Discovery and structure-activity-relationship study of novel conformationally restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.10.029

The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1^R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1^wt and IDH2^R140Q.

Full text of DOI:10.1016/j.bmcl.2017.10.029

Accepted Manuscript
Discovery and structure-activity-relationship study of novel conformationally
restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhib-
itors
Qiangang Zheng, Shuai tang, Xianlei Fu, Ziqi Chen, Yan Ye, Xiaojing Lan, Lei
Jiang, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
PII:
S0960-894X(17)31014-4
https://doi.org/10.1016/j.bmcl.2017.10.029
BMCL 25358
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 August 2017
13 October 2017
14 October 2017
Please cite this article as: Zheng, Q., tang, S., Fu, X., Chen, Z., Ye, Y., Lan, X., Jiang, L., Huang, Y., Ding, J., Geng,
M., Huang, M., Wan, H., Discovery and structure-activity-relationship study of novel conformationally restricted
indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors, Bioorganic & Medicinal Chemistry
Letters (2017), doi: https://doi.org/10.1016/j.bmcl.2017.10.029
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Discovery and structure-activity-relationship
study of novel conformationally restricted
indane analogues for mutant isocitric
dehydrogenase 1 (IDH1) inhibitors
Leave this area blank for abstract info.
Qiangang Zhenga,# , Shuai Tangb,#, Xianlei Fua , Ziqi Chenb , Yan Yea,b, Xiaojing Lanb, Lei Jianga ,Ying Huanga,
Jian Dingb , MeiyuGengb , Min Huangb,*,Huixin Wan a,*

Bioorganic & Medicinal Chemistry Letters
jour nal homepage: w ww.elsevier. com
Discovery and structure-activity-relationship study of novel conformationally
restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1)
inhibitors
Qiangang Zhenga,# , Shuai tangb,#, Xianlei Fua , Ziqi Chenb, Yan Yea,b , Xiaojing Lanb, Lei Jianga, Ying
Huanga, Jian Dingb , MeiyuGengb , Min Huangb,*, Huixin Wana,*
a Shanghai Haihe Pharmaceutical, Co.,Ltd. 421 Newton Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203,China
b Shanghai Institute of Materia Medica, Chinese Academy of Science, 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203,
China
#, these authors contributed equally to this work.
*, corresponding authors.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via
structure-based rational design were reported. The optimal compounds demonstrated both potent
inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell
Accepted
line, favorable PK properties and great selectivity against IDH1wt and IDH2 R140Q
.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
IDH1 inhibitor
indane amide
structure-based rational design
Isocitrate dehydrogenase family, including IDH1, IDH2 and
IDH3, are important metabolic enzymes, that can convert
isocitrate to α-ketoglutarate (α-KG). Somatic cancer-associated
IDH mutations have been identified in multiple hematologic and
solid tumors, such as acute myeloid leukemia (AML),1 glioma,2
inhibitors. AG120 is one of the most advanced compound entered
into clinical trials as a mutant IDH1 inhibitor discovered by
Agios and has shown promising clinical benefit with 38% overall
8
response rate for advanced hematologic malignancies. This
compound contains a metabolic labile amide bond and two
epimerizable tertiary centers. In light of these, we proposed a
novel conformationally restricted scaffold with a quaternary
center at the backbone of AG120 (Figure 1).
cholangiocarcinoma
cancer
(IHCC),3
malignant
chondrosarcomas4 and others.5 IDH mutations often occur at
R132 in IDH1 or R140 and R172 in IDH2, which are located in
the catalytic pocket of these enzymes. Significantly, these
mutations allow IDH enzymes to gain a unique activity, that
catalytically converts α-KG to an onco-metabolite 2-
hydroxyglutarate (2-HG). The onco-metabolite (2-HG) is
strongly associated to impaired hematopoietic differentiation and
promotes leukemia due to its ability of global DNA
hypermethylation.6 Pharmacological blockade of mutant IDH1
enzyme effectively inhibits colony formation of patient-derived
IDH-mutated AML cells but not that of normal CD34+ bone
marrow cells.7 As such, mutant IDH has now become a
therapeutic target of great interest for cancer, especially AML,
although the contribution of mutant IDH to tumorigenic
properties remains to be elucidated.
