2′ Biaryl amides as novel and subtype selective M1 agonists. Part I: Identification, synthesis, and initial SAR

Article abstract of DOI:10.1016/j.bmcl.2010.04.128

Biaryl amides were discovered as novel and subtype selective M₁ muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M₁ agonist potency and intrinsic activity, and subtype selectivity for M₁ over M_2-5, are described.

Full text of DOI:10.1016/j.bmcl.2010.04.128

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3540–3544
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
20 Biaryl amides as novel and subtype selective M1 agonists. Part I:
Identification, synthesis, and initial SAR
*
*
Brian Budzik , Vincenzo Garzya , Dongchuan Shi, James J. Foley, Ralph A. Rivero, Christopher J. Langmead,
*
Jeannette Watson, Zining Wu, Ian T. Forbes, Jian Jin
Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Biaryl amides were discovered as novel and subtype selective M1 muscarinic acetylcholine receptor ago-
nists. The identification, synthesis, and initial structure–activity relationships that led to compounds 3j
and 4c, possessing good M1 agonist potency and intrinsic activity, and subtype selectivity for M1 over
M2–5, are described.
Received 20 March 2010
Revised 26 April 2010
Accepted 27 April 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Subtype selective M1 muscarinic
acetylcholine receptor agonist
Novel M1 agonists
20 Biaryl amides
Five muscarinic acetylcholine receptor (mAChR) subtypes, M1–
M5, are known to date.1–3 These seven-transmembrane (7TM)
receptors share a common orthosteric ligand-binding site with
an extremely high sequence homology, which explains why it
has been difficult historically to identify subtype selective ligands.3
M1–M5 mAChRs are widely distributed in mammalian organs and
the central and peripheral nerve system where they mediate
important neuronal and autocrine functions including memory
and attention mechanisms, motor control, and nociception.4,5 In
particular, selective M1 agonism has been suggested as a therapeu-
tic approach in dementia including Alzheimer’s disease and
age-associated memory impairment or cognitive impairment asso-
ciated with Schizophrenia.6 Furthermore, recent clinical results
from pan MAChR agonists have resulted in severe GI and CV effects
which further demonstrates the need for selective agonists of M1.25
AC-42, the first subtype selective M1 agonist, achieved the high
degree of subtype selectivity via binding to an allosteric binding
site unique to M1 mAChRs.7 More recently, TBPB and its analogs
were also reported as subtype selective M1 allosteric agonists.8
We herein describe the identification, synthesis, and initial struc-
ture–activity relationships (SAR) of biaryl amides as novel and sub-
type selective M1 agonists.
Data mining of the corporate databases resulted in the identifi-
cation of biaryl amide 1, a compound prepared for the M3 antago-
nist program, as a hit with good M1 agonist potency and intrinsic
activity (IA), and good subtype selectivity for M1 over M2 and M3
(Fig. 1).9,10 Compound 1 was subsequently found to be also selec-
tive for M1 over M4 and M5. On the basis of the good M1 agonist
activity and subtype selectivity, 1 was considered an acceptable
starting point for our hit-to-lead chemistry optimization aimed
at improving potency and identifying tractable SAR.
We began our initial exploration by replacing the 4-amino-
methyl piperidine of 1 using the solution phase route11 that had
been used for the original synthesis of 1 (Scheme 1). Suzuki
coupling of pinacol ester 6 with 2,4-dichlorothiazole12 followed
by basic hydrolysis gave acid 7, which via EDC coupling with
NH
H
N
O
S
N
Cl
* Corresponding authors. Present address: 1031 Perkiomenville Road, Perkio-
menville, PA 18074, USA. Tel.: +1 610 754 9132 (B.B.); +44 1279 627488 (V.G);
Present address: Center for Integrative Chemical Biology & Drug Discovery, Division
of Medicinal Chemistry & Natural Products, Eshelman School of Pharmacy, The
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7363, USA. Tel.:
+1 919 843 8459; fax: +1 919 843 8465 (J.J.).
