Design and synthesis of 1,3,5-triazine derivatives as novel inverse agonists of nuclear retinoic acid receptor-related orphan receptor-γ

Article abstract of DOI:10.3987/COM-16-S(S)16

1,3,5-Triazine structure is a versatile chemical species for development of functional molecules, including biologically active compounds. We report herein the design, synthesis and biological evaluation of novel inverse agonists of nuclear retinoic acid receptor-related orphan receptor-γ (RORγ), in which the 2-anilino-1,3,5-triazine moiety was used as a scaffold for structural development. Among the synthesized compounds, 13b exhibited potent and selective inverse agonistic activity toward RORγ, being more potent than the lead compound T0901317 (7). The results suggest that the 2-anilino-1,3,5-triazine moiety is a useful scaffold for development of inhibitory ligands of nuclear receptors.

Full text of DOI:10.3987/COM-16-S(S)16

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HETEROCYCLES, Vol. 95, No. 1, 2017, pp. 547-556. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 8th July, 2016, Accepted, 6th September, 2016, Published online, 19th October, 2016
DOI: 10.3987/COM-16-S(S)16
DESIGN AND SYNTHESIS OF 1,3,5-TRIAZINE DERIVATIVES AS
NOVEL INVERSE AGONISTS OF NUCLEAR RETINOIC ACID
RECEPTOR-RELATED ORPHAN RECEPTOR-γ
Kazuma Kaitoh, Hirozumi Toyama, Yuichi Hashimoto, and Shinya Fujii*
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1
Yayoi, Bunko-ku, Tokyo 113-0032, Japan. E-mail: fujiis@iam.u-tokyo.ac.jp
Abstract – 1,3,5-Triazine structure is a versatile chemical species for
development of functional molecules, including biologically active compounds.
We report herein the design, synthesis and biological evaluation of novel inverse
agonists of nuclear retinoic acid receptor-related orphan receptor-γ (RORγ), in
which the 2-anilino-1,3,5-triazine moiety was used as a scaffold for structural
development. Among the synthesized compounds, 13b exhibited potent and
selective inverse agonistic activity toward RORγ, being more potent than the lead
compound T0901317 (7). The results suggest that the 2-anilino-1,3,5-triazine
moiety is a useful scaffold for development of inhibitory ligands of nuclear
receptors.
The aromatic nitrogen heterocycle 1,3,5-triazine (s-triazine) is a versatile functionality or core scaffold of
a wide variety of functional molecules.1 For instance, 2,4,6-trisubstituted-1,3,5-triazine derivatives such
as DMT-MM2 and TriBOT3 are synthetically convenient and useful reagents for organic reactions.
Triazines have also been widely utilized in medicinal chemistry. For example, triazine-based
phosphodiesterase inhibitor irsogladine (1) is clinically used as a mucosal protective agent,4 and kinase
inhibitors such as phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)
inhibitor gedatolisib (2)5 and Tie-2 kinase inhibitor 36 have been developed. Introduction of three
arbitrary substructures into the 1,3,5-triazine core is a facile method not only to prepare chemical libraries,
but also to investigate structure-activity relationships (SARs). This approach has yielded several
biologically active compounds, such as microtubule destabilizer 47 and transient receptor potential
vanilloid 1 (TRPV1) blocker 5.8 We have also recently developed novel triazine-based NF-κB inhibitors
such as 69 (Figure 1).

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Figure 1. Examples of biologically active compounds bearing a 1,3,5-triazine moiety
To expand the utility of the 1,3,5-triazine substructure in the field of drug discovery, we have investigated
application of the triazine moiety as a part of a novel multi-template. The foundation of the
multi-template approach is that the number of three-dimensional spatial structures (fold structures) of
human proteins is only approximately 1000, which is much smaller than the number of human proteins,
estimated to be 50,000-70,000.10-12 The multi-template approach is a promising strategy to develop novel
drug candidates, and we have previously employed multi-templates such as thalidomide13 and
diphenylmethane14 to obtain various biologically active compounds. In this paper, we report the design
and synthesis of transcription modulators based on a novel template structure incorporating a
1,3,5-triazine moiety.
Here, we focused on inverse agonistic activity towards retinoic acid receptor-related orphan receptor-γ
(RORγ). RORγ is a member of the nuclear receptor superfamily of ligand-dependent factors that regulate
DNA transcription.15 Increased transcriptional activation of RORγ is thought to be involved in
autoimmune diseases,16 and therefore RORγ inverse agonists, which inhibit the constitutive activity of
RORγ, would be candidate drugs for treatment of these diseases. A sulfonamide derivative T0901317 (7,
Figure 2) bearing a (1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenyl moiety, which was originally
developed as a nuclear liver X receptor (LXR) agonist,17 also shows RORγ inverse agonist activity.18
Based on the structural motif of 7, we have developed several analogues, such as 819 and 9,20 as RORγ
inverse agonists (Figure 2). Those structural development studies suggested that the
(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenyl moiety of 7 is an essential pharmacophore for RORγ