Figure 1. From AG120 to the indane analogue compound 1b.
The installation of a quaternary center at α-position of amide
would prevent epimerization and potentially slow down amide
hydrolysis. Among these fused rings shown in Table 1, the
indane analogue 1b retained most of the biochemical and cellular
activities of AG120. Compound 1b showed moderate activities in
both IDH1R132H enzymatic assay (IC50=94 nM) and the 2-HG
production inhibitory assay in HT1080 (IC50=21 nM), a human
sarcoma cell line carrying mutant IDH1. It was a very
Mutant IDH has now become a therapeutic target of great interest
in the field of antitumor drug discovery, and several big
pharmaceutical companies and new start-ups have paid much
more attention to discovery and development of mutant IDH

molecules were stabilized by two critical hydrogen bonds (HB),
formed by its two terminal carbonyl groups with Tyr272 and
Ala111. Additional two HBs were formed by the cyano pyridine
with the main chain NH of Leu120 and Ile128. These four HBs
provided key interactions for binding. The indane moiety formed
π-π stacking with the indole ring of Trp267 and hydrophobic
interactions with Val255, Ala258 and Met259. Further, the docking
model suggested that compound 1a or compound 1c was less
favored than compound 1b, proved by the 3-fold decrease in
enzymatic potency for 1a and 1c (Table 1). However, loss of two
hydrogen bonds between compound 1b’(S, R) and the protein
resulted in a dramatic decrease of enzymatic potency (Figure 2-
b).
encouraging start point for us to improve the in vitro potency of
this series of indane analogues.
Table 1. Enzymatic inhibition activities of different fused ring
analogues 1a-1c.
Cmpd
n
IDH1R132H
IC50 (nM)
2-HG
HT1080 a
IC50(nM)
NT
1
2
3
270
94
1a
1b
1c
21
275
NT
a, Compounds with IDH1R132H IC50 <100 nM was tested against 2-HG
production inhibitions on HT1080. NT, means not test.
Encouraged by these results, herein we would describe the
discovery, optimization and SAR studies of
a
novel
conformationally restricted indane analogues as mutant IDH1
inhibitors. A multi-step approach to synthesize the designed
compounds would involve three key steps (Scheme 1): (a)
Indanone and aromatic amine containing UGI reaction; (b)
Buchwald-Hartwig coupling with amide-NH and haloaromatic
2-a
2-b
Figure 2. Superimposition of the putative binding modes for compounds. 2-a,
binding mode for compound 1b (blue sticks) and AG120 (green sticks) with
IDH1R132H; 2-b, binding mode for compound 1b (blue sticks) and 1b’ (gray
9
sticks) bound to mutant IDH1R132H
.
ring; (c) Separation of diastereomers on HPLC or flash
10
chromatography.
When X is CH, a four components UGI
Since the activities between analog 1b (X = N) and 5a (X = CH)
were quite similar (Table 2), we focused on the SAR exploration
on analogs with X = CH due to their synthetic feasibility. In
continuation with SAR studies, we first explored the top left side
chain R group modification using a variety of cycles (Table 2).
Replacement of 4-membered ring with 6-membered ring (5b) led
to slight improvement in potency. The smaller cyclopropyl
methyl analogue (5c) decreased potency by three fold.
Interestingly, replacement of CH2(compound 5e) with O in the
cyclohexyl group of compound 5d caused loss of almost all the
activity, which indicated that the hydrophilicity of R group
might be unfavorable to the protein interaction. Similarly, rigid
phenyl ring replacement (compound 5f) was also unfavorable to
the interaction.
