Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection

Article abstract of DOI:10.1002/anie.201606496

Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp²-rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp³character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

Full text of DOI:10.1002/anie.201606496

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606496
German Edition: DOI: 10.1002/ange.201606496
Drug Discovery
3
Partially Saturated Bicyclic Heteroaromatics as an sp -Enriched
Fragment Collection
David G. Twigg, Noriyasu Kondo, Sophie L. Mitchell, Warren R. J. D. Galloway,
Hannah F. Sore, Andrew Madin, and David R. Spring*
Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th birthday
3
Abstract: Fragment-based lead generation has proven to be an
effective means of identifying high-quality lead compounds for
drug discovery programs. However, the fragment screening sets
sp -richness in both the design of screening collections and the
subsequent development of hits to leads.
Examples of previous studies aiming to synthesize collec-
2
3
often used are principally comprised of sp -rich aromatic
tions of sp -enriched fragments have been limited. Diversity-
oriented synthesis
been used to generate 3D fragment collections, but there
remains an unmet need to access new scaffold types. Recently
[
7,11]
[12]
compounds, which limits the structural (and hence biological)
diversity of the library. Herein, we describe strategies for the
synthesis of a series of partially saturated bicyclic hetero-
and natural product derivatives have
3
[13]
aromatic scaffolds with enhanced sp character. Subsequent
there have been calls
for new approaches and method-
derivatization led to a fragment collection featuring regio- and
stereo-controlled introduction of substituents on the saturated
ring system, often with formation of new stereocenters.
ologies for designing fragments with multiple synthetically
accessible growth vectors in three dimensions, to allow rapid
and efficient elaboration of hits to leads after initial screening,
[
14]
with some early success.
F
ragment-based drug discovery (FBDD) is a well-estab-
With these points in mind, the study described herein was
aimed at developing efficient synthetic routes to a series of
partially saturated bicyclic heteroaromatic (PSBH) fragments
[1]
lished method for generating high-quality hits and leads.
The approval of the B-Raf kinase inhibitor vemurafenib
[
2]
3
(
Zelboraf) in 2011 and the Bcl-2 inhibitor venetoclax
with enhanced sp content relative to existing fragment
[
3]
(
Venclexta) in 2016, coupled with the ongoing evaluation
libraries. Compounds featuring PSBHs have been shown to
[
4]
[15]
of over 20 candidates in clinical trials, validates this
approach as a complementary strategy to other hit-discovery
techniques such as high-throughput screening. While the
growing prevalence of fragment-based approaches is encour-
aging, evaluation of many existing fragment libraries shows
a predominance of (hetero)aromatic, “flat” compounds, with
a deficiency of chiral, sp -rich examples.
Studies by Ritchie et al. and Lovering et al. demon-
strate improvements in project progression by, for example,
display bioactivity against a range of targets (Figure 1), and
so a series of related fragments might be expected to serve
effectively as a screening collection for FBDD applications.
The targets of this study featured a variable aromatic
heterocycle fused to a partially saturated carbocycle. The
heterocycle could bear either a polar (e.g., amino) group,
which should greatly enhance aqueous solubility, a property
[
5]
3
[6,7]
[8]
[9]
[7,14]
necessary for fragment screening at higher concentrations,
3
increasing the fraction of sp centers within molecules or
restricting the number of aromatic rings. Furthermore,
computational analysis demonstrates that greater 3D con-
formational character is observed in compounds that have
been clinically evaluated in humans, compared to those found
[10]
in commercial libraries. This indicates the importance of
[*] D. G. Twigg, Dr. N. Kondo, S. L. Mitchell, Dr. W. R. J. D. Galloway,
Dr. H. F. Sore, Prof. D. R. Spring
Department of Chemistry, University of Cambridge
Lensfield Rd, Cambridge, CB2 1EW (UK)
E-mail: spring@ch.cam.ac.uk
Dr. N. Kondo
Shionogi & Co. Ltd.
1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825 (Japan)
Dr. A. Madin
AstraZeneca UK Ltd.
310 Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ (UK)
Figure 1. Selected examples of bioactive compounds containing func-
tionalized partially saturated bicyclic heteroaromatics (highlighted in
red).
Supporting information for this article (including all data supporting
this study) can be found under:
http://dx.doi.org/10.1002/anie.201606496.
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Table 1: Synthesis of pyrazole-based PSBH scaffolds.
Scheme 1. General synthetic strategy toward PSBH scaffolds 1 and
subsequent incorporation of new functionalities (2) or rings (3).
or alternatively a hydrophobic (e.g., chloro) group, which can
[
16]
forge key interactions with protein targets. The synthetic
route (Scheme 1) employed modular and divergent
a
approach, using simple cross-coupling and alkylation reac-
tions to install a pair of terminal olefins that could be reliably
Step
[
17]
cyclized through ring-closing metathesis (RCM).