1, M1 FLIPR pEC50 = 6.6, IA = 84 %
M2 FLIPR pIC50 < 5
M3 FLIPR pIC50 < 5
M4 FLIPR pIC50 < 5
M5 FLIPR pIC50 < 5
E-mail addresses: torqux@yahoo.com (B. Budzik), vincenzo.2.garzya@gsk.com
(V. Garzya), jianjin@unc.edu, jianjin19380@yahoo.com (J. Jin).
Figure 1. Structure and in vitro profile of 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.128

B. Budzik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3540–3544
3541
A first generation study of the activity of simple substituents
around the amide phenyl moiety of 1 was conducted by substitu-
tion of the appropriate benzoic acid for biaryl acid 7 in Scheme 1.
As shown in Figure 2, all such structures were inactive, implying
a 2’ substituted biaryl structure like that of hit 1 is required for
M1 agonist activity.
NH
H
OEt
OH
N
a, b
c, d
B
O
O
O
O
O
N
S
N
S
Cl
Cl
6
7
1
After our initial exploration of simple substituents on the amide
phenyl yielded no improvements, we developed an efficient and
robust solid phase route amenable to rapid modification of the
biaryl region for further exploration of this series (Scheme 2).
1-Boc-4-(aminomethyl)piperidine was loaded onto 2,6-dime-
thoxy-4-polystyrenebenzyloxy benzaldehyde resin (DMHB resin)14
via reductive amination to give 8, followed by coupling with a
2-haloaryl acid, affording resin-bound aryl amides 9. Suzuki cou-
pling of amides 9 with various aryl boronic acids followed by resin
cleavage produced the targeted biaryl amides in good yields and
purity.15
We focused our next generation examination of the biaryl re-
gion on exploring 2’ biaryls like hit 1, specifically examining SAR
of the lower aryl. For synthesis of these compounds we used the
solid phase route of Scheme 2, but also used the route in Scheme
3,16 where intermediate 10 allowed use of aryl halides to install
the lower aryl complementing the use of aryl boronic acids to in-
stall the lower aryl in the route of Scheme 2.
Scheme 1. First generation exploration of diamine region. Reagents and conditions:
(a) 2,4-dichlorothiazole, Pd(PPh3)4, 2 M Cs2CO3, DME, 80 °C, 16 h; (b) LiOH, EtOH, rt,
16 h; (c) 1-Boc-4-(aminomethyl)piperidine or various amines or Boc-protected
diamines, EDC, HOAt, CH2Cl2, rt, 16 h; (d) 4 M HCl, MeOH or 50% TFA/CH2Cl2, rt, 16 h
(if required).
various mono boc-protected diamines or amines followed by
deprotection gave final compounds exemplified by 1.13
As shown in Table 1, replacement of the 4-aminomethyl piperi-
dine with a tertiary amine bridged analogue (1a) gave modest activ-
ity,10 while the 2,2,6,6-tetramethyl piperidine analogue (1b) was
inactive. Substitution of pyridine for piperidine (1c), or replacement
of nitrogen with oxygen as a nonbasic hydrogen bond acceptor (1d)
also gave no activity. Pyrrolidines 1e–g were inactive, as were piper-
idines 1h–j, morpholine 1k, and homopiperazine 1l.
Table 1
First generation diamine region SAR
As shown in Table 2, in exploration of the lower aryl as a substi-
tuted phenyl, a wide variety of substitutions (2a–m) gave inactive
compounds with the exception of 2d, its 3-Cl phenyl moiety giving
a 0.6 log potency increase over the chlorothiazole of 1. Several
unsubstituted heterocycles were tried, but given unsubstituted thi-
azole 2n (des-Cl 1) was inactive, it is not surprising compounds
2o–u were also inactive. An alternate Cl-substituted heterocycle
was also inactive (2v).
NH
H
N
O
N
S
Cl
Compd
Structure
M1 pEC50 IA%
NH
H
R
6.6
84
N
NH
N
H
N
1
O
6.1
63
R = H, F, Cl, Me, OMe, CN, CF3, Ph
all M1 pEC50 < 5.0
H
N
1a
1b
1c
Figure 2. Activity with simple substituents on amide phenyl.
