromene- 7-carboxylic acid (a) Synthesis of methyl 4-azido-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylate Methyl 4-bromo-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (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 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]chromenecarboxylate (50.0 mg, 60%) as a white solid.
LC/MS ESI (+): 290 (M+1) H-NMR (400MHz, CDCl ): δ 7.97 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 4.77 (t, 1H, 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]chromenecarboxylic acid Methyl 4-azido-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxylate (15.0 mg, 0.05 mmol) was dissolved in THF/H O (0.5 mL, 3/1 v/v), and LiOH·H O (21.7 mg, 0.52 mmol) was added. The reaction mixture was stirred at 60°C for 15 hours, 1N HCl (3.0 mL) was added, and extracted with CH Cl . The organic extract was washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure to obtain 4-azido-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxylic acid (10.0 mg, 70%) as an off-white solid.
LC/MS ESI (-): 274 (M-1) Example 1) Synthesis of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2- b][1,4]oxazine carboxamide (a) Synthesis of 2-chloro(4-chlorophenoxy)pyridinamine 2,6-Dichloropyridineamine (3.0 g, 18.40 mmol) and 4-chlorophenol (4.7 g, 36.80 mmol) were dissolved in sulfolane (96.0 mL) and K CO (5.1 g, 36.80 mmol) was added. The reaction mixture was stirred at 160°C for 24 hours, cooled to room temperature, H O was added, and extracted with EtOAc. The organic extract was washed with 1N NaOH aqueous solution and brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain 2-chloro(4-chlorophenoxy)pyridinamine (2.5 g, 53%) as a white solid.
LC/MS ESI (+): 255 (M+1) H-NMR (400MHz, DMSO-d ): δ 7.45 (d, 2H, J=8.8Hz), 7.12 (d, 2H, J=8.8Hz), 6.55 (brs, 2H), 6.31 (d, 1H, J=1.6Hz), 5.93 (d, 1H, J=1.6Hz) (b) Synthesis of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide 1-(Methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine carboxylic acid (190.0 mg, 0.61 mmol) was dissolved in CH Cl (6.1 mL), and DMF (1.2 μL, 0.01 mmol) and (COCl) (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- (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarbonyl chloride. To the residue, 2-chloro(4-chlorophenoxy)pyridinamine (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 15 hours and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide (166.0 mg, 50%) as a white solid.
LC/MS ESI (+): 550 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.87 (brs, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.58 (s, 2H), 7.45 (dd, 2H, J=8.8, 2.1Hz), 7.22 (s, 1H), 7.18 (dd, 2H, J=8.8, 2.1Hz), 4.29 (t, 2H, J=4.9Hz), 3.82 (t, 2H, J=4.6Hz), 3.11 (s, 3H) 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 LC/MS ESI (+): 578 (M+1) N-(2-chloro(4-chlorophenoxy)pyridin- H-NMR(400MHz, DMSO-d ): δ 10.94 (s, 4-yl)-3,3-dimethyl(methylsulfonyl)- 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.67 (s, 1H), 2 2,3-dihydro-1H- 7.58 (s, 1H), 7.53 (d, 2H, J=8.8Hz), 7.31 (s, thieno[3',2':4,5]benzo[1,2-b][1,4]oxazine- 1H), 7.25 (d, 2H, J=8.8Hz), 3.68 (s, 2H), 3.38 7-carboxamide (s, 3H), 1.36 (s, 6H) LC/MS ESI (+): 564 (M+1) H-NMR(400MHz, DMSO-d ): δ 11.10 (s, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 4-yl)(methylsulfonyl)-1,2,3,4- 3 7.70 (d, 1H, J=1.2Hz), 7.55 (d, 2H, J=8.8Hz), tetrahydrothieno[3',2':4,5]benzo[1,2- 7.33 (s, 1H, J=1.2Hz), 7.29 (d, 2H, J=8.8Hz), b][1,4]oxazepinecarboxamide 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+1) H-NMR(400MHz, DMSO-d ): δ 10.98 (s, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 4-yl)-8,8-dimethyl(methylsulfonyl)- 4 7.67 (s, 1H), 7.53 (d, 2H, J=8.7Hz), 7.32 (s, ,6,7,8-tetrahydrothieno[2,3-g]quinoline- 1H), 7.26 (d, 2H, J=8.7Hz), 3.79 (t, 2H, 2-carboxamide J=5.7Hz), 3.12 (s, 3H), 1.85 (t, 2H, J=5.7Hz), 1.37 (s, 6H) LC/MS ESI (+): 679 (M+1) tert-butyl 7-((2-chloro(4- H-NMR (400MHz, DMSO-d ): δ 10.93 (brs, chlorophenoxy)pyridinyl)carbamoyl)- 1H), 8.35 (s, 1H), 8.24 (s, 1H), 8.03 (d, 1H, 1-(methylsulfonyl)-2,3- J=8.7Hz), 7.60 (d, 1H, J=1.3Hz), 7.47 (d, 2H, dihydrothieno[2,3-g]quinoxaline-4(1H)- J=8.8Hz), 7.24 (d, 1H, J=1.3 Hz), 7.19 (d, 2H, carboxylate 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+1) H-NMR (400MHz, DMSO-d ): δ 10.98 (s, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 4-yl)(methylsulfonyl)-5,6,7,8- 6 7.66 (s, 1H), 7.53 (d, 2H, J=8.8Hz), 7.28 (s, tetrahydrothieno[2,3-g]quinoline 1H), 7.26 (d, 2H, J=8.8Hz), 3.75 (t, 2H, carboxamide J=6.3Hz ), 3.06 (s, 3H), 2.93 (t, 2H, J=6.5Hz), 1.95-1.99 (m, 2H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.81 (brs, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7 4-yl)methyl(methylsulfonyl)- 7.55 (d, 2H, J=8.7Hz), 7.33 (s, 1H), 7.32 (s, 1,2,3,4-tetrahydrothieno[2,3- 1H), 7.28 (d, 2H, J=8.7Hz), 3.79 (t, 2H, g]quinoxalinecarboxamide J=5.3Hz ), 3.53 (t, 2H, J=5.3Hz ), 3.04 (d, 6H, J=2.6Hz) N-(2-chloro(4-chlorophenoxy)pyridin- LC/MS ESI (+): 549 (M+1). 4-yl)(methylsulfonyl)-3,4-dihydro-2H- H-NMR (400MHz, DMSO-d ): δ 10.94 (s, thieno[3,2-g]chromenecarboxamide 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.67 (d, 1H, J=1.1Hz), 7.59 (s, 1H), 7.53 (d, 2H, J=8.9Hz), 7.31 (d, 1H, J=1.1Hz), 7.27 (d, 2H, J=8.9Hz), 4.82 (m, 1H), 4.46-4.53 (m, 1H), 4.31-4.36 (m, 1H), 3.18 (s, 3H), 2.53-2.69 (m, 1H), 2.29-2.40 (m, 1H).
LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.90 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.69 (s, 1H), N-(2-chloro(4-chlorophenoxy)pyridin- 7.59 (d, 1H, J=1.4Hz), 7.44-7.48 (m, 2H), 4-yl)(methylsulfonyl)-2,3,4,5- 9 7.25 (s, 1H), 7.17-7.21 (m, 2H), 4.78 (t, 1H, tetrahydrothieno[3',2':4,5]benzo[1,2- J=5.4Hz), 4.29-4.34 (m, 1H), 3.68-3.73 (m, b]oxepinecarboxamide 1H), 2.81 (s, 3H), 2.25-2.50 (m, 1H), 2.16- 2.19 (m, 1H), 2.04-2.04 (m, 1H), 1.70-1.74 (m, 1H) LC/MS ESI (+): 547 (M+1) H-NMR (400MHz, DMSO-d ): δ 11.0 (s, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 4-yl)(methylsulfonyl)-5,6,7,8- 7.66 (d, 1H, J=1.3Hz), 7.53 (d, 2H, J=8.9Hz), tetrahydronaphtho[2,3-b]thiophene 7.31 (d, 1H, J=1.3Hz), 7.26 (d, 2H, J=8.9Hz), carboxamide 4.76-4.79 (m, 1H), 3.01 (s, 3H), 2.82-2.94 (m, 2H), 2.43-2.46 (m, 1H), 2.14-2.20 (m, 2H), 1.62-1.66 (m, 1H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.94 (brs, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.65 (s, 1H), 4-yl)methyl(methylsulfonyl)-3,4- 11 7.57 (s, 1H), 7.52 (d, 2H, J=8.5Hz), 7.30 (s, dihydro-2H-thieno[3,2-g]chromene 1H), 7.25 (d, 2H, J=8.3Hz), 4.49-4.54 (m, carboxamide 1H), 4.20-4.24 (m, 1H), 2.98 (s, 3H), 2.62 (m, 1H), 2.15-2.22 (m, 1H), 1.84 (s, 3H) LC/MS ESI (+): 549 (M+1) H-NMR(400MHz, DMSO-d ):δ 10.96 (brs, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), N-(2-chloro(4-chlorophenoxy)pyridin- 7.60 (d, 1H, J=1.2Hz), 7.45-7.47 (m, 2H), 12 4-yl)(methylsulfonyl)-5,8-dihydro-6H- 7.25 (d, 1H, J=0.8Hz), 7.18-7.22 (m, 2H), thieno[3,2-g]isochromenecarboxamide 4.96 (d, 1H, J=15.6Hz), 4.82 (d, 1H, J=15.6Hz), 4.60 (d, 1H, J=12.8Hz), 4.48 (s, 1H), 4.03 (dd, 1H, J=12.8, 3.6Hz), 2.63 (s, LC/MS ESI (+): 567 (M+1) N-(2-chloro(4-chlorophenoxy)pyridin- H-NMR (400MHz, DMSO-d ): 4-yl)fluoro(methylsulfonyl)-3,4- 13 δ 10.92 (brs, 1H), 8.27 (s, 1H), 8.24 (s, 1H), dihydro-2H-thieno[3,2-g]chromene 7.64 (s, 1H), 7.58 (s, 1H), 7.46 (d, 2H, carboxamide J=8.8Hz), 7.21 (s, 1H), 7.18 (d, 2H, J=8.8Hz), 4.46-4.52 (m, 1H), 4.33-4.38 (m, 1H), 2.93 (s, 3H), 2.87-2.93 (m, 1H), 2.60-2.67 (m, 1H) LC/MS ESI (-): 581 (M-1) H-NMR (400MHz, DMSO-d6): δ 11.13 (s, N-(2-chloro(4-chlorophenoxy)pyridin- 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 4-yl)-8,8-difluoro(methylsulfonyl)- 14 7.67 (d, 1H, J=1.1Hz), 7.52 (d, 2H, J=8.9Hz), ,6,7,8-tetrahydronaphtho[2,3- 7.31 (d, 1H, J=0.7Hz), 7.26 (d, 2H, J=8.9Hz), b]thiophenecarboxamide 4.91 (m, 1H), 3.19 (s, 3H), 2.80-2.90 (m, 1H), 2.70-2.75 (m, 1H), 2.36-2.45 (m, 2H) Example 15) Synthesis of N-(2-chloro( p-tolyloxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxamide (a) Synthesis of 2-chloro(p-tolyloxy)pyridinamine To a solution of 2,6-dichloropyridinamine (200.0 mg, 1.23 mmol) in sulfolane (4090.0 µl) were added p-cresol (265.0 mg, 2.45 mmol) and K CO (339.0 mg, 2.45 mmol).
The reaction mixture was stirred at 160°C for 30 hours. The reaction mixture was extracted with EtOAc. The organic extract was washed with 1N-NaOH and brine, dried over anhydrous Na SO , filtered and concentrated. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) and solidification with ACN/ether/Hex to obtain 2-chloro(p-tolyloxy)pyridin amine (160.0 mg, 56 %) as a light brown amorphous.
H-NMR (400MHz, CDCl ): δ 7.17 (d, 2H, J=8.2Hz), 7.00 (d, 2H, J=8.5Hz), 6.30 (d, 1H, J=1.7Hz), 5.81 (d, 1H, J=1.7Hz), 4.22 (brs, 2H), 2.35 (s, 3H) (b) Synthesis of N-(2-chloro(p-tolyloxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide The synthesis procedure of Example 1-b was repeated except for using 2-chloro (p-tolyloxy)pyridinamine (41.3 mg, 0.18 mmol) to obtain N-(2-chloro(p- tolyloxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene carboxamide (51.0 mg, 60 %) as a white amorphous.
LC/MS ESI (+): 529 (M+1) H-NMR (400MHz, DMSO-d6): δ 10.89 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.64 (d, 1H, J=1.4Hz), 7.58 (s, 1H), 7.27 (d, 2H, J=8.3Hz), 7.21 (d, 1H, J=1.4Hz), 7.08 (d, 2H, J=8.4Hz), 4.81 (m, 1H), 4.44-4.51 (m, 1H), 4.29-4.34 (m, 1H), 3.16 (s, 3H), 2.59-2.67 (m, 1H), 2.32-2.34 (m, 4H) 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] Ex. Compound Analysis data LC/MS ESI (+): 583 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.97 (s, N-(2-chloro(3- 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.65-7.74 (m, (trifluoromethyl)phenoxy)pyridinyl)- 16 4H), 7.55-7.59 (m, 2H), 7.40 (d, 1H, 4-(methylsulfonyl)-3,4-dihydro-2H- J=1.2Hz), 4.81-4.84 (m, 1H), 4.49-4.53 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.31-4.34 (m, 1H), 3.17 (s, 3H), 2.60- 2.68 (m, 1H), 2.35-2.36 (m, 1H) LC/MS ESI (+): 583 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.98 (s, N-(2-chloro(4- 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.85 (d, 2H, (trifluoromethyl)phenoxy)pyridinyl)- 17 J=8.6Hz), 7.71 (s, 1H), 7.59 (s, 1H), 7.41-7.45 4-(methylsulfonyl)-3,4-dihydro-2H- (m, 3H), 4.82-4.83 (m, 1H), 4.49-4.52 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.31-4.35 (m, 1H), 3.17 (s, 3H), 2.60- 2.65 (m, 1H), 2.36-2.39 (m, 1H) LC/MS ESI (+): 583 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.98 (s, N-(2-chloro(3,5- 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.70 (d, 2H, dichlorophenoxy)pyridinyl) J=1.2Hz), 7.59 (s, 1H), 7.56 (t, 1H, J=2.0Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.44 (d, 2H, J=2.0Hz), 7.37 (s, 1H), 4.82-4.84 thieno[3,2-g]chromenecarboxamide (m, 1H), 4.46-4.52 (m, 1H), 4.32-4.35 (m, 1H), 3.17 (s, 3H), 2.60-2.65 (m, 1H), 2.36- 2.39 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.96 (s, N-(2-chloro(4-chloro 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.67-7.69 (m, fluorophenoxy)pyridinyl) 2H), 7.58 (s, 1H), 7.47 (d, 1H, J=10.3Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.35 (s, 1H), 7.15 (d, 1H, J=10.3Hz), 4.83- thieno[3,2-g]chromenecarboxamide 4.85 (m, 1H), 4.49-4.52 (m, 1H), 4.30-4.34 (m, 1H), 3.17 (s, 3H), 2.60-2.65 (m, 1H), 2.36- 2.39 (m, 