Design, synthesis and structure activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl carboxamide scaffold

Article abstract of DOI:10.1016/j.bmcl.2016.03.037

The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer therapy. Herein we describe our efforts in identifying potent pan-PIM inhibitors that are derived from our previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address metabolic stability.

Full text of DOI:10.1016/j.bmcl.2016.03.037

Accepted Manuscript
Design, synthesis and structure activity relationship of potent pan-PIM kinase
inhibitors derived from the pyridyl carboxamide scaffold
Gisele A. Nishiguchi, Matthew T. Burger, Wooseok Han, Jiong Lan, Gordana
Atallah, Victoriano Tamez, Mika Lindvall, Cornelia Bellamacina, Pablo Garcia,
Paul Feucht, Tatiana Zavorotinskaya, Yumin Dai, Kent Wong
PII:
S0960-894X(16)30256-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.037
BMCL 23680
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 January 2016
9 March 2016
10 March 2016
Please cite this article as: Nishiguchi, G.A., Burger, M.T., Han, W., Lan, J., Atallah, G., Tamez, V., Lindvall, M.,
Bellamacina, C., Garcia, P., Feucht, P., Zavorotinskaya, T., Dai, Y., Wong, K., Design, synthesis and structure
activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl carboxamide scaffold, Bioorganic
& Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.037
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Design, synthesis and structure activity relationship of potent pan-PIM
kinase inhibitors derived from the pyridyl carboxamide scaffold
Gisele A. Nishiguchi a,*, Matthew T. Burger a, Wooseok Han a, Jiong Lan a, Gordana Atallah a, Victoriano
Tamez a, Mika Lindvall a, Cornelia Bellamacina a, Pablo Garcia b, Paul Feucht b, Tatiana Zavorotinskaya b,
Yumin Dai b, Kent Wong a
a Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4560 Horton Street,
Emeryville, California 94608, United States
b Oncology, Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California
94608, United States
Abstract: The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be
upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions
among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer
therapy. Herein we describe our efforts in identifying potent pan-Pim inhibitors that are derived from our
previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address
metabolic stability.
The Pim kinases (Pim-1, Pim-2 and Pim-3) have emerged as attractive pharmacologic targets in
cancer therapy given their roles in cell-cycle progression, cell survival and tumorogenesis.1 Pim
oncogenes are known to be overexpressed and dysregulated in a variety of cancers and more recent
evidence points to hematologic malignancies as a potential oncology indication.2 The Pim kinases are a
family of serine/threonine kinases that are constitutively active and lack regulatory domains, hence they
are regulated at both the transcriptional and translational levels.3 They share a high level of sequence
* Corresponding Author at present address: 250 Massachusetts Avenue, Cambridge, MA 02139. Tel.: +1 617 871
3463. E-mail address: gisele.nishiguchi@novartis.com (G. A. Nishiguchi).

homology within the family (>61%)4 and are differentiated from other kinases by a unique structure of
their active site, which provides the opportunity for small molecule designs to generate highly selective
kinase inhibitors.5 At the same time, the Pim kinases are characterized by significantly different ATP Km’s
within their own family (ATP Km for Pim-2 is 4 µM compared to 160 µM and 40 µM for Pim-1 and Pim-3
respectively), which makes it challenging to obtain cellular potent pan-PIM inhibitors, especially for cell
lines that are Pim-2 dependent.6 Functional similarities and compensatory roles in oncogenesis among
the Pim kinase isoforms have been reported,7 which emphasizes the significance of targeting all three
members of the Pim family for effective inhibition. Several cellular active and novel pan-PIM kinase
inhibitors have now emerged,8 offering the opportunity to evaluate the therapeutic benefits of pan-Pim
inhibition in the clinic.
Figure 1: HTS hit (1a), tool compound (1b) and strategies to mitigate clearance
Figure 2: X-ray structure of PIM447 (1c) in Pim-1 (PDB: 5DWR).
We previously reported the optimization of a singleton HTS hit (1a) that led to the discovery of 1b
(Figure 1), a highly potent and selective pan-Pim inhibitor with demonstrated efficacy on Pim-2 driven
multiple myeloma (KMS-11) and acute myeloid leukemia (EOL-1) subcutaneous tumor mouse models.8j
Compound 1b served as an in-vivo tool for pan-Pim target validation. More recently, we also disclosed the