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inverse agonistic activity of these derivatives, and that small structural modifications can significantly
affect the activity and selectivity.21
Figure 2. Examples of developed RORγ inverse agonists bearing a
(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenyl moiety
On the basis of these considerations, we planned to develop RORγ inverse agonists bearing a novel
template structure that would enable facile investigation of SAR. For this purpose, we designed the
2-anilino-1,3,5-triazine scaffold shown in Figure 3. Diarylamine is an established multi-template for
nuclear receptor ligands, and the (1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenyl moiety is considered to
be a pharmacophore motif of RORγ inverse agonists. The 4- and 6-positions of 1,3,5-triazine are
available as points of structural modification. In order to exert inhibitory activity toward nuclear receptors,
appropriate substituents on ligands are needed to induce the inactive conformation of the receptors. In
addition, in the case of derivatives of 7, small structural modifications are known to alter the activity and
selectivity, as mentioned above.21 Therefore, we investigated the utility of the designed template structure
and also carried out a pilot SAR study to examine the effect of small differences in structure (Figure 3).
Figure 3. Design scheme of novel RORγ inverse agonists
The designed 1,3,5-triazine derivatives were synthesized in three steps as illustrated in Scheme 1. We had
initially intended to introduce the aniline moiety in the first step, but found that the following step of
alkoxylation did not proceed in sufficient yield. Therefore firstly the alkoxy group and then phenoxy

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groups were introduced, and the (1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)phenylamino moiety was
connected at the final step (Scheme 1).
Scheme 1. Synthesis of the designed 2-anilino-1,3,5-triazine derivatives. Reagents and conditions: (a)
NaHCO3, MeOH or EtOH, 0 °C, 74% (11a), 25% (11b); (b) R2C6H4OH, i-Pr2EtN, CH2Cl2, rt, 68-84%;
(c) 4-HO(CF3)2C-C6H4NH2, i-Pr2EtN, DMSO, 100 °C, 8-77%.
Table 1. Biological activity of 7 and synthesized compounds 13a-e. N.A.; No activity was observed at the
concentration of 10 μM.
The biological activities of synthesized compounds 13a-e and the lead compound 7 were evaluated by
luciferase reporter gene assay in HEK293 cells. Since compound 7 exhibits agonistic activity toward
LXRα and β,17 FXR21 and PXR (SXR),23 as well as inverse agonistic activity toward RORα and γ, we
evaluated not only inverse agonistic activity toward hRORγ, but also agonistic activities toward hLXRα,
hLXRβ, hFXR, and hPXR. The results of reporter gene assays are summarized in Table 1. Compound 7
exhibited activity toward all tested nuclear receptors, as reported. On the other hand, the synthesized
compounds 13a-e exhibited significant hRORγ inverse agonistic activity, but did not exhibit agonistic
activity toward the other tested nuclear receptors. The results suggested that the designed template