1H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): 10.92 (brs, N-(2-chloro(4-chloro 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), methylphenoxy)pyridinyl) 7.58 (s, 1H), 7.50 (d, 1H, J=8.7Hz), 7.25-7.26 (methylsulfonyl)-3,4-dihydro-2H- (m, 2H), 7.09 (dd, 1H, J=8.6, 2.8Hz), 4.82 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.45-4.51 (m, 1H), 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.32-2.35 (m, LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): 10.92 (s, 1H), N-(2-chloro(4-chloro 8.30 (s, 1H), 8.06 (s, 1H), 7.64 (m, 1H), 7.58 methylphenoxy)pyridinyl) (s, 1H), 7.47 (m, 1H), 7.35 (dd, 1H, J=8.6, (methylsulfonyl)-3,4-dihydro-2H- 2.6Hz), 7.26 (m, 1H), 7.19 (d, 1H, J=8.6Hz), thieno[3,2-g]chromenecarboxamide 4.81 (m, 1H), 4.45-4.51 (m, 1H), 4.30-4.34 (m, 1H), 3.19 (s, 3H), 2.60-2.67 (m, 1H), 2.32- 2.36 (m, 1H), 2.12 (s, 3H) LC/MS ESI (+): 545 (M+1) H-NMR (400MHz, DMSO-d6): δ 10.88 (s, N-(2-chloro(4- 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.63 (d, 1H, methoxyphenoxy)pyridinyl) J=1.2Hz), 7.58 (s, 1H), 7.19 (d, 1H, 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]chromenecarboxamide 4.81 (m, 1H), 4.44-4.51 (m, 1H), 4.29-4.34 (m, 1H), 3.79 (s, 3H), 3.16 (s, 3H), 2.59-2.67 (m, 1H), 2.30-2.39 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.90 (brs, N-(2-chloro(4-chloro 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.62 (dd, 1H, fluorophenoxy)pyridinyl) 23 J=10.4, 2.4Hz), 7.57 (s, 1H), 7.51 (s, 1H), (methylsulfonyl)-3,4-dihydro-2H- 7.30-7.41 (m, 3H), 4.73-4.75 (m, 1H), 4.38- thieno[3,2-g]chromenecarboxamide 4.45 (m, 1H), 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.61 (m, 1H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 585 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.88 (brs, N-(2-chloro(3,4- 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.65 (d, 1H, dichlorophenoxy)pyridinyl) J=8.8Hz), 7.60 (s, 1H), 7.57 (d, 1H, J=2.7Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.51 (s, 1H), 7.27 (s, 1H), 7.20 (dd, 1H, J=8.8, thieno[3,2-g]chromenecarboxamide 2.7Hz), 4.73-4.75 (m, 1H), 4.38-4.45 (m, 1H), 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.60 (m, 1H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 549 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.87 (brs, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.60 (s, 1H), N-(2-chloro(3-chlorophenoxy)pyridin- 7.51 (s, 1H), 7.43 (t, 1H, J=8.1Hz), 7.28-7.31 4-yl)(methylsulfonyl)-3,4-dihydro-2H- (m, 2H), 7.26 (d, 1H, J=1.3Hz), 7.12-7.15 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.73-4.75 (m, 1H), 4.38-4.45 (m, 1H), 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.60 (m, 1H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 533 (M+1) N-(2-chloro(4-fluorophenoxy)pyridin- H-NMR (400MHz, DMSO-d ): δ 10.84 (brs, 26 4-yl)(methylsulfonyl)-3,4-dihydro-2H- 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.57 (s, 1H), thieno[3,2-g]chromenecarboxamide 7.51 (s, 1H), 7.18-7.26 (m, 5H), 4.74-4.76 (m, 1H), 4.38-4.44 (m, 1H), 4.24-4.26 (m, 1H), 3.09 (s, 3H), 2.53-2.60 (m, 1H), 2.27- 2.32 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.87 (brs, N-(2-chloro(3-chloro 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.59 (d, 1H, fluorophenoxy)pyridinyl) 27 J=0.8Hz), 7.44-7.53 (m, 3H), 7.19-7.24 (m, (methylsulfonyl)-3,4-dihydro-2H- 2H), 4.74-4.75 (m, 1H), 4.38-4.45 (m, 1H), thieno[3,2-g]chromenecarboxamide 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.57 (m, 1H), 2.24-2.32 (m, 1H) LC/MS ESI (+): 599 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.95 (brs, N-(2-chloro(4- 1H), 8.28 (brs, 1H), 8.06 (s, 1H), 7.66 (s, 1H), (trifluoromethoxy)phenoxy)pyridinyl)- 28 7.57 (s, 1H), 7.47 (d, 2H, J=8.8Hz), 7.33-7.36 4-(methylsulfonyl)-3,4-dihydro-2H- (m, 3H), 4.81-4.82 (m, 1H), 4.45-4.52 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.29-4.34 (m, 1H), 3.16 (s, 3H), 2.60- 2.64 (m, 1H), 2.31-2.39 (m, 1H) LC/MS ESI (+): 599 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.96 (brs, N-(2-chloro(3- 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.67 (d, 1H, (trifluoromethoxy)phenoxy)pyridinyl)- J=1.2Hz), 7.58-7.62 (m, 2H), 7.37 (d, 1H, 4-(methylsulfonyl)-3,4-dihydro-2H- J=0.8Hz), 7.26-7.32 (m, 3H), 4.81-4.82 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.45-4.52 (m, 1H), 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.30-2.39 (m, LC/MS ESI (+): 580 (M+1) H-NMR (400MHz, DMSO-d6): δ 10.87 (brs, N-(2-chloro(3-chloro 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H), methoxyphenoxy)pyridinyl) 7.50 (s, 1H), 7.22 (s, 1H), 6.89-6.90 (m, 1H), (methylsulfonyl)-3,4-dihydro-2H- 6.85-6.86 (m, 1H), 6.74-6.75 (m, 1H), 4.74- thieno[3,2-g]chromenecarboxamide 4.75 (m, 1H), 4.38-4.43 (m, 1H), 4.23-4.27 (m, 1H), 3.75 (s, 3H), 3.09 (s, 3H), 2.53-2.57 (m, 1H), 2.29-2.32 (m, 1H) LC/MS ESI (+): 566 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.90 (brs, N-(2-chloro(3-chloro 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), fluorophenoxy)pyridinyl) 7.51 (s, 1H), 7.31-7.32 (m, 1H), 7.30 (s, 1H), (methylsulfonyl)-3,4-dihydro-2H- 7.20 (s, 1H), 7.16-7.19 (m, 1H), 4.74-4.75 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.38-4.43 (m, 1H), 4.23-4.27 (m, 1H), 3.09 (s, 3H), 2.53-2.57 (m, 1H), 2.29-2.32 (m, N-(2-chloro(3-fluoro LC/MS ESI (+): 563 (M+1) 32 methoxyphenoxy)pyridinyl) H-NMR (400MHz, DMSO-d ): δ 10.86 (brs, (methylsulfonyl)-3,4-dihydro-2H- 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H), thieno[3,2-g]chromenecarboxamide 7.50 (s, 1H), 7.22 (s, 1H), 6.64-6.72 (m, 2H), 6.61 (s, 1H), 4.74-4.76 (m, 1H), 4.38-4.44 (m, 1H), 4.24-4.26 (m, 1H), 3.72 (s, 3H), 3.09 (s, 3H), 2.53-2.60 (m, 1H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 529 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.83 (brs, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), N-(2-chloro(m-tolyloxy)pyridinyl)- 7.50 (s, 1H), 7.28 (t, 