NH
<5.0
<5.0
H
N
DMHB
a
NBoc
DMHB
HN
b
N
NBoc
NBoc
H
N
N
H2N
X
O
O
H
N
1d
1e
<5.0
<5.0
9
8
c, d
NH
H
H
N
NH
N
H
N
Ar
O
1f
<5.0
N
H
Scheme 2. Solid phase synthesis of biaryl amides. Reagents and conditions: (a) 2,6-
dimethoxy-4-polystyrenebenzyloxybenzaldehyde (DMHB resin), Na(OAc)3BH,
DIEA, 10% AcOH in NMP, rt, 16 h; (b) various substituted 2-haloaryl acids, DIC,
NMP, rt, 16 h; (c) ArB(OH)2, Pd(PPh3)4, 2 M Cs2CO3, DME, 80 °C; (d) 50% TFA/DCE, rt,
1 h.
H
N
1g
1h
<5.0
<5.0
NH
H
N
NH
H
N
NBoc
NH
1i
<5.0
H
N
H
N
a
b, c
NH
NH
OH
H
N
B
O
B
O
O
Ar
O
O
O
O
1j
<5.0
<5.0
<5.0
O
H
10
1k
1l
N
NH
H
H
N
Scheme 3. Installation of lower aryl via aryl halides. Reagents and conditions: (a) 1-
Boc-4-(aminomethyl)piperidine, EDC, HOAt, CH2Cl2, rt, 16 h; (b) various aryl
halides, Pd(PPh3)4, 2 M Cs2CO3, DME, 80 °C, 3 h; (c) 50% TFA/DCE or 4 M HCl,
MeOH, rt.
N

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B. Budzik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3540–3544
Table 2
SAR of lower aryl
we turned our attention to a precision study of the effect of adding
a single methyl group at each position around the 4-aminomethyl
piperidine moiety, using the 3-Cl biphenyl from 2d in the biaryl. In
Scheme 4, LiAlH4 reduction of a primary amide,17 obtained via EDC
coupling of NH3 with the appropriate acid, gave Boc-protected dia-
mines required for the syntheses of 4b–d. Reductive amination18 of
the appropriate ketone gave the Boc-protected diamine needed for
4e, while 4f was obtained by N-methylation of the secondary
amide.
NH
H
N
Ar
O
Compd
Ar = Ph, Ph substituent=
M1 pEC50 IA%
2a
2b
2c
2d
3-F
4-F
2-Cl
3-Cl
<5.0
<5.0
<5.0
7.2
We found addition of a single methyl at each position19 (Table
4, positions 1–6) gave an inactive compound, with the exception
of compound 4c. We were delighted to find addition of a 3 methyl
on the piperidine in 4c gave a 0.5 log potency increase over the
unsubstituted piperidine of 2d (data for 2d also shown for
reference).
Encouraged by compound 4c, we carried out a third generation
study of the diamine region. In Scheme 5, reductive cyanation of
the appropriate ketone20 via tosylmethyl isocyanide (TosMIC), fol-
lowed by LiAlH4 reduction to obtain the required diamine, and
then amide coupling led to 5a, 5c, and 5e, while LiAlH4 reduction
of the appropriate primary amide20 followed by amide coupling
led to 5d.
86
2e
2f
2g
2h
2i
2j
2k
2l
4-Cl
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
All
3-Me
4-Me
2-OMe
3-OMe
4-OMe
3-CF3
4-CF3
2m
3-Ac, NAc, Ph, COOH, CN, N(CH3)2, OCF3, SO2Me,
CONH2, CON(CH3)2, CH2OMe, SO2NH2
<5.0
Ar = Heterocyclic
1
4-Chloro-1,3-thiazol-2-yl
6.6
84
c
d, e
a, b
2n
2o
2p
2q
2r
2s
2t
2u
2v
1,3-Thiazol-2-yl
Thien-2-yl
Thien-3-yl
Pyridin-3-yl
Pyridin-4-yl
2-Furyl
1-Naphthyl
2-Naphthyl
5-Chlorothien-2-yl
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
<5.0
NBoc
NBoc
NBoc
NBoc
4c
H2N
H2N
H2N
H2N
HO
HO
O
O
O
d, e
h, b, c
b, c
f, g
NH
4b
d, e
NBoc
4d
4e
After discovery of the 3-Cl phenyl of 2d as a potency enhancing
replacement for the chlorothiazole of 1, we pursued a second gen-
eration lower phenyl disubstituted array where the 3-Cl was held
fixed and a second substituent added systematically to the four
remaining positions, shown in Table 3.