This
[c]
[d]
[g]
m
R
X
A (7)
B (8)
C (9)
D (10)
allowed excellent control of the carbocycle ring size and the
position and orientation of the resultant endocyclic olefin
growth vector, which could undergo subsequent functional-
ization to produce a range of fragments suitable for screening
and/or further elaboration.
[
a]
[h]
a
b
c
0
0
0
0
H
H
H
H
85%
80%
55%
86%
55%
59%
45%
–
–
–
–
–
–
84%
89%
65%
[e]
f]
d
[
e
0
H
–
–
29%
83%
We selected pyrazole and pyridine as representative
aromatic heterocycles. Whilst previous studies have shown
[
a]
b]
f
g
h
0
1
1
Me
H
H
76%
61%
–
69%
82%
–
44%
70%
36%
90%
93%
59%
[
[
18]
the synthesis of related structures, they have incorporated
less control over the position of the olefin and do not feature
the amino group found in many of our compounds. Further-
more, there are only very few examples where the olefin is
used as a branch point and further functionalized beyond
[
h]
Reaction conditions: [a] R’-BF K (1.5 equiv), Pd(dppf)Cl ·CH Cl
2
5 mol%), K CO (3.0 equiv), THF/H O, 708C. [b] 5 (1.0 equiv), LDA
3
2
2
(
(
2
3
2
1.2 equiv), CuBr (20 mol%), allyl bromide (1.2 equiv), THF, À788C to
RT. [c] TFA, CH Cl , RT. [d] NaH (1.5 equiv), alkyl bromide (1.5 equiv),
2
2
[
15a,19]
simple reduction.
THF or DMF, 708C. [e] NaH (1.5 equiv), 11 (1.5 equiv), THF, 708C. [f] 12
(2.0 equiv), K CO (3.0 equiv), DMF, RT, 43%; then NaH (1.5 equiv), allyl
Starting from readily available 3-nitro-1H-pyrazole (4), 2-
2
3
(
trimethylsilyl)ethoxymethyl (SEM) protection, selective
iodide (1.5 equiv), DMF, RT, 68%. [g] Grubbs II (10 mol%), CH
Cl ,
2 2
4
08C. [h] Hoveyda-Grubbs II (10 mol%), toluene, 1108C or CH Cl , RT.
iodination, and subsequent Suzuki coupling with potassium
vinyltrifluoroborate gave vinyl derivative 7a (Table 1).
Deprotection followed by N-alkylation with an alkyl bromide
of varying C-chain length provided metathesis precursors 9a–
c, which upon treatment with either Grubbsꢀ or Hoveyda-
2
2
THF=tetrahydrofuran, TFA=trifluoroacetic acid, DMF=N,N-dimethyl-
formamide.
could be rendered synthetically tractable, however, either
through bis-Boc protection or through substitution with a 2-
chloro group, which itself can serve as a synthetic handle.
nd
Grubbsꢀ 2 generation catalysts yielded the desired scaffolds
1
[20]
0a–c. Inclusion of further heteroatoms in the formation of
medium-sized partially saturated rings was achieved through
treatment of vinyl intermediate 8a with either tosylate 11
Bis-Boc substrate 14 (prepared in one step from 13) was
functionalized at the 5-position using either Suzuki coupling
(for vinyl substituents) or Stille coupling (for allyl substitu-
ents) to produce intermediates 15a,d–f. Treatment with LDA
and trapping of the resultant anion with a variable alkyl
bromide electrophile gave a range of metathesis substrates
(16a–f), which under standard ring-closing metathesis con-
ditions yielded PSBH scaffolds 17a–f. The 2-chloro substrate
18 could be allylated in the 5-position by using an excess of
i-PrMgCl·LiCl and trapping the resultant organometallic
intermediate with allyl bromide. Allylation at the 4-methyl
position and RCM gave scaffold 17g in superior yields.
Following PSBH synthesis, a series of simple one-, two-, or
three-step functionalizations were performed on selected
pyrazole and pyridine scaffolds to demonstrate the synthetic
utility of the olefin p-bond as a growth vector and to generate
a variety of new stereocenters (Scheme 2).
(
leading, after RCM, to O-containing fragment 10d), or 3-
Boc-1,2,3-oxathiazolidine 2,2-dioxide 12, which gave access to
the N-containing scaffold 10e after allylation and metathesis.
Use of a different Suzuki coupling partner gave methyl-
substituted product 7 f, which could be elaborated to PSBH
fragment 10 f. Alternatively, direct allylation at the C-5
position of SEM-protected intermediate 5 could be achieved
upon treatment with lithium diisopropylamide (LDA) and
allyl bromide. This led, in an analogous way, to scaffolds 10g–
h with non-conjugated olefins.