1H, J=7.7Hz), 7.15 (s, 33 4-(methylsulfonyl)-3,4-dihydro-2H- 1H), 7.03 (d, 1H, J=7.6Hz), 6.95 (s, 1H), 6.91- thieno[3,2-g]chromenecarboxamide 6.93 (m, 1H), 4.74-4.76 (m, 1H), 4.38-4.44 (m, 1H), 4.24-4.26 (m, 1H), 3.09 (s, 3H), 2.53- 2.60 (m, 1H), 2.27 (s, 3H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 551 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.94 (brs, N-(2-chloro(3,4- 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), difluorophenoxy)pyridinyl) 34 7.47-7.58 (m, 3H), 7.31 (s, 1H), 7.10-7.14 (m, (methylsulfonyl)-3,4-dihydro-2H- 1H), 4.81-4.82 (m, 1H), 4.45-4.51 (m, 1H), thieno[3,2-g]chromenecarboxamide 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.30-2.39 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): 10.99 (brs, N-(2-chloro(5-chloro 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), fluorophenoxy)pyridinyl) 7.62 (dd, 1H, J=6.9, 2.6Hz), 7.59 (s, 1H), (methylsulfonyl)-3,4-dihydro-2H- 7.47-7.52 (m, 1H), 7.41-7.45 (m, 2H), 4.82 thieno[3,2-g]chromenecarboxamide (m, 1H), 4.45-4.49 (m, 1H), 4.31-4.35 (m, 1H), 3.17 (s, 3H), 2.60-2.64 (m, 1H), 2.35- 2.39 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): 11.00 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.66 (d, 1H, N-(2-chloro(3-chloro J=1.2Hz), 7.59 (s, 1H), 7.55 (td, 1H, J=8.4, fluorophenoxy)pyridinyl) 36 1.6Hz), 7.47 (s, 1H), 7.15 (td, 1H, J=9.2, (methylsulfonyl)-3,4-dihydro-2H- 1.6Hz), 7.34 (td, 1H, J=8.4, 2.8Hz), 4.82-4.83 thieno[3,2-g]chromenecarboxamide (m, 1H), 4.49-4.53 (m,1H), 4.32-4.35 (m, 1H), 3.17 (s, 3H), 2.60-2.65 (m, 1H), 2.36-2.39 (m, LC/MS ESI (+): 561 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.92 (s, N-(2-chloro(5-chloro 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.64 (d, 1H, methylphenoxy)pyridinyl) 37 J=1.2Hz), 7.58 (s, 1H), 7.40 (d, 1H, J=7.8Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.28 (m, 3H), 4.81 (m, 1H), 4.44-4.52 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.59- 2.64 (m, 1H), 2.34-2.39 (m, 1H), 2.11 (s, 3H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.86 (brs, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.59 (s, 1H), N-(2-chloro(3-chloro 7.51 (s, 1H), 7.38 (d, 1H, J=8.3Hz), 7.29 (s, methylphenoxy)pyridinyl) 38 1H), 7.20 (s, 1H), 7.05 (d, 1H, J=8.3Hz), 4.74- (methylsulfonyl)-3,4-dihydro-2H- 4.76 (m, 1H), 4.38-4.44 (m, 1H), 4.24-4.26 thieno[3,2-g]chromenecarboxamide (m, 1H), 3.09 (s, 3H), 2.53-2.60 (m, 1H), 2.30 (s, 3H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 583 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.90 (brs, N-(2-chloro(2- 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.78 (d, 1H, (trifluoromethyl)phenoxy)pyridinyl)- J=7.8Hz), 7.72 (t, 1H, J=7.8Hz), 7.59 (s, 1H), 4-(methylsulfonyl)-3,4-dihydro-2H- 7.51 (s, 1H), 7.38-7.44 (m, 2H), 7.33 (s, 1H), thieno[3,2-g]chromenecarboxamide 4.74-4.76 (m, 1H), 4.38-4.44 (m, 1H), 4.24- 4.26 (m, 1H), 3.09 (s, 3H), 2.53-2.57 (m, 1H), 2.27-2.32 (m, 1H) LC/MS ESI (+): 599 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.91 (brs, N-(2-chloro(2- 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), (trifluoromethoxy)phenoxy)pyridinyl)- 40 7.51 (s, 1H), 7.33-7.50 (m, 5H), 4.74-4.75 (m, 4-(methylsulfonyl)-3,4-dihydro-2H- 1H), 4.38-4.43 (m, 1H), 4.23-4.27 (m, 1H), thieno[3,2-g]chromenecarboxamide 3.09 (s, 3H), 2.53-2.57 (m, 1H), 2.27-2.32 (m, LC/MS ESI (+): 547 (M+1) H-NMR (400MHz, DMSO-d6): δ 10.94 (s, N-(2-chloro(2-fluoro 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.64 (d, 1H, methylphenoxy)pyridinyl) J=1.3Hz), 7.58 (s, 1H), 7.36 (d, 1H, J=1.1Hz), (methylsulfonyl)-3,4-dihydro-2H- 7.14-7.24 (m, 3H), 4.81 (m, 1H), 4.44-4.52 thieno[3,2-g]chromenecarboxamide (m, 1H), 4.30-4.34 (m, 1H), 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) H-NMR (400MHz, DMSO-d ): δ 10.81 (brs, N-(2-chloro(4-chloro 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.53 (s, 1H), methoxyphenoxy)pyridinyl) 7.50 (s, 1H), 7.22 (d, 1H, J=2.3Hz), 7.17 (d, (methylsulfonyl)-3,4-dihydro-2H- 1H, J=8.4Hz), 7.14 (s, 1H), 7.01 (dd, 1H, thieno[3,2-g]chromenecarboxamide J=8.4, 2.3Hz), 4.73-4.74 (m, 1H), 4.38-4.44 (m, 1H), 4.23-4.27 (m, 1H), 3.69 (s, 3H), 3.09 (s, 3H), 2.52-2.57 (m, 1H), 2.20-2.27 (m, 1H) Examples 43 and 44) Separation of ( S)- N-(2-chloro(4- chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxamide and ( R)- N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxamide from rac- N- (2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2- g]chromenecarboxamide The racemate of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide (100.0 mg, 0.18 mmol) obtained in Example 8 was separated by preparative HPLC (Daicel Chiralpak IA, dichloromethane/ethanol=98/2, 10.0mL/min, 254nm, 35°C) into (S)-N-(2-chloro(4- chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene- 7-carboxamide (45.0 mg, 45%) and (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide (44.0 mg, 44%).
Example 43) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide LC/MS ESI (+): 549 (M+1).
H-NMR (400MHz, DMSO-d ): 10.96 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.52 (d, 2H, J=8.80Hz), 7.31 (s, 1H), 7.27 (d, 2H, J=8.80Hz), 4.82 (m, 1H), 4.45-4.51 (m, 1H), 4.30-4.34 (m, 1H), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.29-2.39 (m, 1H).
HPLC: Daicel Chiralpak IA, 0.46 cm I.D. x 15 cm L, dichloromethane/ethanol=98/2, 1.0mL/min, 254nm, 35 C, t = 3.08 min.
Example 44) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide LC/MS ESI (+): 549 (M+1).
H-NMR (400MHz, DMSO-d ): 11.03 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.52 (d, 2H, J=8.79Hz), 7.31 (s, 1H), 7.26 (d, 2H, J=8.79Hz), 4.82 (m, 1H), 4.45-4.51 (m, 1H), 4.30-4.33 (m, 1H), 3.16 (s, 3H), 2.60-2.64 (m, 1H), 2.30-2.39 (m, 1H).
HPLC: Daicel Chiralpak IA, 0.46 cm I.D. x 15 cm L, dichloromethane/ethanol=98/2, 1.0mL/min, 254nm, 35 C, t = 3.95 min.
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.