reaction afforded the indane amide backbone, subsequently a
Buchwald-Hartwig cross coupling reaction was followed with
diastereomers isolation from moderate to high yields. However,
when X is N, classical UGI conditions (step a, Scheme 1) by
mixing all the components in dried MeOH did not proceed well
with recovery of most of starting materials. Compound 2 was
formed in less than 5% yield. We reasoned the low yield might
be due to the weak nucleophile of 3-amino-5-F pyridine and thus
slow imine formation. Instead, a stepwise UGI reaction was
conducted under more forcing conditions to prepare imine 4 (step
d, Scheme 1). Then the resulting imine 4 reacted with acid and
isocyanide to afford the intermediate 2, following with a
Buchwald-Hartwig reaction and diastereomers separation to
afford the desired target compound 1b (S,S’) and 1b’ (S, R’). In
our in-house biochemical assay, the (S, S) diastereomer
(IDH1R132H IC50 for compound 1b and 5a was 94 nM and 85 nM
respectively) are more potent than the (S, R) diastereomer
(IDH1R132H IC50 for compound 1b’ and 5a’was both >10 000
nM).
Table 2. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 1b and 5a-5f.
Cmpd
R
X
IDH1R132H
IC50(nM)
2-HG HT1080 a
IC50(nM)
1b
N
94
85
21
25
CH
5a
5b
5c
CH
CH
80
15
Scheme 1. General synthetic route of indane analogues. Reagents and
conditions: (a) anhydrous MeOH, rt, overnight, <5% yield; (b)Cs2CO3,
Pd2(dba)3, XantPhos, anhydrous 1,4-dioxane, N2, 80oC, sealed tube, 3h, 50-
72%; (c) diastereomers separation; (d) ClCH2CH2Cl, 4 Å MS, N2, 5% TiCl4,
reflux, 12h; (e) anhydrous MeOH, rt, overnight, 30-50%.
266
NT
From the docking model (Figure 2-a), compound 1b overlayed
well with AG120 in the same allosteric pocket in mutant
IDH1R132H crystal structure (PDB ID: 5tqh). 11 These two

338
148
95
NT
NT
NT
6c
6d
6e
CH
CH
CH
37
<10
NT
NT
5d
5e
5f
>1000
>1000
45
5
6f
6g
6h
Therefore compound 5a, 5b and 5d were subjected to
microsomal stability test. As shown in Table 3, the geminal di-F
substitution in compound 5b could significantly improve the
metabbolitic stability of compound 5d. The geminal di-F
substituted cyclobutyl group (compound 5a) could be further
metabolic more stable and have slower turnover rate than
compound 5d. Hence gem di-F cyclobutyl group was fixed for
further lead optimization.
172
NT
186
NT
The SAR for F or Cl substituted indane scaffold was also
explored (Table 5). When fluorine atom was introduced at 4-, 5-,
6-, or 7-position to indane, the potency of compound 7a and 7d
was slightly better than that of compound 7b and 7c. Fluorine at
4- or 7-position seemed to produce additional hydrophobic
interaction based on docking model. Then larger Cl atom was
installed at 4- or 7-position to indane ring system (7e and 7f),
which led to improved cellular activity (7e and 7f, 21 nM and 7.5
nM respectively). To our surprise, when R1 is F, only 4-Cl indane
analogue could keep the inhibition potency of IDH1R132H, while
7-Cl indane analogue lost 2 fold of its potency.
Table 3. Mice, rat and human microsomal stabilities of
compound 5a, 5b and 5d.
Cmpd
Clint in vitro(mL/min/g protein)
Mouse
54.1
Rat
3.7
Human
3.1
5a
5b
5d
567
24
35
2359
1145
1005
Table 5. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 5a and 7a-7h.
With the fixed left side chain, substitutions on top benzene (R1)
were screened in Table 4. Removal of 3-F group (compound 6a)
from compound 5a or replacement of 3-F group with 3-Cl
(compound 6b) both resulted in a 3-fold decrease of enzymatic
potency. Then another fluorine was added to the different
position in the phenyl ring of compound 5a resulted in compound
6c-6f. Interestingly, 3, 5-di fluorine analogue(6f) demonstrated
improved enzymatic and cellular potency (45 nM and 5 nM
respectively) and only 3, 4- di fluorine analogue (6e) could retain
the enzymatic activity of compound 5a, while 2,4-difluorine
(compound 6c) and 2,3-difluorineanalogues (6d) were 2-3 fold
less potent than compound 5a. As observed in above, the
corresponding Cl substitution was not as effective as fluorine
analogue (6g vs 6f, 6h vs 6e). These results suggested that the
meta-fluorine atom might have some hydrophobic interaction
with the hydrophobic pocket consisted of the Leu120 and Trp124
side chains.