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structure is a reasonable scaffold for RORγ inverse agonists, and the developed compounds show
selectivity for RORγ over other receptors. Regarding hRORγ inverse agonistic activity, each compound
exhibited significant activity. It is suggested that introduction of an ortho-substitution at the phenoxy
moiety and elongation of the alkoxy group could enhance the potency in comparison to that of the parent
compound 13a, and compounds 13b and 13e were more potent than 7 (Table 1).
Figure 4. Docking simulations of novel triazine derivatives and hRORγ. Binding modes of 13b (left), 13e
(center), and overlay of the common conformation of the two compounds and 7 (right). The common
conformation is indicated with ball-and-stick models (carbon in yellow) and 7 is displayed with carbon in
gray. The protein surface is displayed as a mesh.
In order to elucidate the SAR, we conducted docking simulations of the compounds using AutoDock
4.2.24 Compounds 13b, 13c and 13e were docked with the X-ray crystal structure of hRORγ
ligand-binding domain (PDB ID: 4NB6).21 The calculation generated multiple docked conformations of
the compounds, and we compared the four conformations of each compound with lowest energy. In the
calculated structures, each compound occupies the ligand-binding pocket at which 7 is located in the
X-ray structure. Regarding the potent compounds 13b and 13e, one conformation among the four of 13b
is almost identical to one of the four of 13e (Figures 4a, 4b and 4c). On the other hand, the less potent 13c
did not show a similar low-energy conformation. Therefore, the conformation common to 13b and 13e
might be an active conformation of the developed triazine derivatives. In this putative active
conformation, the 2-anilino-4-phenoxytriazine scaffold mimics the synclinal bended conformation of
sulfonamide 7 (Figure 4c). The calculated structure also suggests that the ortho-methyl group of 13b and
ethyl group of 13e are located in the proximal region, and increase of hydrophobic interaction in this
region might enhance the activity of the compounds.
In conclusion, we have developed novel RORγ inverse agonists by utilizing the 2-anilino-1,3,5-triazine
scaffold as a template structure. The designed template structure is useful for facile SAR investigation.

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Among the compounds synthesized, 13b exhibited potent and selective RORγ inverse agonistic activity,
being approximately three times more potent than the known compound 7. The SAR information
obtained here should be useful for further structural development of RORγ inverse agonists. Furthermore,
the designed template structure could also be useful as a novel multi-template for development of ligands
of other nuclear receptors.
EXPERIMENTAL
Chemistry
General remarks. 1H NMR and 13C NMR spectra were recorded on a JEOL JNM-GX500 spectrometer.
Chemical shifts are expressed in δ (ppm) values with tetramethylsilane (TMS) as a reference. The
following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass
spectra were collected on a Bruker Daltonics micrOTOF-II in the negative ion modes. All melting points
were determined on Yanagimoto micro melting point apparatus and are uncorrected.
2,4-Dichloro-6-methoxy-1,3,5-triazine (11a). Cyanuric chloride (9.23 g, 50.0 mmol) was added to a
solution of sodium hydrogen carbonate (4.20 g, 50.0 mmol) in MeOH (200 mL) at 0 °C. The mixture was
stirred for 20 min at 0 °C, then poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried over sodium sulfate and concentrated. The residue was purified by
1
recrystallization from n-hexane to afford 6.67 g (74%) of 11a as colorless crystals. H-NMR (500 MHz,
CDCl3) δ 4.14 (3H, s); 13C-NMR (125 MHz, CDCl3) δ 172.70, 171.63, 57.09.
2,4-Dichloro-6-ethoxy-1,3,5-triazine (11b)ꢀꢁCyanuric chloride (1.86 g, 10.1 mmol) was added to a
solution of sodium hydrogen carbonate (843 mg, 10.0 mmol) in EtOH (40 mL) at 0 °C. The mixture was
stirred for 25 min at 0 °C, then poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried over sodium sulfate and concentrated. The residue was purified by
recrystallization from n-hexane to afford 493 mg (2.54 mmol, 25%) of 11b as colorless crystals. 1H-NMR
13
(500 MHz, CDCl3) δ 4.57 (2H, q, J = 7.3 Hz), 1.47 (3H, t, J = 7.2 Hz); C-NMR (125 MHz, CDCl3) δ
172.64, 171.07, 66.75, 14.09.
General procedure for the synthesis of compounds 12a-12e.
The appropriate phenol (1.0 eq.) in CH2Cl2 (5 mL) and N,N-diisopropylethylamine (1.0 eq.) in CH2Cl2 (5
mL) were added dropwise to a solution of 11a or 11b (1 eq.) in CH2Cl2 (10 mL) at room temperature. The
mixture was stirred for 30 min at room temperature. The reaction mixture was washed with dilute
hydrochloric acid and brine, dried over sodium sulfate and concentrated. The residue was purified by
silica gel chromatography (eluent: n-hexane/EtOAc 10:1 or 5:1).
2-Chloro-4-methoxy-6-phenoxy-1,3,5-triazine (12a). Colorless solid (Yield: 69%); 1H-NMR (500 MHz,
13
CDCl3) δ 7.44 (2H, t, J = 7.2 Hz), 7.30 (1H, t, J = 7.4 Hz), 7.18 (2H, m), 4.02 (3H, s); C-NMR (125