discovery of PIM447 (1c, Figure 2), a compound currently in several clinical trials belonging to the
aminocyclohexyl pyridyl carboxamide chemical series.8c This series emerged from a medicinal chemistry
strategy to investigate the effect of the A-ring carbon-linker on in-vitro liver microsomal stability. The high
hepatic extraction ratio (ER_H) in both rat and human liver microsomes for the tool compound 1b combined
with the extensive metabolism that takes place in the piperidine A-ring according to met ID studies in human
liver microsomes, posed both developability and toxicity risks.8c Therefore, in conjunction to the cyclohexyl
strategy that led to 1c, an alternative series was investigated that explored heteroaryl moieties as the A-ring
with the similar goal of assessing the effect of this modification on the microsomal stability (Figure 1).
However, such a strategy would require the removal of the basic amine and a priori, it was unknown if that
would be tolerated from a potency perspective and the effect it would have on the physicochemical
properties of the compounds. Therefore, we anticipated that the A-ring aromatization strategy would require
potency and physicochemical properties re-optimization due to potentially distinct A-ring conformation and
the lower basicity of a heteroaryl amine relative to 1b. Herein, we describe our medicinal chemistry strategy
and our findings in the generation of a potent pan-Pim inhibitor series.
Based on the published crystal structure illustrating the binding mode of 1c in Pim-1 (Figure 2),8c
the basic amine makes two hydrogen bonds to the Asp128 side chain carboxylate and the Glu171 backbone
carbonyl in the ribose patch. We postulated that we could mimic these interactions with a heteroaryl-NH2
moiety while also providing vectors in which we could further explore the surrounding region of the pocket by
substituting off the heteroaryl.
With this strategy in mind, Schemes 1 and 2 illustrate general methods for how compounds were
synthesized. Introduction of the D-ring on intermediate I via Suzuki-Miyaura coupling followed by hydrolysis
of the methyl ester afforded carboxylic acid II (Scheme 1). This intermediate was reacted with 4-
chloropyridin-3-amine in the presence of EDC and HOAt at room temperature to provide intermediate III.
Carbon-carbon bond formation to install the A-ring was achieved via Suzuki-Miyaura reaction utilizing
Pd(dppf)Cl2-DCM as the catalyst and the corresponding boronic ester or boronic acid, or alternatively via
conversion of III to the corresponding boronic ester, followed by Suzuki-Miyaura reaction with a heteroaryl
halide. Individual A-ring boronic esters and halides were synthesized as previously described.9

Scheme 1. Representative example for the synthesis of compounds illustrated in Tables 1 and 2 .
Reagents and Conditions: (a) (i) 2-fluorophenylboronic acid, Pd(dppf)Cl2-DCM, DME/2M Na2CO3, 120 oC; (ii)
LiOH; (b) 4-chloropyridin-3-amine, HOAt, EDCI, DCM or DMF; (c) heteroarylboronic acid, Pd(dppf)Cl2-DCM,
dioxane/2M Na2CO3, 120 oC; (d) (i) KOAc, bis(pinacolato)diboron, Pd(dppf)Cl2-DCM, dioxane, 120-150 oC;
(ii) heteroarylhalide, Pd(dppf)Cl2-DCM, DME/2M Na2CO3, 110 oC
Alternatively, C and D ring diversification was introduced by first making the boronic ester of the
Cbz protected chloro-aminopyridine V to give boronic ester VI, followed by cross-coupling with the
corresponding heteroaryl halide to afford intermediate VII (Scheme 2). Deprotection of the Cbz under
hydrogenolysis conditions followed by amide bond formation in the presence of HOAt and EDC afforded final
compound IX after Boc group deprotection and HPLC purification.
Scheme 2. Representative example for the synthesis of compounds illustrated in Table 3. Reagents and
Conditions: (e) bis(pinacolato)diboron, Pd2(dba)3, PCy3, KOAc, dioxane, 90 oC; (f) heteroaryl halide,
Pd(dppf)Cl2-DCM, DME/2M Na2CO3, 90 oC; (g) H2, Pd/C; (h) (i) HOAt, EDC, NMP and carboxylic acid; (ii)
TFA
The compounds were tested in Pims-1, 2 and 3 biochemical assays where each Pim isoform was
screened with ATP concentrations at or below its corresponding ATP Km and obtained Ki’s are reported.
Based on our previous work in this scaffold, Pim-2 biochemical potency was the most challenging among the
three isoforms, so we focused on obtaining potent Pim-2 activity. By introducing a 4-pyridine as the A-ring
(2b), a significant reduction of Pim-2 biochemical potency was observed relative to the aminopiperidine A-
ring (2a). With the goal of obtaining the hydrogen bond interactions in the ribose patch, the amino
substituent at the 2-position of the pyridine (2c) was introduced and gratifyingly, a 10-fold increase in
potency was observed, to achieve a compound with reasonable activity for Pim-2. Slightly improved potency