The results of the disubstitution study in Table 3 show clear SAR
trends for adding another substituent to the 3-chlorophenyl moi-
ety. Additional substitution at the 4 (3d–f) or the 6 (3j–k) position
gave disubstituted compounds of good activity, while substitution
at the 2 (3a–c) or 5 (3g–i) position caused large activity losses.
After our broad initial exploration of the diamine region with a
diverse set of replacements (Table 1) resulted in no improvements,
i, h
d, e
NH
NBoc
NBoc
O
H2N
k, l, e
j
H
N
4f
Br
O
Scheme 4. Syntheses of 4b-f.17–19 Reagents and conditions: (a) 3-Me-4-carboxyl
piperidine HCl, Boc2O, Et3N, CH2Cl2, rt; (b) 2 M NH3 in MeOH, EDC, HOAt, CH2Cl2, rt,
16 h; (c) (i) LiAlH4, ꢀ78 °C to rt, THF; (ii) Na2SO4ꢁ10H2O; (d) 30-chloro-1,10-
biphenyl-2-carboxylic acid, EDC, HOAt, CH2Cl2, rt, 16 h; (e) 4 M HCl, MeOH, rt; (f)
2,4-lutidine, SeO2, pyridine, 90 °C, 1 h; (g) PtO2, H2 (60 psi), AcOH, 16 h; (h) Boc2O,
Et3N, CH2Cl2, rt, 15 min; (i) NH4HCO2, 10% Pd/C, MeOH/H2O 9:1, rt, 16 h; (j) 2-Br
benzoic acid, 1-Boc-4-(aminomethyl)piperidine, EDC, HOAt, CH2Cl2, rt, 16 h; (k) 3-
Cl phenylboronic acid, Pd(PPh3)4, 2 M Cs2CO3, DME, 80 °C, 4 h; (l) powdered KOH,
MeI, DMSO, rt, 10 min.
Table 3
Disubstitution SAR of lower phenyl with 3-Cl fixed
NH
H
N
Table 4
O
Mono-methylation SAR of diamine region
6
5
2
2
Cl
3
1
6
N
4
N
Compd M1 pEC50 IA%
2
F
Cl
Me
4
O
5
3a
6.0
66
7.6
76
<5.0
17
8.0
111
3b
<5.0
16
7.3
59
<5.0
24
7.4
100
3c
<5.0
5
Cl
4
5
6
3d
3g
3j
3e
3h
3k
3f
3i
3l
7.9
91
5.8
52
6.8
86
Compd
4a
1
4b
2
4c
3
4d
4
4e
5
4f
6
2d
n/a
M1 pEC50
IA%
<5.0
16
<5.0
28
7.7
99
<5.0
45
<5.0
26
<5.0
2
7.2
86

B. Budzik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3540–3544
3543
Table 6
Bn
c, e
Bn
a, b
Subtype selectivity profiles of selected compounds24
N
N
5a
5c
5d
5e
H2N
H2N
H2N
O
O
Compd
M1 pEC50 IA%
M2 pIC50
<5.0
M3 pIC50
<5.0
M4 pIC50
<5.0
M5 pIC50
1
6.6
84
7.2
86
7.9
96
8.0
111
7.7
99
<5.0
<5.0
6.1
c, d
c
a, b
b
NBoc
N
NBoc
N
2d
3f
3j
5.1
6.4
5.7
5.4
5.4
6.6
6.0
5.9
5.3
6.4
5.8
5.5
5.3
H2N
4c
<5.0
O
c
a, b
N
N
H2N
O
In conclusion, we have identified a novel biphenyl amide series
as potent and subtype selective M1 agonists. Initial optimization of
the series resulted in compounds such as 3j and 4c with good M1
agonist potency and intrinsic activity, and up to 100-fold selectiv-
ity for M1 over M2–5. Additional SAR and optimization of this series,
including further exploration of the upper aryl, middle linker, and
diamine regions, as well as rat PK profiles of optimized compounds,
shall be reported.