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MHz, CDCl3) δ 173.41, 172.91, 172.36, 151.51, 129.86, 126.62, 121.41, 56.36.
2-Chloro-4-methoxy-6-(2-methylphenoxy)-1,3,5-triazine (12b). Colorless solid (Yield: 74%); 1H-NMR
(500 MHz, CDCl3) δ 7.28 (1H, dd, J = 7.4, 1.7 Hz), 7.24 (1H, dt, J = 7.3, 1.7 Hz), 7.21 (1H, dt, J = 7.3,
1.3 Hz), 7.07 (1H, dd, J = 7.7, 1.4 Hz), 4.00 (3H, s), 2.19 (3H, s); 13C-NMR (125 MHz, CDCl3) δ 173.46,
172.95, 172.17, 150.19, 131.59, 130.08, 127.32, 126.74, 121.49, 56.30, 16.32.
2-Chloro-4-methoxy-6-(3-methylphenoxy)-1,3,5-triazine (12c). Colorless solid (Yield: 73%); 1H-NMR
(500 MHz, CDCl3) δ 7.31 (1H, dt, J = 7.4, 1.1 Hz), 7.10 (1H, d, J = 7.4 Hz), 6.97 (1H, s), 6.96 (1H, d, J =
6.9 Hz), 4.02 (3H, s), 2.39 (3H, s); 13C-NMR (125 MHz, CDCl3) δ 173.38, 172.90, 172.42, 151.47,
140.15, 129.52, 127.40, 121.85, 118.35, 56.33, 21.51.
2-Chloro-4-methoxy-6-(4-methylphenoxy)-1,3,5-triazine (12d). Colorless solid (Yield: 68%); 1H-NMR
(500 MHz, CDCl3) δ 7.22 (2H, d, J = 8.0 Hz), 7.05 (2H, td, J = 3.2, 5.6 Hz), 4.02 (3H, s), 2.37 (3H, s).
1
2-Chloro-4-ethoxy-6-phenoxy-1,3,5-triazine (12e). Colorless solid (Yield: 84%); H-NMR (500 MHz,
CDCl3) δ 7.43 (2H, tt, J = 2.3, 8.0 Hz), 7.30 (1H, t, J = 7.4 Hz), 7.17 (2H, dt, J = 2.3, 8.0 Hz), 4.44 (2H, q,
J = 5.9 Hz), 1.39 (3H, t, J = 7.2 Hz).
General procedure for the synthesis of compounds 13a-e.
To a solution of 12a-e in DMSO (500 PL) were added 4-(hexafluoro-2-hydroxyisopropyl)aniline (2 eq.)
and N,N-diisopropylethylamine (2 eq.) at room temperature. The mixture was stirred for 15 min at 100 °C,
then poured into dilute hydrochloric acid and extracted with EtOAc. The organic layer washed with brine,
dried over sodium sulfate and concentrated. The residue was purified by recrystallization from MeOH.
2-{4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropyl)anilino}-4-methoxy-6-phenoxy-1,3,5-triazine
(13a).
Colorless solid (Yield: 27%); mp 145.7-147.6 °C; 1H-NMR (500 MHz, CDCl3) δ 7.60 (4H, br), 7.44 (2H,
t, J = 8.0 Hz), 7.38 (1H, s), 7.30 (1H, t, J= 7.4 Hz), 7.20 (2H, d, J = 7.4 Hz), 4.01 (3H, s), 3.59 (1H, s);
HRMS (ESI-) m/z 459.0905 [(M-H)- :calcd. for C19H14F6N4O3, 459.0886].
2-{4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropyl)anilino}-4-methoxy-6-(2-methylphenoxy)-1,3,5-
triazine (13b). Colorless solid (Yield: 8%); mp 201.8-203.5 °C; 1H-NMR (500 MHz, CDCl3) δ 7.66 (4H,
br), 7.30 (1H, s), 7.29 (1H, d, J = 7.4 Hz), 7.25 (1H, t, J = 8.9 Hz), 7.22 (1H, t, J = 6.9 Hz), 7.11 (1H, dd,
J = 1.4, 7.7 Hz), 4.01 (3H, s), 3.54 (1H, s), 2.21 (3H, s); HRMS (ESI-) m/z 473.1048 [(M-H)- :calcd. for
C20H16F6N4O3, 473.1043].
2-{4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropyl)anilino}-4-methoxy-6-(3-methylphenoxy)-1,3,5-
triazine (13c). Colorless solid (Yield: 77%); mp 167.1-168.8 °C; 1H-NMR (500 MHz, CDCl3) δ 7.60 (4H,
br), 7.35 (1H, s), 7.31 (1H, t, J = 7.7 Hz), 7.11 (1H, d, J = 7.4 Hz), 7.01 (1H, s), 7.00 (1H, d, J = 8.0 Hz),
4.01 (3H, s), 3.52 (1H, s), 2.39 (3H, s); HRMS (ESI-) m/z 473.1041 [(M-H)- :calcd. for C20H16F6N4O3,
473.1043].