was obtained with the corresponding difluorophenyl D-ring (2g). Compounds 2d and 2e where the amino
group is moved around the heteroaromatic ring were not as potent, presumably due to suboptimal interaction
with the ribose patch residues (Glu171 and/or Asp128).
Investigation of other A-ring heterocycles (Table 1) that could maintain similar orientation of the
amino group of 2c such as in compounds 2f, 2h and 2i enabled us to identify the 4-amino-substituted
pyrimidine as an additional heterocycle (2h) with a slightly lower clogP than the corresponding pyridine
matched-pair (cLogP: 2.3 vs 2.7). While the Ki’s of compounds 2g and 2h are reasonable, further
improvement in potency was desired, given that based on our previous experience with this chemotype,
picomolar biochemical inhibition would be needed for efficacious cellular inhibition.
Table 1 – A-ring heteroaryl SAR
Pim-1
Ki (µM)
Pim-2
Ki (µM)
Pim-3
Ki (µM)
Compound
2a
R
X
H
<0.001
0.008
<0.003
0.317
0.035
<0.003
0.021
0.003
2b
2c
H
H
<0.001
2d
2e
H
F
0.004
0.028
0.158
0.187
0.012
0.036

2f
2g
2h
2i
H
F
F
F
0.003
0.002
0.004
0.006
0.094
0.008
0.027
0.050
0.006
<0.003
0.005
0.005
Additional potency improvement could be achieved by designing and synthesizing compounds
with various substitutions on the heteroaryl A-ring which probed the hydrophobic dimple under the glycine
rich loop (Table 2). Similar to the aminocyclohexyl and aminopiperidine chemical series, small
hydrophobic substituents, such as methyl, located at the 6-position of the pyridine A-ring provided a >3-
fold increase in Pim-2 biochemical potency (2g vs 3b). As shown in Table 2, methyl (3b), methoxy (3c)
and trifluoromethyl (3f) substituents were efficient in driving the biochemical potency further in both the
pyridine and pyrimidine heterocycles. Polarity in this region, represented by compound 3d with the amino
group was detrimental to potency.
Table 2: Selected SAR of analogs targeting potency improvement via A-ring substitutions along with rat
and human hepatic extraction ratios
Pim-1
Ki (µM)
Pim-2
Ki (µM)
Pim-3
Ki (µM)
ER_H
rat/human
Compound
R
X
cLogP

2g
3a
3b
3c
3d
3e
3f
F
H
F
F
H
F
F
<0.001
<0.001
<0.001
<0.001
0.017
0.009
0.004
<0.003
<0.003
<0.003
<0.003
0.015
-
2.7
3.1
3.2
3.6
2.1
2.8
3.2
0.95/0.95
0.94/0.96
-
<0.003
0.004
0.120
-
<0.001
<0.001
<0.003
<0.003
<0.003
<0.003
0.82/0.82
0.91/0.77
We were able to obtain an X-ray co-crystal structure of compound 3a and confirm the binding
mode in Pim-1. As shown in Figure 3, the A-ring pyridine amine forms a H-bond with the sidechain of
amino acid Asp128 and interacts with the backbone amide at residue Glu171 while the methyl group
occupies the hydrophobic dimple under the P-loop (top of protein omitted for clarity). The C-ring amino-
pyridine makes a single hydrogen bond to the hinge and the pyridine B-ring nitrogen interacts with the
Lys67 residue in a similar fashion as in the binding mode of 1c. The lower hinge is occupied by the 2-
fluorophenyl moiety.
Figure 3. X-ray structure of 3a in Pim-1 (2.1Å, PDB: 5IIS).