Scheme 5. Syntheses of 5a, 5c-e.22 Reagents and conditions: (a) tosylmethyl
isocyanide (TosMIC), KOtBu, DME, 0 °C, 45 min, rt 1 h; (b) (i) LiAlH4, THF, rt, 16 h;
(ii) Na2SO4ꢁ10H2O; (c) 30-chlorobiphenyl-2-carboxylic acid (5c–e) or 30,4-dichloro-
1,10-biphenyl-2-carboxylic acid23 (5a), EDC, HOAt, CH2Cl2, rt, 16 h; (d) 4 M HCl,
MeOH, 16 h; (e) (i)
reflux 1 h.
a-chloroethyl chloroformate, K2CO3, DCE, reflux 1 h; (ii) MeOH,
We found (Table 5) that although the 3 methyl in 4c was bene-
ficial, geminal dimethyl 5a21 was inactive. Other modifications
including moving the N outside the ring (5b22), and a bridged
piperidine (5c) also destroyed activity. Bicyclic tertiary amines
5d and 5e were inactive, as was 5f22 despite the fact the same moi-
ety showed modest activity with the 4-chloro-1,3-thiazol-2-yl of 1
as the lower aryl (compound 1a in Table 1).
Acknowledgments
We thank Bing Wang for NMR and Qian Jin for LC/MS support.
Supplementary data
Promising compounds were evaluated in M2–5 selectivity as-
says. We were pleased to find as we improved M1 agonist potency
and intrinsic activity, we were able to maintain subtype selectivity
(Table 6). For example, compounds 3j and 4c were potent full ago-
Supplementary data (experimental procedures detailing the
preparation of 1 via the route outlined in Scheme 1) associated
with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2010.04.128.
nists with 100-fold or greater selectivity for M1 over M2–5
.
References and notes
Table 5
Third iteration diamine region SAR
1. Caulfield, M. P.; Birdsall, N. J. M. Pharmacol. Rev. 1998, 50, 279.
2. Eglen, R. M. Prog. Med. Chem. 2005, 43, 105.
3. Hulme, E. C.; Birdsall, N. J. M.; Buckley, N. J. Ann. Rev. Pharmacol. Toxicol. 1990,
30, 633.
X
4. Caulfield, M. P. Pharmacol. Ther. 1993, 58, 319.
5. Eglen, R. M. Auto. Autacoid Pharmacol. 2006, 26, 219.
NH
H
N
6. Fisher, A.; Pittel, Z.; Haring, R.; Bar-Ner, N.; Kligerspatz, M.; Natan, N.; Egozi, I.;
Sonego, H.; Marcovitch, I.; Brandeis, R. J. Mol. Neurosci. 2003, 20, 349.
7. (a) Spalding, T. A.; Trotter, C.; Skjaerbaek, N.; Messier, T. L.; Currier, E. A.;
Burstein, E. S.; Li, D.; Hacksell, U.; Brann, M. R. Mol. Pharmacol. 2002, 61, 1297;
(b) Langmead, C. J.; Fry, V. A. H.; Forbes, I. T.; Branch, C. L.; Christopoulos, A.;
Wood, M. D.; Hedron, H. Mol. Pharmacol. 2006, 69, 236.
8. (a) Jones, C. K.; Brady, A. E.; Davis, A. A.; Xiang, Z.; Bubser, M.; Tantawy, M. N.;
Kane, A.; Bridges, T. M.; Kennedy, J. P.; Bradley, S. R.; Peterson, T.; Baldwin, R.
M.; Kessler, R.; Deutch, A.; Levey, A. I.; Lindsley, C. W.; Conn, P. J. J. Neurosci.