A similar approach was used to generate PSBH scaffolds
from pyridine 13 (Table 2). Attempts to mask the 2-amino
group as a nitro group proved ineffective since, despite
successful cross-coupling reactions, the 2-nitropyridines were
unstable to strong base and did not undergo the desired
alkylations at the 4-methyl position. Mono-Boc protection
was also unsuitable due to poor yields in the cross-coupling
step, possibly due to catalyst chelation. The 2-amino group
Catalytic hydrogenation of nitropyrazoles 10a–d,f served
to reduce both the olefin p-bond and the nitro group in
moderate to good yields, revealing the latent amino function-
2
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Table 2: Synthesis of pyridine-based PSBH scaffolds.
ality and, in the case of 19 f, creating a new stereocenter.
Other one-step reactions include aziridination, dibromina-
tion, allylic oxidation dihydroxylation, difluorocyclopropana-
tion, hydroxybromination, epoxidation, and hydroboration
(20–28) to introduce functionalities at the 4-, 5- and 6-
positions of the fused pyrazole systems. Demonstrating that
these initial products can serve as intermediates to other
fragments, the products of hydroboration can react further to
incorporate Br, F, and N substituents (30–33), whilst epoxide
2
6 can be opened by nucleophiles such as fluoride and hydride
to form fluorohydrin 35 and alcohol 36. Whilst the yields of
some reactions were modest, sufficient material was obtained
for full characterization and future screening campaigns.
The pyridine-based scaffolds 17a–g can undergo a similar
range of transformations. Catalytic hydrogenation and sub-
sequent acid-mediated deprotection of bis-Boc compounds
Step
B (16)
1
2
[b]
[e]
[f]
R
n
R
R
A (15)
C (17)
a
b
c
d
e
f
Boc N
Boc N
Boc N
Boc N
Boc N
Boc N
Cl
0
0
0
0
0
1
1
H
H
H
Me
Ph
H
H
85%
–
–
60%
69%
77%
60%
68%
41%
79%
95%
94%
54%
94%
83%
65%
91%
2
Me
CF3
H
H
H
2
2
87%
92%
78%
73%
2
1
7a–f generated novel fragments, many of which include new
2
[
[
c]
stereocenters (37a–f). Aziridination, dibromination, dihy-
droxylation, hydroboration, a-bromoketone formation, and
hydroxybromination were also carried out (38–43). Further
reactions included amino-alcohol (44) and epoxide (45)
formation, both from bromohydrin 43. 3-Chloro fragments
46–51 could also be readily accessed using similar conditions.
Calculation of a range of physicochemical properties was
carried out on all of the PSBH products. Almost all fragments
were shown to conform to the so-called “Rule of Three”, a set
2
d]
g
H
H
Reaction conditions: [a] Boc O (2.5 equiv), DMAP (0.1 equiv), THF,
08C. [b] R’-BF K or R’-B(MIDA) (1.5 equiv), Pd(dppf)Cl ·CH Cl
3 2 2 2
10 mol%), K CO (3.0 equiv), THF/H O, 708C. [c] Allyltributyltin
1.1 equiv), Pd(PPh ) (10 mol%), KF (2 equiv), toluene, 1108C.
2
7
(
(
[
2
3
2
3
4
d] i-PrMgCl.LiCl (1.5 equiv), allyl bromide (1.2 equiv), THF, À158C to
RT. [e] LDA (1.2 equiv), alkyl bromide (1.5 equiv), THF, À788C to RT.
[
f] Grubbs II (5 mol%), CH Cl , 408C. DMAP=4-dimethylaminopyri-
2 2
dine.
Scheme 2. Functionalization of PSBH scaffolds. For reaction conditions, see the Supporting Information.
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Table 3: Mean physicochemical properties of fragment collections.
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[
[
1
3
transformations to generate a collection of sp -rich fragments,
6
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Acknowledgements
Our research is supported by the EPSRC, BBSRC, MRC,
Wellcome Trust, and ERC (FP7/2007-2013; 279337/DOS).
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Society Wolfson Research Merit award.
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nitrogen heterocycles · synthetic methods
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Published online: && &&, &&&&
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Communications
Drug Discovery
D. G. Twigg, N. Kondo, S. L. Mitchell,
W. R. J. D. Galloway, H. F. Sore, A. Madin,
D. R. Spring*
&&&& — &&&&
3
Partially Saturated Bicyclic
Heteroaromatics as an sp -Enriched
Fragment Collection
2D or not 2D: A collection of partially
saturated bicyclic pyridine- and pyrazole-
based fragments, derived from a diverse
set of readily accessible branch-point
scaffolds, is presented. Their enhanced
sp content, compared to typical frag-
ment libraries, allows excellent control of
3D growth vectors in drug development
applications.
3
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!