Having achieved picomolar potency across all three Pim isoforms, we evaluated the in vitro liver
microsomal stability for the series. Compounds were incubated with rat or human liver microsomes at 1
µM for 30 min and hepatic extraction ratios (ER_H) were determined using a well-stirred liver model.10 As
illustrated in Table 2, compounds tested displayed high ER_H in rat and human microsomes. Both
pyridine and pyrimidine heterocycles had similar poor metabolic stability independent of the methyl or
trifluoromethyl substituent. We hypothesized that perhaps the lipophilicity of our compounds was driving
the low microsomal stability. By comparing the measured logD for this series with the measured logD of
the aminocyclohexyl series, we were in a more lipophilic space (logD for 3f is 4.3 and logD for 1c is 1.1).
Therefore, we focused our strategy around lowering the cLogP and assessing whether such an approach
would improve the microsomal stability. Towards designing more polar compounds, we had previously
established that both the A and B rings were optimized for potency with little opportunity for further
polarity introduction. We turned our attention towards the much less explored C and D rings where efforts
focused upon the incorporation of polar heterocycles to reduce hydrophobicity.
We designed and synthesized several combinations of A/B rings with more polar C/D rings, with
the goal of lowering the cLogP into a range of 1-2. Several representative examples are illustrated in
Table 3 along with their rat and human extraction ratios. The replacement of the difluorophenyl moiety by
a thiazole ring, analog 4a, was well-tolerated based on biochemical assays however the ER_H was not
improved relative to 3f albeit the lower cLogP. A slightly improved human ER_H was observed with the
methylpyrimidine A-ring combination with thiazole D-ring 4b, however this came at the expense of Pim-2
biochemical potency. By switching the polar strategy towards the C-ring, the addition of one nitrogen

lowered the cLogP to 2 (compound 4c) and this modification provide compounds trending towards more
acceptable human ER_H (0.58), although detrimental to Pim-2 biochemical potency.
Table 3: Biochemical activity, rat and human hepatic extraction ratios of compounds with lower cLogP
Pim-1
Ki (µM)
Pim-2
Ki (µM)
Pim-3
Ki (µM)
ER_H
rat/human
Compound
4a
Structure
cLogP
<0.001
<0.001
<0.001
<0.003
0.009
0.007
<0.003
<0.003
<0.003
0.89/0.87
0.81/0.64
0.80/0.58
1.5
4b
4c
1.1
2.0
In general, it was extremely challenging to find the appropriate balance between physicochemical
properties and potency while addressing the metabolic stability for the heteroaryl series. Furthermore,
the potencies of the A-ring heteroaryl compounds in a cell proliferation assay were inferior by ~10 fold
(compound 4a KMS-11 luc EC50 1.5 µM) compared to the earlier aminocyclohexyl series (compound 1c
KMS-11 luc EC50 0.17 µM). This result coupled with the high rat and human intrinsic clearance and low
aqueous solubility contributed to a no-go decision to progress this series into further pre-clinical studies.
In retrospect, the basic amine present in both the aminopiperidine and aminocyclohexyl scaffolds (Figure
1) proved instrumental in retaining the desired potency and physicochemical properties that could not be
replicated using the described heteroaryl approach.
In conclusion, replacement of the A-ring cyclohexyl moiety in the pyridyl carboxamide scaffold
with various amino heterocycles generated a novel chemical series of potent pan-Pim inhibitors. The
potency of this series was optimized by utilizing structure-based drug design as well as previous SAR
from a related chemical series. A new X-ray structure was determined for a representative example of
this series which confirmed the binding mode for the scaffold as well as the key contacts that the
heteroaryl amine makes with the protein. While weak cellular potency and poor metabolic stability
prevented further advancement for these compounds, this SAR investigation proved to be a

complementary medicinal chemistry optimization effort that aided in the discovery of PIM447, a
compound currently in several Phase I clinical trials.
Acknowledgments
The authors would like to thank Weiping Jia and Dhazi Tang for analytical chemistry support.
Supplementary Data
Supplementary Data (synthesis of compounds and assay experimental details) associated with this article
can be found in the online version, at http://XXX
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10. See Supplementary Information