2008, 28, 10422; (b) Bridges, T. M.; Brady, A. E.; Kennedy, J. P.; Daniels, R. N.;
Miller, N. R.; Kim, K.; Breininger, M. L.; Gnetry, P. R.; Brogan, J. T.; Jones, C. K.;
Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2008, 18, 5439; (c) Miller, N.
R.; Daniels, R. N.; Bridges, T. M.; Brady, A. E.; Conn, P. J.; Lindsley, C. W. Bioorg.
Med. Chem. Lett. 2008, 18, 5443.
O
Cl
Compd
X=
H
Structure
M1 pEC50 IA%
7.2
86
NH
NH
H
N
2d (ref.)
5a
Cl
H
<5.0
<5.0
H
N
NH2
9. Fluorometric imaging plate reader (FLIPR) assays were used to measure M1
agonist potency and intrinsic activity, and M2-5 subtype selectivity. For FLIPR
assay details, see: Budzik, B. W; Cooper, D. G.; Forbes, I. F.; Jin, J.; Shi, D.; Smith,
P. W.; Walker, G. R. WO Patent 2007036711-A1, 2007; Chem. Abstr. 2007, 146,
401966.
5b22
H
N
H
N
H
5c
H
<5.0
10. The biological assay results in the paper are
a mean of at least two
H
N
determinations with standard deviation of < 0.3. We report agonist potency
in pEC50 defined as the negative log of the EC50 value in molarity.
11. Full experimental procedures are available in Supplementary data detailing the
preparation of 1 via the route of Scheme 1.
12. Reynard, P.; Robber, M.; Moreau, R. C. Bull. Soc. Chim. Fr. 1962, 1735.
13. All new compounds in this paper were characterized via LC/MS and 1H
NMR.
14. (a) Jin, J.; Graybill, T. L.; Wang, M. A.; Davis, L. D.; Moore, M. L. J. Comb. Chem.
2001, 3, 97; (b) Available from Polymer Laboratories, part number: 1466–6689,
150–300 lm, 1.5 mmol/g loading.
15. Experimental procedures exemplifying use of the solid phase route of Scheme
2 to produce 2d and 3f:
H
N
H
N
5d
5e
5f
H
H
H
<5.0
<5.0
<5.0
H
N
N
N
H
N
DMHB resin-bound 1-Boc-4-(aminomethyl)piperidine 8:

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B. Budzik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3540–3544
produced likewise by substitution of the appropriate aryl boronic acid in step c
a
DMHB
HN
(or benzoic acid in step b for the compounds of Figure 2). The remainder of the
compounds were made via the route of Scheme 3 using aryl halides (see note16
below).
DMHB
resin
NBoc
16. Experimental procedures exemplifying use of the route of Scheme 3 to produce
3j:
8
To a 250 mL shaker vessel was added 2,6-dimethoxy-4-polystyrenebenzyloxy-
benzaldehyde14 (DMHB resin) (10 g, 1.5 mmol/g, 15 mmol) and 150 mL of 1-
methyl-2-pyrrolidinone (NMP). 1-Boc-4-(aminomethyl)piperidine (16.1 g,
75 mmol), AcOH (15 mL), and Na(OAc)3BH (19.1 g, 90 mmol) was then
added. The resulting mixture was shaken briefly and then immediately
vented, this procedure being repeated until no more pressure builds up in
the vessel, then the mixture was shaken for 15 min, vented again, then shaken
at rt overnight. The mixture was then washed with NMP (150 mL ꢂ 2), DCM
(150 mL ꢂ 2), MeOH (150 mL ꢂ 2) and DCM (150 mL ꢂ 2). The resulting resin
was dried in a vacuum oven at 35 °C overnight to yield DMHB resin-bound 1-
Boc-4-(aminomethyl)piperidine 8 (15 mmol, loading 100%).