[Table 4] Ex. Compound Analysis data LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.97 (brs, (S)-N-(2-chloro(4- 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.63 (s, 1H), chlorophenoxy)pyridinyl)fluoro 45 7.58 (s, 1H), 7.45 (d, 2H, J=8.7Hz), 7.22 (s, (methylsulfonyl)-3,4-dihydro-2H- 1H), 7.19 (d, 2H, J=8.7Hz), 4.46-4.53 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.32-4.36 (m, 1H), 3.24 (s, 3H), 2.87- 2.94 (m, 1H), 2.61-2.71 (m, 1H) LC/MS ESI (+): 567 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.91 (brs, (R)-N-(2-chloro(4- 1H), 8.26 (s, 1H), 8.23 (s, 1H), 7.63 (s, 1H), chlorophenoxy)pyridinyl)fluoro 46 7.57 (s, 1H), 7.46 (d, 2H, J=8.7Hz), 7.21 (s, (methylsulfonyl)-3,4-dihydro-2H- 1H), 7.19 (d, 2H, J=8.7Hz), 4.46-4.49 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.31-4.37 (m, 1H), 3.24 (s, 3H), 2.86- 2.90 (m, 1H), 2.64-2.70 (m, 1H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.94 (brs, (S)-N-(2-chloro(4- 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.65 (s, 1H), chlorophenoxy)pyridinyl)methyl 47 7.57 (s, 1H), 7.52 (d, 2H, J=8.5Hz), 7.30 (s, (methylsulfonyl)-3,4-dihydro-2H- 1H), 7.25 (d, 2H, J=8.3Hz), 4.49-4.54 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.20-4.24 (m, 1H), 2.98 (s, 3H), 2.62 (m, 1H), 2.15-2.22 (m, 1H), 1.84 (s, 3H) LC/MS ESI (+): 563 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.94 (brs, (R)-N-(2-chloro(4- 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.65 (s, 1H), chlorophenoxy)pyridinyl)methyl 48 7.57 (s, 1H), 7.52 (d, 2H, J=8.5Hz), 7.30 (s, (methylsulfonyl)-3,4-dihydro-2H- 1H), 7.25 (d, 2H, J=8.3Hz), 4.49-4.54 (m, thieno[3,2-g]chromenecarboxamide 1H), 4.20-4.24 (m, 1H), 2.98 (s, 3H), 2.62 (m, 1H), 2.15-2.22 (m, 1H), 1.84 (s, 3H) LC/MS ESI (+): 580 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.86 (brs, (S)-N-(2-chloro(3-chloro 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.62 (s, 1H), methoxyphenoxy)pyridinyl) 7.51 (s, 1H), 7.22 (s, 1H), 6.89-6.90 (m, 1H), (methylsulfonyl)-3,4-dihydro-2H- 6.85-6.86 (m, 1H), 6.74-6.76 (m, 1H), 4.74- thieno[3,2-g]chromenecarboxamide 4.75 (m, 1H), 4.39-4.44 (m, 1H), 4.23-4.27 (m, 1H), 3.73 (s, 3H), 3.09 (s, 3H), 2.52-2.57 (m, 1H), 2.28-2.32 (m, 1H) Examples 50) Synthesis of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxalinecarboxamide tert-butyl 7-((2-chloro(4-chlorophenoxy)pyridinyl)carbamoyl) (methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate (7.0 mg, 10.78 µmol) was dissolved in CH2Cl2 (108.0 µl), 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 mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN : 0.1% formic acid in H O) to obtain N-(2-chloro(4- chlorophenoxy)pyridinyl)(methylsulfonyl)-1,2,3,4-tetrahydrothieno[2,3- g]quinoxalinecarboxamide (2.5 mg, 42 %) as white amorphous.
Examples 51) Synthesis of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)oxo-5,6,7,8-tetrahydronaphtho[2,3- b]thiophenecarboxamide To a solution of N-(2-chloro(4-chlorophenoxy)pyridinyl) (methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxamide (20.0 mg, 0.04 mmol) in acetic anhydride (1.0 ml, 10.58 mmol) was added chromium oxide(VI) (11.0 mg, 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 CH CN : 0.1% formic acid in H O) to obtain N-(2-chloro(4- chlorophenoxy)pyridinyl)(methylsulfonyl)oxo-5,6,7,8-tetrahydronaphtho[2,3- b]thiophenecarboxamide (5.0 mg, 24 %) as a white amorphous.
LC/MS ESI (+): 561 (M+1) H-NMR (400MHz, DMSO-d ): δ 11.14 (s, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.68 (d, 1H, J=1.2Hz), 7.52 (d, 2H, J=8.8Hz), 7.33 (d, 1H, J=1.2Hz), 7.26 (d, 2H, J=8.8Hz), 4.99 (m, 1H), 3.17 (s, 3H), 3.02-3.09 (m, 1H), 2.79-2.83 (m, 1H), 2.61-2.67 (m, Examples 52) Synthesis of N-(2-chloro(4-chlorophenoxy)pyridinyl) (1 H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2- g]chromenecarboxamide To a suspension of 4-(1H-pyrazolyl)-3,4-dihydro-2H-thieno[3,2-g]chromene carboxylic acid (17.0 mg, 0.06 mmol) in CH Cl (0.3 ml) were added (COCl) (9.6 µl, 0.11 2 2 2 mmol) and DMF (0.4 µl, 5.66 µmol). The reaction mixture was stirred at 40°C for 1hour, and concentrated under reduced pressure to obtain 4-(1H-pyrazolyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarbonyl chloride. To the residue, 2-chloro(4- chlorophenoxy)pyridinamine (28.9 mg, 0.11 mmol) and 1,4-dioxane (0.3 ml) was added.
The reaction mixture was stirred at 80°C overnight. The reaction mixture was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH3CN : 0.1% formic acid in H O) to obtain N-(2-chloro(4-chlorophenoxy)pyridinyl)(1H- 40 pyrazolyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide (21.0 mg, 69 %) as a white solid.
LC/MS ESI (+): 537 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.77 (brs, 1H), 8.08 (s, 1H), 7.74 (d, 1H, J=2.0Hz), 7.55 (s, 1H), 7.43-7.48 (m, 4H), 7.33 (s, 1H), 7.16-7.20 (m, 3H), 6.23-6.25 (m, 1H), 5.80 (t, 1H, J=6.2Hz), 4.27-4.3 (m, 2H), 2.31-2.43 (m, 2H) Compounds from Examples 53 to 55 were synthesized through the synthesis route of Example 52, and data of these compounds are listed as follows.
[Table 5] Ex. Compound Analysis data LC/MS ESI (+): 554 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.93 (s, N-(2-chloro(4- 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), chlorophenoxy)pyridinyl)(2- 53 7.48-7.53 (m, 3H), 7.24-7.29 (m, 3H), 5.43- oxopyrrolidinyl)-3,4-dihydro-2H- .47 (m, 1H), 4.29-4.42 (m, 2H), 3.24-3.29 (m, thieno[3,2-g]chromenecarboxamide 1H), 2.95-3.00 (m, 1H), 2.35-2.44 (m, 2H), 2.11-2.22 (m, 1H), 1.90-2.03 (m, 3H) LC/MS ESI (+): 496 (M+1) N-(2-chloro(4- H-NMR (400MHz, DMSO-d ): δ 10.89 (brs, chlorophenoxy)pyridinyl)cyano- 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 3,4-dihydro-2H-thieno[3,2-g]chromene- 7.49 (s, 1H), 7.46 (d, 2H, J=8.8Hz), 7.23 (s, 7-carboxamide 1H), 7.19 (d, 2H, J=8.8Hz), 4.57-4.60 (m, 1H), 4.23-4.26 (m, 2H), 2.22-2.33 (m, 2H) LC/MS ESI (+): 512 (M+1) H-NMR (400MHz, DMSO-d ): δ 10.96 (brs, 4-azido-N-(2-chloro(4- 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.65 (s, 1H), chlorophenoxy)pyridinyl)-3,4- 55 7.56 (s, 1H), 7.52 (d, 2H, J=8.8Hz), 7.31 (s, dihydro-2H-thieno[3,2-g]chromene 1H), 7.26 (d, 2H, 8.8Hz), 5.09 (t, 1H, carboxamide J=3.9Hz), 4.35-4.40 (m, 1H), 4.16-4.23 (m, 1H), 2.23-2.25 (m, 1H), 1.98-2.05 (m, 1H) Examples 56) Synthesis of N-(3-chloro(2-(4-chlorophenyl)propan yl)phenyl)(methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2- b][1,4]oxazinecarboxamide (a) Synthesis of 1-chloronitro(propenyl)benzene To a suspension of 1-bromochloronitrobenzene (7.2 g, 30.59 mmol), 4,4,5,5- tetramethyl(propenyl)-1,3,2-dioxaborolane (5.1 g, 30.59 mmol) and Na CO (9.7 g, 91.76 mmol) in DME (120.0 mL)/H O (30.0 mL) was added Pd(PPh ) (1.8 g, 1.53 2 3 4 mmol). The reaction mixture was refluxed overnight. Pd(PPh ) (0.7 g, 0.61 mmol) was more added and stirred for 4hours. 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 Na SO , filtered and concentrated. The residue was purified by NH-silica column chromatography (hexane only) to give 1-chloronitro(propenyl)benzene (6.3 g) as a crude yellow oil.