Cmpd
R1
R2
IDH1R132H
IC50(nM)
85
2-HG HT1080 a
IC50(nM)
25
H
H
H
H
H
H
H
F
H
5a
7a
7b
7c
7d
7e
7f
4-F
68
108
138
51
27
NT
NT
52
5-F
6-F
7-F
4-Cl
7-Cl
4-Cl
7-Cl
67
21
Table 4. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 5a and 6a-6h.
49
7.5
14
53
7g
7h
F
180
NT
After elucidated the SAR at three regions of this scaffold, we
continued to expand the exploration on oxoproline group.
According to the data from Table 6, the R isomer (8a)
dramatically decreased its potency and proline analogue
(compound 8b) also lost most of its potency due to loss of the
hydrogen bond with Ala111. Interestingly, the carbamate analogue
(compound 8c) exhibited a little improvement in enzymatic
potency.
Cmpd
IDH1R132H
IC50(nM)
85
2-HG HT1080 a
IC50(nM)
25
5a
260
255
NT
NT
6a
6b
Table 6. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 5a and 8a-8c.

Table 8). Compound 10a and 10b retained enzymatic and
cellular potency, while compound 10c and 10d resulted in
decreased activity in cellular potency. Interestingly, compound
10e demonstrated excellent enzymatic potency (5.6 nM, 9-fold
and 15-fold improvement in comparison with that of compound
6f and 1b, respectively), but disappointedly did not transfer to
more active cellular potency (29 nM in HT1080). We postulated
that the lower permeability associated with the higher tPSA value
in this compound might produce this result.
Cmpd
L
IDH1R132H
IC50(nM)
2-HG HT1080 a
IC50(nM)
85
25
5a
8a
Table 8. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 6f, 7f and 10a-
10e.
NT
NT
>10000
635
8b
8c
58
19
Cmpd
R1
R2
A
B
IDH1R132H
IC50(nM)
45
2-HG HT1080 a
tPSA
IC50(nM)
5
Finally, the bottom right R3 group was investigated (Table 7).
Based on the docking model, the N atom on pyridine interacted
with the Ile128 residue through hydrogen bond. In consistent with
this hypothesis, 60-fold potency decrease was observed with the
phenyl replacement (9a). The CN group (9b) was also crucial to
potency (9b). Different substitution was thus designed to mimic
this CN group. Pyrazine analogue (9c) decreased potency by two
fold (128 nM), while the analogues with methoxyl group (9d) or
methyl sulfonyl group (9e) were almost inactive. Pyrimidine
nitrile compound 9f improved the enzymatic potency by two fold
(22 nM), but reduced the cellular activity by three fold (14.9 nM)
possibly due to its poor physical and chemical property of
aminopyrimidinyl group.
F
H
F
H
Cl
H
CH2 CH
CH2 CH
106
106
115
115
118
127
127
6f
49
54
42
22
40
5.6
7.5
8.9
9
7f
O
O
CH
CH
N
10a
10b
10c
10d
10e
H
H
F
Cl
Cl
H
CH2
O
42
308
29
N
H
Cl
O
N
To our delight, compound 6f and 7f with excellent cellular
potency (IC50<10 nM) also showed moderate to high selectivity
against wild type IDH1 (79 and 36 fold respectively) and mutant
IDH2R140Q (>2000 fold) (Table 9). These two compounds were
also progressed into primary mice pharmacokinetic (PK) study.
Good PK parameters were observed with low clearance (<1.5
L/h/Kg) and high bioavailability (>30%) in mice (Table 10). It
indicated that these two selected compounds might have good in
vivo efficacy in nude mice.
Table 7. Enzymatic inhibition and 2-HG production
inhibition activities in HT1080 for compound 6f and 9a-9f.