Preparation of t-butyl 4-({[2-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2-yl)
benzoyl] amino} methyl)piperidine-1-carboxylate 10 (step a): 2-Carbo-
xyphenylboronic acid pinacol ester (33 g, 0.13 mol, 1 equiv), 1-Boc-4-
(aminomethyl)piperidine (28.5 g, 0.13 mol, 1 equiv), HOAt (18.1 g, 0.13 mol,
1 equiv), EDC (25.5 g, 0.13 mol, 1 equiv), and DCM (900 mL) were combined at
rt and stirred overnight. The reaction was washed 3 ꢂ 500 mL H2O, dried
Na2SO4, and evaporated, the residue mixed with 750 mL DME, then evaporated
again on a 50 °C water bath for 1 h, followed by drying in vacuo overnight to
give 10 which was used without further purification (27.8 g, 47%).
1H NMR (400 MHz, DMSO-d6) d 9.43 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.48 (m,
1H), 7.39 (m, 2H), 3.92 (m, 2H), 3.28 (m, 2H), 2.70 (m, 2H), 1.77 (m, 1H), 1.65
(m, 2H), 1.39 (s, 9H), 1.21 (s, 12H), 1.07 (m, 2H). MS (ES+) 445 [M+H]+.
Preparation of 3j from 10 (steps b, c): 10 (75 mg, 0.17 mmol, 1 equiv), 2-bromo-
DMHB resin-bound t-butyl 4-{[(2-iodobenzoyl)amino] methyl}piperidine-1-
carboxylate 9:
DMHB
NBoc
b
DMHB
HN
4-chloro-1-fluorobenzene (36 mg, 0.17 mmol, 1 equiv), 2 M Cs2CO3 (188 lL,
NBoc
N
0.38 mmol, 2.2 equiv), and DME (10 mL) were combined. The mixture was
sparged with Ar for 30 s, then Pd(PPh3)4 (10 mg, 0.009 mmol, 0.05 equiv)
added. The mixture was refluxed overnight under Ar with stirring. Aqueous
layer was discarded, and DME layer evaporated and the residue treated with
50% TFA/DCM to deprotect Boc, followed by evaporation, the residue purified
via HPLC to yield 50-chloro-20-fluoro-N-(piperidin-4-ylmethyl)-1,10-bi phenyl-
2-carboxamide trifluoroacetate 3j (42 mg, 54%).
O
I
9
8
To DMHB resin-bound 1-Boc-4-(aminomethyl) piperidine 8 [5 g, 1.16 mmol/g
(theoretical loading), 5.8 mmol] in DCE/DMF (1:1, 150 mL) was added 2-
iodobenzoic acid (14.4 g, 58 mmol) and DIC (9.1 mL, 58 mmol). The mixture
was shaken at rt 16 h and then washed with DMF (100 mL ꢂ 2), DCM
(100 mL ꢂ 2), MeOH (100 mL ꢂ 2) and DCM (100 mL ꢂ 2). The resulting resin
was dried in a vacuum oven at 35 °C overnight to yield DMHB resin-bound t-
butyl 4-{[(2-iodobenzoyl)amino] methyl} piperidine-1-carboxylate (9,
5.8 mmol). An analytical amount of the resin was cleaved with 50% TFA/DCE
for 10 min. The resulting solution was concentrated in vacuo and dissolved in
0.5 mL of MeOH. MS (ES+) 345 [MꢀBoc+H]+.
1H NMR (500 MHz, CDCl3) d 8.52 (m, 1H), 8.16 (m, 1H), 7.53 (m, 2H), 7.43 (m,
1H), 7.35 (d, J = 7.5 Hz, 1H), 7.33–7.28 (m, 2H), 7.05 (m, 1H), 6.35 (t, J = 5.8 Hz,
1H), 3.37 (m, 2H), 3.18 (m, 2H), 2.84 (m, 2H), 1.78–1.64 (m, 3H), 1.41 (m, 2H).
MS (ES+) 347 [M+H]+.
17. Significant amounts of byproduct with reduction of Boc to methyl was
produced in step(s) c of Scheme 4.
18. For method of step (i) in Scheme 4, see: Allegretti, M.; Berdini, V.; Cesta, M. C.;
Curti, R.; Nicolini, L.; Topai, A. Tetrahedron Lett. 2001, 42, 4257.
19. Compound 4c was ꢃ50:50 cis to trans, 4b was 80:20 cis to trans (by NMR
studies). Compound 4a was made in one step by EDC, HOAt coupling of
commercially available 30-chlorobiphenyl-2-carboxylic acid and 1-methyl-4-
(aminomethyl)piperidine.