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2-{4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropyl)anilino}-4-methoxy-6-(4-methylphenoxy)-1,3,5-
triazine (13d). Colorless solid (Yield: 69%); mp 207.3-208.2 °C; 1H-NMR (500 MHz, CDCl3) δ 7.60 (4H,
br), 7.31 (1H, s), 7.22 (2H, d, J = 8.0 Hz), 7.07 (2H, td, J = 3.4, 5.4 Hz), 4.01 (3H, s), 3.53 (1H, s), 2.39
(3H, s); HRMS (ESI-) m/z 473.1054 [(M-H)- :calcd. for C20H16F6N4O3, 473.1043].
4-Ethoxy-2-{4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)anilino}-6-phenoxy-1,3,5-triazine
(13e).
Colorless solid (Yield: 69%); mp 164.8-165.6 °C; 1H-NMR (500 MHz, CDCl3) δ 7.57 (4H, br), 7.43 (2H,
t, J = 8.0 Hz), 7.35 (1H, s), 7.30 (1H, t, J = 7.2 Hz), 7.20 (2H, d, J = 8.0 Hz), 4.43 (2H, q, J = 7.1 Hz),
3.57 (1H, s), 1.40 (3H, t, J = 6.9 Hz); HRMS (ESI-) m/z 473.1049 [(M-H)- :calcd. for C20H16F6N4O3,
473.1043].
Reporter gene assay
pcDNA3.1(-)-hRORα1, pcDNA3.1(-)-hRORβ1, pcDNA3.1(-)-hRORγ1 and RORE-TK-Luc were
provided by Itsuu Laboratory. CMX-β-GAL was provided by Professor Dr. Makoto Makishima (Nihon
University School of Medicine). pVP16-PXR was kind gift from Professor Dr. Hitoshi Shirakawa
(Graduate School of Agricultural Science, Tohoku University). HEK 293 cells were cultured in DMEM
containing 5% FBS, penicillin and streptomycin mixture at 37 °C in a humidified atmosphere of 5% CO2
in air. Cells were seeded at a density of 20% confluence/96-well plate 24 h prior to transfection. Cells in
each well were cotransfected with 150 ng of a nuclear receptor expression plasmid, 500 ng of a luciferase
reporter and 10 ng of CMX-β-GAL expression vector. Transfections were performed by the calcium
phosphate co-precipitation method. After 24 h, transfected cells were treated with test compounds or
DMSO for 24 h. Treated cells were assayed for luciferase activity with a Wallac ARVO SX 1420
Multilabel Counter (PerkinElmer). The luciferase activity of each sample was normalized by the level of
β-galactosidase activity. Each transfection was carried out in triplicate.
Docking simulation
The structure of the LBD of RORγ was prepared from the Protein Data Bank accession 4NB6. Polar
hydrogens were added, and partial atomic charges were assigned using AutoDockTools (ADT).
Molecular docking was performed using AutoDock 4.2 with Genetic Algorithm.
ACKNOWLEDGEMENTS
We thank Professor Dr. Hitoshi Shirakawa (Graduate School of Agricultural Science, Tohoku University)
and Dr. Shoko Sato (Department of Biological Science and Technology, Tokyo University of Science) for
providing pVP16-PXR plasmid. This work was partially supported by Platform for Drug Discovery,
Informatics, and Structural Life Science, and the JSPS KAKENHI (Grant No. 26293025 (Y.H.), No.
25460146 (S.F.).