H-NMR (400MHz, CDCl ): δ 8.19 (t, 1H, J=1.7Hz), 8.11 (t, 1H, J=1.8Hz), 7.74 (t, 1H, J=1.7Hz), 5.30 (s, 1H), 2.19 (s, 3H) (b) Synthesis of 1-(2-bromopropanyl)chloronitrobenzene To a solution of 1-chloronitro(propenyl)benzene (6.3 g, 22.14 mmol) in Et O (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.NaHCO aqueous solution was added under ice bath and the resulting mixture was extracted with Et O. The organic extract was washed with sat. NaHCO aqueous solution and brine, dried over anhydrous Na SO , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 19 : 1) to obtain 1-(2-bromopropanyl) chloronitrobenzene (5.3 g, 62% in 2 steps) as an ivory solid.
H-NMR (400MHz, CDCl ): δ 8.34 (t, 1H, J=1.9Hz), 8.13 (t, 1H, J=1.9Hz), 7.26 (t, 1H, J=1.8Hz), 2.21 (s, 6H) (c) Synthesis of 1-chloro(2-(4-chlorophenyl)propanyl)nitrobenzene 1-(2-Bromopropanyl)chloronitrobenzene (2.0 g, 7.18 mmol) and chlorobenzene (10.9 mL, 0.11 mol) were dissolved in 1,2-dichloroethane (70.0 mL), and AlCl (2.9 g, 21.54 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours, H O was added, and extracted with CH Cl . The organic extract was washed with 2 2 2 brine, dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH CN: 0.1% formic acid in H O) to obtain 1-chloro(2-(4-chlorophenyl)propan yl)nitrobenzene (1.95 g, 88%) as a yellow oil.
H-NMR (400MHz, CDCl ): δ 8.06 (t, 1H, J=1.8Hz ), 7.99 (t, 1H, J=1.9Hz ), 7.47 (t, 1H, J=1.7Hz ), 7.29 (d, 2H, J=8.5Hz), 7.12 (d, 2H, J=8.5Hz), 1.70 (s, 6H) (d) Synthesis of 3-chloro(2-(4-chlorophenyl)propanyl)aniline 1-chloro(2-(4-chlorophenyl)propanyl)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 NH Cl (1.68 g, 31.4 mmol) were added at room temperature. The reaction mixture 40 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 chromatography (amine silica gel, n-Hex : EtOAc = 9 : 1) to obtain 3-chloro(2-(4- chlorophenyl)propanyl)aniline (1.49 g, 85%) as a yellow oil.
LC/MS ESI (+): 280 (M+1) H-NMR (400MHz, CDCl ): δ 7.22 (d, 2H, J=8.7Hz), 7.14 (d, 2H, J=8.7Hz), 6.60 (t, 1H, J=1.7 Hz ), 6.50 (t, 1H, J=1.9 Hz ), 6.32 (t, 1H, J=1.9 Hz ),3.64 (s, 2H), 1.59 (s, (e) Synthesis of N-(3-chloro(2-(4-chlorophenyl)propanyl)phenyl) (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide The synthesis procedure of Example 1-b was repeated except for using 3-chloro (2-(4-chlorophenyl)propanyl)aniline (12.1 mg, 0.04 mmol) to obtain N-(3-chloro(2- (4-chlorophenyl)propanyl)phenyl)(methylsulfonyl)-2,3-dihydro-1H- thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide (12.8 mg, 77%) as a white solid.
LC/MS ESI (+): 575 (M+1) H-NMR(400MHz, DMSO-d ): δ 10.47 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.50 (t, 1H, J=1.6Hz), 7.39 (d, 2H, J=8.6Hz), 7.28 (d, 2H, J=8.6Hz), 7.03 (m, 1H), 4.37 (t, 2H, J=4.2Hz), 3.91 (t, 2H, J=4.4Hz), 3.19 (s, 3H), 1.66 (s, 6H).
Experimental Examples Experiments were performed as shown below for the compounds prepared in Examples above.
Experimental Example 1) Experiment on the inhibition of STAT3 and STAT1 activities v ia 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 Scientific) and 150 μg/mL G-418 solution (Cat No. 04 727 894 001, Roche). The reporter gene assay using LNCaP stable cell line was performed in RPMI1640 medium containing 3% DCC-FBS 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% CO for 24 hours, and then treated with the compounds listed in Examples which were diluted in various concentrations.
Subsequently, IL-6 was added to each well with a final concentration of 10 ng/mL. Upon 40 completion of the treatment with the compounds and IL-6, the cells were cultured at 37°C, under 5% CO for 24 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded.
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 (BMG LABTECH) using a luciferase assay system (Cat No. E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No.
G7573, Promega), and shaken for 10 minutes in order to measure 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. 1-2) Experiment on the inhibition of STAT1 activity A human osteosarcoma cell line (U2OS stable cell line; pGL4-STAT1-TA-luc), which contains a stably operating STAT1 promoter, was cultured in McCoy 5'A medium (Cat No. 16600, Life Technologies) containing 10% FBS (Cat No. SH30396, Thermo Scientific) and 1000 μg /mL G418 solution (Cat No. 04 727 894 001, Roche). The reporter gene assay using U2OS stable cell line was performed in McCoy 5'A medium containing 10% FBS without G-418 solution. U2OS stable cells were plated in two (2) white 96-well plates with 25,000 cells/50 μL in each well. The cells were cultured at 37°C, under 5% CO for 24 hours, and then treated with the compounds listed in Examples which were diluted in various concentrations. Subsequently, IFN-γ was added to each well with a final concentration of 50 ng/mL. Upon completion of the treatment with the compounds and IFN-γ, the cells were cultured at 37°C, under 5% CO for 8 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded.
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 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 (BMG LABTECH) using a luciferase assay system (Cat No. E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No.
G7573, Promega), and shaken for 10 minutes in order to measure 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.
The results of evaluation on the inhibitory effect of the compounds listed in the Examples on the dimerization of STAT3 and STAT1 obtained via the STAT3 and STAT1 reporter gene assays are shown in Table 6 below.
[Table 6] IC (µM) IC (µM) IC (µM) IC (µM) 50 50 50 50 Ex. Ex. pSTAT3 pSTAT1 pSTAT3 pSTAT1 1 0.0026 >50 2 0.17 >50 3 0.01 >50 4 0.93 >50 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 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 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 >50 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 >50 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 of STAT1 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 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 sub-cultured in a 96-well plate by counting the exact number of cells using Tali Image- based Cytometer (Life Technologies). In a 96-well plate, NCI-N87 was employed with 5,000 cells/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 concentrations. Upon completion of the compounds treatment, NCI-N87 cells were cultured at 37°C under 5% CO 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 CellTiter-Glo solution (Cat No. G7573, Promega) and shaken for 10 minutes, followed by being subjected to the measurement using 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 were used as a positive control.
The results of the inhibitory effects of the compounds prepared in Examples against the growth of cancer cells are shown in Tables 7 to 8 below.