Cmpd
R3
IDH1R132H
IC50(nM)
45
2-HG HT1080 a
Table 9. Selectivity of compound 6f and 7f against IDH1wt
and mutant IDH2.
IC50(nM)
5
Cmpd
IDH1R132H
IC50(nM)
45
IDH1wt
IC50(nM)
3560
IDH2R140Q
IC50(nM)
>100
IDH1wt/ID
H1R132H
IDH2R140Q
/
6f
IDH1R132H
>2200 fold
>2040 fold
9a
1. 2605
>10000
2. NT
NT
6f
7f
79 fold
36 fold
49
1780
>100
3. 9b
4.
4.1.1. 128
4.1.2. NT
9c
Table 10. Mouse PK parameters of compound 6f and 7f
Cmpd
Cl(L/hr/Kg)
(iv, 1 mpk)
0.5
Vss
(L)
1
AUC(ng/mL.hr)
(iv, 1mpk)
1984
AUC(ng/mL.hr)
(po,5mpk)
3620
F(%)
4.1.4.1. >10000
4.1.4.4.1. 2965
4.1.4.2. NT
4.1.3. 9d
4.1.4.
4.1.4.4.2. NT
4.1.4.3. 9e
6f
7f
87
38
4.1.4.4.
1.2
1.9
834
3780
4.1.4.4.3. 9f
22
14.9
iv formulation: 5%DMSO/95% saline; po formulation: 0.4%MC in deionized
water.
4.1.4.4.4.
In summary, a novel class of conformationally restricted indane
analogues for IDH1 inhibitors were discovered and optimized via
We further attempted to combine all optimized structural features
from different part of molecular into one compound (10a-10e,

12. All synthesized compounds in this article were characterized by
HNMR and LCMS. Their purity was at least 95% for the
enzymatic and cellular assay and 98% for mouse PK study.
structure-based rational design. The most advanced analogues 6f
and 7f showed potent enzymatic and cellular activities, favorable
mouse PK properties and great selectivity against wide-type
IDH1 and mutant IDH2. These promising results strongly
supported further development of these compounds into orally
selective mutant IDH1 lead compounds.
Supplementary Material
Chemistry, biological assay information and docking method.
This material is available free of charge via the internet.
Acknowledgements
This work was supported by the China International Science and
Technology Cooperation Program (No. 2015DFM30040 to MH) and a
grant from the National Natural Science Foundation of China (No.
81573464 to MH).
References and notes
1. (a) Zhou, K.G.; Jiang, L.J.; Shang, Z.; Wang, J.; Huang, L.; Zhou,
J. Leukemia & Lymphoma, 2012, 53(12), 2423-2429. (b) Abbas
S.; Lugthart, S.; Kavelaars, F.; Schelen, A; Koenders, J;
Zeilemaker, A; van Putten Wim, J. L.; Rijneveld, A W;
Lowenberg, B; Valk, P. J. M. Blood, 2010, 116(12), 2122-6. (c)
Di Nardo, C. D.; Jabbour, E.; Ravandi, F.; Takahashi, K.; Daver,
N.; Routbort, M.; Patel, K. P.; Brandt, M.; Pierce, S.; Kantarjian,
H.; Garcia-Manero, G. Leukemia, 2016, 30(4), 980-984. (d)
Paschka, Peter; Schlenk, R.F.; Gaidzik, V. I.; Habdank, M.;
Kroenke, J.; Bullinger, L.; Spaeth, D.; Kayser, S.; Zucknick, M.;
Goetze, K.; Horst, H.; Germing, U.; Doehner, H.; Doehner, K. J.
Clin. Oncol. 2010, 28, 3636.
2. (a) Houillier, C.; Wang, X.; Kaloshi, G.; Mokhtari, K.; Guillevin,
R.; Laffaire, J.; Paris, S.; Boisselier, B.; Idbaih, A.; Laigle-
Donadey, F.; Hoang-Xuan, K.; Sanson, M.; Delattre, J-Y.