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REFERENCES
1. G. Giacomelli and A. Porcheddu, 1,3,5-Triazine, Chapter 3, pp. 197-290, ed. by A. R. Katritzky, C.
A. Ramsden, E. F. V. Scriven, and R. J. K. Taylor, 'Comprehensive Heterocyclic Chemistry III, 3rd
Ed. Vol. 9, Six-membered Rings with Three or more Heteroatoms, and their Fused Carbocyclic
Derivatives', Elsevier, Amsterdam, 2008.
2. M. Kunishima, C. Kawachi, F. Iwasaki, K. Terao, and S. Tani, Tetrahedron Lett., 1999, 40, 5327; M.
Kunishima, C. Kawachi, K. Hioki, K. Terao, and S. Tani, Tetrahedron, 2001, 57, 1551.
3. K. Yamada, H. Fujita, and M. Kunishima, Org. Lett., 2012, 14, 5026; H. Fujita, N. Hayakawa, and
M. Kunishima. J. Org. Chem., 2015, 80, 11200.
4. F. Ueda, S. Aratani, K. Mimura, K. Kimura, A. Nomura, and H. Enomoto, Arzneim.-Forsch., 1984,
34, 474; F. Ueda, S. Aratani, K. Mimura, K. Kimura, A. Nomura, and H. Enomoto,
Arzneim.-Forsch., 1984, 34, 478; T. Kyoi, M. Oka, K. Noda, and Y. Ukai, Life Sci., 2004, 75, 1833.
5. A. M. Venkatesan, C. M. Dehnhardt, E. Delos Santos, Z. Chen, O. Dos Santos,ꢀS. Ayral-Kaloustian,
G. Khafizova, N. Brooijmans, R. Mallon, I. Hollande, L. Feldberg,ꢀJ. Lucas, K. Yu, J. Gibbons, R. T.
Abraham, I. Chaudhary, and T. S. Mansour, J. Med. Chem., 2010, 53, 2636.
6. B. L. Hodous, S. D. Geuns-Meyer, P. E. Hughes, B. K. Albrecht, S. Bellon, J. Bready, S. Caenepeel,
V. J. Cee, S. C. Chaffee, A. Coxon, M. Emery, J. Fretland, P. Gallant, Y. Gu, D. Hoffman, R. E.
Johnson, R. Kendall, J. L. Kim, A. M. Long, M. Morrison, P. R. Olivieri, V. F. Patel, A. Polverino, P.
Rose, P. Tempest, L. Wang, D. A. Whittington, and H. Zhao, J. Med. Chem., 2007, 50, 611.
7. H.-S. Moon, E. M. Jacobson, S. M. Khersonsky, M. R. Luzung, D. P. Walsh, W. Xiong, J. W. Lee, P.
B. Parikh, J. C. Lam, T.-W. Kang, G. R. Rosania,, A. F. Schier, and Y.-T. Chang, J. Am. Chem. Soc.,
2002, 124, 11608.
8. M. Vidal-Mosquera, A. Fernández-Carvajal, A. Moure, P. Valente, R. Planells-Cases, J. M.
González-Ros, J. Bujons, A. Ferrer-Montiel, and A. Messeguer, J. Med. Chem., 2011, 54, 7441.ꢀ
9. S. Fujii, T. Kobayashi, A. Nakatsu, H. Miyazawa, and H. Kagechika, Chem. Pharm. Bull., 2014, 62,
700.
10. N. V. Grishin, J. Struct. Biol., 2001, 134, 167.
11. E. V. Koonin, Y. I. Wolf, and G. P. Karev, Nature, 2002, 420, 218.
12. M. A. Koch, L.-O. Wittenberg, S. Basu, D. A. Jeyaraj, E. Gourzoulidou, K. Reinecke, A. Odermatt,
and H. Waldmann, Proc. Natl. Acad. Sci. USA, 2004, 101, 16721.
13. T. Noguchi-Yachide, A. Aoyama, M. Makishima, H. Miyachi, and Y. Hashimoto, Bioorg. Med.
Chem. Lett., 2007, 17, 3957; M. Tetsuhashi, M. Ishikawa, M. Hashimoto, Y. Hashimoto, and H.
Aoyama, Bioorg. Med. Chem., 2010, 18, 5323; K. Motoshima, K. Sugita, Y. Hashimoto, and M.
Ishikawa, Bioorg. Med. Chem. Lett., 2011, 21, 3041; K. Motoshima, M. Ishikawa, Y. Hashimoto,