[Table 7] IC50 IC50 IC50 IC (µM) Ex. (µM) Ex. (µM) Ex. Ex. (µM) NCI-N87 NCI-N87 NCI-N87 NCI-N87 1 0.0083 2 1.2 3 0.045 4 4.1 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 0.018 22 0.071 23 0.0056 24 0.0038 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 50 0.0091 51 0.20 52 0.40 53 4.4 54 0.32 55 1.2 56 0.019 [Table 8] IC (µM) IC (µM) IC (µM) IC (µM) 50 50 50 50 Ex. Ex. Ex. Ex.
MDA-MB-468 MDA-MB-468 MDA-MB-468 MDA-MB-468 7 0.0065 8 0.0032 9 0.023 10 0.0019 11 0.0052 12 0.0028 13 0.0066 14 0.026 0.0089 16 0.0039 17 0.0023 18 0.0043 19 0.0025 20 0.0024 21 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 various kinds of cancer cells.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

Claims (19)

WHAT IS CLAIMED IS:
1. A compound selected from the group consisting of a heterocyclic derivative 5 represented by formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof: Rc (R ) (R ) A L B wherein 10 one of X and X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -N(Rx)-, or -N(-Rx')-, and the other is –C(-Rx'')(-Rx'')-, -N(-Rx'')-, -C(=O)-or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl, haloC alkyl, C alkoxy-C alkyl, C alkylcarbonyl-C alkyl, 1-6 1-6 1-6 1-6 1-6 1-6 15 C alkenyl, amino, or aminoC alkyl; 2-7 1-6 Rx' is haloC alkyl, C alkoxycarbonyl, cyano, nitro, azido, amino, or a 3-6 1-6 1-4 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 O and unsubstituted or substituted with oxo; 20 Rx'' is each independently hydrogen, halogen, nitro, amino, C alkyl, C alkoxy, 1-6 1-6 haloC alkoxy, carbamoylC alkyl, C alkylamino-C alkyl, C alkoxycarbonyl, or diC 1-6 1-6 1-6 1-6 1-4 1- alkylamino-C alkyl; 6 1-6 one of Y and Z is -S- or -NH-, and the other is -CH= or -N=; Lx is a saturated or unsaturated C hydrocarbon chain not containing or 25 containing 1 to 3 heterogroups selected from the group consisting of -O-, -NH-, -N=, -S-, - S(=O)- and -S(=O) - in the chain, and unsubstituted or substituted with at least one Rx'' moiety; A and B are each independently a monocyclic- or bicyclic-saturated or unsaturated C carbocycle or 5- to 12-membered heterocycle; 3-10 30 Rc is =O, =NH, =N(-C alkyl), or =N(-OH); R is hydrogen or C alkyl; N 1-6 L is -[C(-R )(-R ')] -, -[C(-R )(-R ')] -O-, -O-, -NH-, -N(C alkyl)-, -S(=O) -, - B L L m L L n 1-6 2 C(=O)-, or -C(=CH )-, wherein m is an integer of 0 to 3, n is an integer of 1 to 3, R and R ' are each independently hydrogen, hydroxy, halogen or C alkyl, or R and R ' are L 1-6 L L 35 linked together to form C alkylene; R is hydrogen, halogen, cyano, C alkyl, haloC alkyl, cyanoC alkyl, C A 1-6 1-6 1-6 1- alkylcarbonyl, C alkoxy, haloC alkoxy, cyanoC alkoxy, C alkylamino, diC 6 1-6 1-6 1-6 1-6 1- alkylamino, C alkylthio, C alkylaminocarbonyl, diC alkylaminocarbonyl, C 6 1-6 1-6 1-6 2- 8alkynyl, C1-6alkoxycarbonylamino-C1-6alkoxy, aminoC1-6alkoxy, or 3- to 6-membered 5 heterocyclyl; R is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C alkylamino, C alkyl, haloC alkyl, cyanoC alkyl, C alkoxy, 1-6 1-6 1-6 1-6 1-6 haloC alkoxy, cyanoC alkoxy, C cycloalkyloxy, C alkenyl, C alkenyloxy, C 1-6 1-6 3-8 2-8 2-8 2- alkynyl, C alkynyloxy, C carbocyclyl-oxy, C alkylamino-C alkoxy, diC 8 2-8 3-10 1-6 1-6 1- 10 alkylamino-C alkoxy, C alkoxy-carbonyl, carbamoyl, carbamoyl-C alkoxy, C 6 1-6 1-6 1-6 1- alkylthio, C alkylsulfinyl, C alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10- 6 1-6 1-6 membered heterocyclyl-C alkyl, 5- to 10-membered heterocyclyl-C alkoxy, or 5- to 10- 1-6 1-6 membered heterocyclyl-oxy; p is an integer of 0 to 4, and, when p is 2 or higher, R moieties are the same as or 15 different from each other; q is an integer of 0 to 4, and, when q is 2 or higher, R moieties are the same as or different from each other; and each of said heterocycle, 3- to 6-membered heterocyclyl, and 5- to 10-membered heterocyclyl moieties independently contains at least one heterogroup selected from the 20 group consisting of -O-, -NH-, -N=, -S-, -S(=O)- and -S(=O)2-.
2. The compound according to claim 1, wherein one of Y and Z is -S- or -NH-, and the other is -CH=; 25 Lx is a saturated C hydrocarbon chain not containing or containing at least one heteroatom selected from the group consisting of O, N and S in the chain, and unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C alkyl and C alkoxy; 1-6 1-6 one of X and X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, -N(Rx)- or -N(-Rx')-, and the 30 other is -C(-Rx'')(-Rx'')-, -N(-Rx'')-, -C(=O)- or -O-; Rs S Rx is ; Xs is =O or =NH; Rs is C alkyl or haloC alkyl; 1-6 1-6 Rx' is haloC alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered 35 heterocyclyl containing at least one heteroatom selected from the group consisting of N, S and O and unsubstituted or substituted with oxo; and Rx'' is hydrogen, halogen, C alkyl, or C alkoxycarbonyl. 1-6 1-4
3. The compound according to claim 2, wherein Y is -CH=; Z is -S-; 5 Rc is =O; R is hydrogen; Lx is a saturated C 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, C alkyl and C alkoxy; 1-6 1-6 10 X is -C(-Rx)(-Rx'')-, -C(-Rx')(-Rx'')-, or -N(Rx)-; X is -C(-Rx'')(-Rx'')-, -C(=O)-, -N(-Rx'')-, or -O-; H C S Rx is ; Xs is =O or =NH; Rx' is haloC alkyl, cyano, nitro, amino, azido, or a 5- to 6-membered 15 heterocyclyl containing 1 to 2 heteroatoms selected from N and O and unsubstituted or substituted with oxo; and Rx'' is hydrogen, halogen, C alkyl, or C alkoxycarbonyl. 1-6 1-4 20
4. The compound according to claim 3, wherein 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 C carbocycle or 5- to 10- 6-10 membered heterocycle; L is -[C(-R )(-R ')] -, -O-, -NH- or -N(C alkyl)-, wherein m is 0 or 1, R and B L L m 1-6 L 25 R ' are each independently hydrogen, hydroxy, halogen or C alkyl, or R and R ' are L 1-6 L L linked together to form C alkylene; R is halogen, C alkoxycarbonylamino-C alkoxy, aminoC alkoxy, or 3- to 6- A 1-6 1-6 1-6 membered heterocyclyl; R is halogen, C alkyl, C alkoxy, haloC alkyloxy, C alkenyloxy, C B 1-6 1-6 1-6 2-6 3- 30 carbocyclyl-oxy, or 5- to 10-membered heterocyclyl-C alkoxy; and 10 1-3 each of said 3- to 6-membered heterocyclyl and 5- to 10-membered heterocyclyl moieties independently contains 1 to 3 heteroatoms selected from the group consisting of O, N and S.
5. The compound according to claim 1, wherein X is -N(-Rx)-; X is -C(-Rx'')(-Rx'')- or -N(-Rx'')-; Y is -CH=; Z is -S-; Rc is =O; RN is hydrogen; 5 Lx is ethylene substituted with one or two Rx'' moieties, Rs S Rx is ; Xs is =O; Rs is methyl; and Rx'' is the same as defined in claim 1.