Neurology, 2010, 75(17), 1560-1566. (b) Yan, H.; Parsons, D. W.;
Jin, G.; McLendon, R.; Ahmed, R. B.; Yuan, W.S.; Kos, I.;
Batinic-Haberle, I.; Jones, S.; Riggins, G. J.; Friedman, H.;
Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K. W.;
Velculescu, V.E.; Vogelstein, B.; Bigner, D. D. New Engl. J Med.
2009, 360(8), 765-773. (c) Parsons, D. W.; Jones, S.; Zhang, X.S.;
Lin, J. C. H.; Leary, R. J.; Angenendt, P.; Mankoo, P.; Carter, H.;
Siu, I.; Gallia, G. L.; Olivi, A.; McLendon, R.; Rasheed, B.; Keir,
S.; Nikolskaya, T.; Nikolsky, Y.; Busam, D. A.; Tekleab, H.; Diaz,
L. A.; Hartigan, J.; Smith, D.; Strausberg, R. ; Marie, S.; Kazue,
N.; Shinjo, S.; Yan, H.; Riggins, G.; Bigner, D.; Karchin, R.;
Papadopoulos, N.; Parmigiani, G.; Vogelstein, B.; Velculescu, V.;
Kinzler, K. Science, 2008, 321, 1807.
3. Saha, S.K.; Parachoniak, C.A.; Ghanta, K. S.; Fitamant, J.; Ross,
K.N.; Najem, M.S.; Gurumurthy, S.; Deshpande, V.; Zhu, A. X.;
Ferrone, C.R.; Bardeesy, N.; Akbay, E.A.; Wong, K-K.; Sia, D.;
Cornella, H.; Miltiadous, O.; Walesky, C.; Apte, U.; Hezel, A.F.;
Yen, K.E.; Straley, K.S.; Travins, J.; Popovici-Muller, J.; Gliser,
C.; Llovet, J.M.;Ramaswamy, S. K. Nature, 2014, 513,110–114.
4. Amary M.F.;, Bacsi K.; Maggiani F.; Damato S.; Halai D.;
Berisha F.; Pollock R.; O'Donnell P.; Grigoriadis A.; Diss T.;
Eskandarpour M.; Presneau N.; Hogendoorn P.C.; Futreal A.;
Tirabosco R.; Flanagan A.M. J Pathol., 2011, 224(3), 334–343.
5. Kang, M. R; Kim, M.; Oh, J.; Kim, Y; Song, S.; Seo, S.; Lee, J.;
Yoo, N.; Lee, S. Int J Cancer,2009, 125(2), 353-355.
6. Reitman Z.J., Parsons D.W., Yan H. Cancer Cell, 2010, 17, 215–
216.
7. Chaturvedi, A.; Cruz, M.; Jyotsana, N.; Sharma, A.; Yun, H.;
Goerlich, K.; Wichmann, M.; Schwarzer, A.; Preller, M.; Thol, F.;
Meyer, J.; Haemmerle, R.; Struys, E.A.; Jansen, E.; Modlich, U.;
Li, Z; Sly, L.; Geffers, R.; Lindner, R.; Manstein, D.; Lehmann, U;
Krauter, J; Ganser, A.; Heuser, M. Blood, 2013, 122, 2877–87.
8. http://investor.agios.com/phoenix.zhtml?c=251862&p=irol-
newsArticle&ID=2227727.
9. Dömling, A.; Ugi, I. Angew. Chem.-Int. Edit. 2000, 39, 3168–
3210.
10. Lemieux, Rene M.; Poovici-muler, Janeta et al.
WO2013107291A1.
11. Levell J.R.;Caferro T.;Chenail G.;Dix I.;Dooley J.; Firestone
B.;Fortin P.D.;Giraldes J.;Gould T.;Growney J.D.;Jones
M.D.;Kulathila R.;Lin F.;Liu G.;Mueller A.;van der Plas
S.;Slocum K.;Smith T.;Terranova R.;Touré B.B.;Tyagi V.;Wagner
T.;Xie X.;Xu M.;Yang F.S.;Zhou L.X.;Pagliarini R.;Cho Y.S.
ACS Med. Chem. Lett., 2016,8(2),151-156.