556
HETEROCYCLES, Vol. 95, No. 1, 2017
and K. Sugita, Bioorg. Med. Chem., 2011, 19, 3156; T. Noguchi-Yachide, K. Sugita, and Y.
Hashimoto, Heterocycles, 2011, 83, 2137.
14. S. Hosoda, A. Tanatani, K. Wakabayashi, M. Makishima, K. Imai, H. Miyachi, K. Nagasawa, and Y.
Hashimoto, Bioorg. Med. Chem., 2006, 14, 5489; M. Kainuma, J. Kasuga, S. Hosoda, K.
Wakabayashi, A. Tanatani, K. Nagasawa, H. Miyachi, M. Makishima, and Y. Hashimoto, Bioorg.
Med. Chem. Lett., 2006, 16, 3213; S. Hosoda and Y. Hashimoto, Bioorg. Med. Chem. Lett., 2007, 17,
5414; S. Hosoda, D. Matsuda, H. Tomoda, M. Hashimoto, H. Aoyama, and Y. Hashimoto, Bioorg.
Med. Chem. Lett., 2009, 19, 4228; K. Maruyama, T. Noguchi-Yachide, K. Sugita, Y. Hashimoto,
and M. Ishikawa, Bioorg. Med. Chem. Lett., 2010, 20, 6661.
15. D. J. Mangelsdorf, C. Thummel, M. Beato, P. Herrlich, G. Schütz, G. K. Umesono, B. Blumberg,
P. Kastner, M. Mark, P. Chambon, and R. M. Evans, Cell, 1995, 83, 835.
16. B. P. Fauber and S. J. Magnuson, J. Med. Chem., 2014, 57, 5871.
17. J. R. Schultz, H. Tu, A. Luk, J. J. Repa, J. C. Medina, L. Li, S. Schwendner, S. Wang, M. Thoolen,
D. J. Mangelsdorf, K. D. Lustig, and B. Sham, Genes Dev., 2000, 14, 2831.
18. N. Kumar, L. A. Solt, J. J. Conkright, Y. Wang, M. A. Istrate, S. A. Busby, R. D. Garcia-Ordonez, T.
P. Burris, and P. R. Griffin, Mol. Pharmacol., 2010, 77, 228.
19. L. A. Solt, N. Kumar, Y. He, T. M. Kamenecka, P. R. Griffin, and T. P. Burris, ACS Chem. Biol.,
2012, 7, 1515.
20. H. Toyama, M. Nakamura, Y. Hashimoto, and S. Fujii, Bioorg. Med. Chem., 2015, 23, 2982.
21. Y. Xue, E. Chao, W. J. Zuercher, T. M. Willson, J. L. Collins, and M. R. Redinbo, Bioorg. Med.
Chem., 2007, 15, 2156; B. P. Fauber, G. de Leon Boenig, B. Burton, C. Eidenschenk, C. Everett, A.
Gobbi, S. G. Hymowitz, A. R. Johnson, M. Liimatta, P. Lockey, M. Norman, W. Ouyang, O. René,
and H. Wong, Bioorg. Med. Chem. Lett., 2013, 23, 6604.
22. K. A. Houck, K. M. Borchert, C. D. Hepler, J. S. Thomas, K. S. Bramlett, L. F. Michael, and T. P.
Burris, Mol. Genet. Metab., 2004, 83, 184.
23. S. J. Langmade, S. E. Gale, A. Frolov, I. Mohri, K. Suzuki, S. H. Mellon, S. U. Walkley, D. F.
Covey, J. E. Schaffer, and D. S. Ory, Proc. Natl. Acad. Sci. USA, 2006, 103, 13807.
24. G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew, D. S. Goodsell, and A. J. Olson, J.
Comput. Chem., 2009, 16, 2785.