6. The compound according to claim 1, wherein X is -CH(-Rx)-; X is -N(-Rx'')-; 15 Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S 20 Rx is ; Xs is =O; Rs is methyl; and Rx'' is the same as defined in claim 1.
7. The compound according to claim 1, wherein X is -C(-Rx)(-Rx'')-; X is -O-; Y is -CH=; 30 Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S Rx is ; Xs is =O; Rs is methyl; and Rx'' is the same as defined in claim 1.
8. The compound according to claim 1, wherein X is -C(-Rx')(-Rx'')-; X is -O-; Y is -CH=; 10 Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; and Rx' and Rx'' are the same as defined in claim 1.
9. The compound according to claim 1, wherein X is -CH(-Rx)-; X is -C(-Rx'')(-Rx'')- or -C(=O)-; 20 Y is -CH=; Z is -S-; Rc is =O; R is hydrogen; Lx is ethylene; Rs S 25 Rx is ; Xs is =O; Rs is methyl; and Rx'' is the same as defined in claim 1.
10. The compound according to claim 1, wherein X is -CH(-Rx)-; X is -C(-Rx'')(-Rx'')-; Y is -CH=; 35 Z is -S-; Rc is =O; R is hydrogen; Lx is -CH -O-; Rs S Rx is ; Xs is =O; Rs is methyl; and Rx'' is the same as defined in claim 1.
11. The compound according to claim 1, wherein X is -C(-Rx)(-Rx'')- or -N(Rx)-; X is -O-; 10 Y is -NH-; Z is -CH=; Rc is =O; R is hydrogen; Lx is propylene; and 15 Rx and Rx'' are the same as defined in claim 1.
12. The compound according to claim 1, which is selected from the group consisting 20 1) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-2,3-dihydro- 1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide; 2) N-(2-chloro(4-chlorophenoxy)pyridinyl)-3,3-dimethyl (methylsulfonyl)-2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide; 3) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-1,2,3,4- 25 tetrahydrothieno[3',2':4,5]benzo[1,2-b][1,4]oxazepinecarboxamide; 4) N-(2-chloro(4-chlorophenoxy)pyridinyl)-8,8-dimethyl (methylsulfonyl)-5,6,7,8-tetrahydrothieno[2,3-g]quinolinecarboxamide; 5) tert-butyl 7-((2-chloro(4-chlorophenoxy)pyridinyl)carbamoyl) (methylsulfonyl)-2,3-dihydrothieno[2,3-g]quinoxaline-4(1H)-carboxylate; 30 6) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,6,7,8- tetrahydrothieno[2,3-g]quinolinecarboxamide; 7) N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl(methylsulfonyl)- 1,2,3,4-tetrahydrothieno[2,3-g]quinoxalinecarboxamide; 8) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro- 35 2H-thieno[3,2-g]chromenecarboxamide; 9) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-2,3,4,5- tetrahydrothieno[3',2':4,5]benzo[1,2-b]oxepinecarboxamide; 10) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,6,7,8- tetrahydronaphtho[2,3-b]thiophenecarboxamide; 11) N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 12) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-5,8- 5 dihydro-6H-thieno[3,2-g]isochromenecarboxamide; 13) N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 14) N-(2-chloro(4-chlorophenoxy)pyridinyl)-8,8-difluoro (methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxamide; 10 15) N-(2-chloro(p-tolyloxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 16) N-(2-chloro(3-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 17) N-(2-chloro(4-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 15 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 18) N-(2-chloro(3,5-dichlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 19) N-(2-chloro(4-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 20 20) N-(2-chloro(4-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 21) N-(2-chloro(4-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 22) N-(2-chloro(4-methoxyphenoxy)pyridinyl)(methylsulfonyl)-3,4- 25 dihydro-2H-thieno[3,2-g]chromenecarboxamide; 23) N-(2-chloro(4-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 24) N-(2-chloro(3,4-dichlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 30 25) N-(2-chloro(3-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 26) N-(2-chloro(4-fluorophenoxy)pyridinyl)(methylsulfonyl)-3,4-dihydro- 2H-thieno[3,2-g]chromenecarboxamide; 27) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 35 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 28) N-(2-chloro(4-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 29) N-(2-chloro(3-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 40 30) N-(2-chloro(3-chloromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 31) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 32) N-(2-chloro(3-fluoromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 5 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 33) N-(2-chloro(m-tolyloxy)pyridinyl)(methylsulfonyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 34) N-(2-chloro(3,4-difluorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 10 35) N-(2-chloro(5-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 36) N-(2-chloro(3-chlorofluorophenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 37) N-(2-chloro(5-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 15 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 38) N-(2-chloro(3-chloromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 39) N-(2-chloro(2-(trifluoromethyl)phenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 20 40) N-(2-chloro(2-(trifluoromethoxy)phenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 41) N-(2-chloro(2-fluoromethylphenoxy)pyridinyl)(methylsulfonyl)- 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 42) N-(2-chloro(4-chloromethoxyphenoxy)pyridinyl)(methylsulfonyl)- 25 3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 43) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 44) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 30 45) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 46) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)fluoro (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 47) (S)-N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl 35 (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 48) (R)-N-(2-chloro(4-chlorophenoxy)pyridinyl)methyl (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 49) (S)-N-(2-chloro(3-chloromethoxyphenoxy)pyridinyl) (methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromenecarboxamide; 40 50) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)-1,2,3,4- tetrahydrothieno[2,3-g]quinoxalinecarboxamide; 51) N-(2-chloro(4-chlorophenoxy)pyridinyl)(methylsulfonyl)oxo- 5,6,7,8-tetrahydronaphtho[2,3-b]thiophenecarboxamide; 52) N-(2-chloro(4-chlorophenoxy)pyridinyl)(1H-pyrazolyl)-3,4- 5 dihydro-2H-thieno[3,2-g]chromenecarboxamide; 53) N-(2-chloro(4-chlorophenoxy)pyridinyl)(2-oxopyrrolidinyl)-3,4- dihydro-2H-thieno[3,2-g]chromenecarboxamide; 54) N-(2-chloro(4-chlorophenoxy)pyridinyl)cyano-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; 10 55) 4-azido-N-(2-chloro(4-chlorophenoxy)pyridinyl)-3,4-dihydro-2H- thieno[3,2-g]chromenecarboxamide; and 56) N-(3-chloro(2-(4-chlorophenyl)propanyl)phenyl)(methylsulfonyl)- 2,3-dihydro-1H-thieno[3',2':4,5]benzo[1,2-b][1,4]oxazinecarboxamide.
13. A pharmaceutical composition for preventing or treating diseases associated with the activation of STAT3 protein, comprising the compound as defined in any one of claims 1 to 12 as an active ingredient.
14. The pharmaceutical composition according to claim 13, wherein the diseases associated with the activation of STAT3 protein is selected from the group consisting of solid cancers, hematological or blood cancers, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological diseases, diabetes, macular degeneration, 25 human papillomavirus infection and tuberculosis.
15. The pharmaceutical composition according to claim 13, wherein the diseases associated with the activation of STAT3 protein are selected from the group consisting of 30 breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B- or T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune diseases comprising rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, 35 diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.
16. A use of the compound as defined in any one of claims 1 to 12 for the manufacture of a medicament for preventing or treating diseases associated with the activation of 40 STAT3 protein.
17. The compound according to any one of claims 1 to 12, substantially as herein described with reference to any example thereof.
18. The pharmaceutical composition according to any one of claims 13 to 15, substantially as herein described with reference to any example thereof. 10
19. The use according to claim 16, substantially as herein described with reference to any example thereof.
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KR10-2015-0128025 2015-09-10
PCT/KR2015/012926 WO2016089062A2 (en) 2014-12-02 2015-11-30 Heterocyclic derivatives and use thereof

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