20. For preparation of the amide starting material for 5d in Scheme 5, see: Jenkins,
S. M.; Wadsworth, H. J.; Bromidge, S.; Orlek, B. S.; Wyman, P. A.; Riley, G. J.;
Hawkins, J. J. Med. Chem. 1992, 35, 2392; For preparation of the ketone starting
material for 5e in Scheme 5, see: Myoung, G. K.; Bodor, E. T.; Wang, C.; Harden,
T. K.; Kohn, H. J. Med. Chem. 2003, 46, 2216.
3’-Chloro-N-(piperidin-4-ylmethyl)-1,10-biphenyl-2-carbox amide trifluoroacetate
(2d):
NH
H
DMHB
N
c, d
N
NBoc
O
O
I
9
Cl
2d
To resin 9 [140 mg, 0.91 mmol/g (theoretical loading), 0.13 mmol] in 7 mL of
DME was added 3-chlorophenyl boronic acid (60 mg, 0.38 mmol), 2 M Cs2CO3
(190 lL, 0.38 mmol), and Pd(PPh3)4 (8 mg, 0.0065 mmol). After purging with
21. The proper comparison compound to 5a, that is, the compound with the 5-Cl
present on upper phenyl but without the geminal dimethyl on piperidine, had
M1 pEC50 = 7.0, IA = 74%.
Ar for 30 s, the mixture was shaken at 80 °C under Ar for 16 h. The resulting
resin was washed with THF (10 mL ꢂ 2), THF–H2O (1:1, 10 mL ꢂ 2), H2O
(10 mL ꢂ 2), THF–H2O (1:1, 10 mL ꢂ 2), THF (10 mL ꢂ 2), DCM (10 mL ꢂ 2).
The washed resin was cleaved [2 ꢂ (4 mL of 50% TFA/DCE, 30 min)], combined
cleavage solution evaporated and the residue purified via HPLC to produce 30-
22. Compound 5b was made via EDC, HOAt coupling of commercially available 30-
chlorobiphenyl-2-carboxylic
acid
and
t-butyl-trans-4-aminomethyl
cyclohexylcarbamate followed by deprotection with 4 M HCl. Compound 5f
was prepared by reduction of commercially available 4-cyanoquinuclidine ((i)
LiAlH4, THF, rt, 16 h; (ii) Na2SO4ꢁ10H2O) followed by EDC, HOAt coupling with
30-chlorobiphenyl-2-carboxylic acid.
chloro-N-(piperidin-4-ylmethyl)-1,10-biphenyl-2-carbox
amide
trifluoroacetate 2d (35 mg, 61%). 1H NMR (400 MHz, DMSO-d6) d 8.46 (m,
1H), 8.34 (t, J = 5.8 Hz, 1H), 8.14 (m, 1H), 7.52 (m, 1H), 7.48–7.39 (m, 6H), 7.34
(m, 1H), 3.20 (m, 2H), 2.96 (m, 2H), 2.73 (m, 2H), 1.56 (m, 1H), 1.50 (m, 2H),
1.13 (m, 2H). MS (ES+) 329 [M+H]+.
23. 30,4-Dichloro-1,1’-biphenyl-2-carboxylic acid was easily made by Suzuki
coupling of methyl 2-bromo-5-chlorobenzoate (3-Cl phenylboronic acid,
Pd(PPh3)4, 2 M Cs2CO3, DME, 80 °C, 4 h) followed by hydrolysis (NaOH,
MeOH, reflux 1 h).
30-Chloro-40-methyl-N-(piperidin-4-ylmethyl)-1,10-bi-phenyl-2-carboxamide
trifluoroacetate 3f was likewise produced by substitution of 3-chloro-4-
methylphenyl-boronic acid in step c.
24. Compounds were also tested in agonist mode for M2-5 and showed no agonist
activity.
25. (a) Heinrich, J. N.; Butera, J. A.; Carrick, T.; Kramer, A.; Kowal, D.; Lock, T.;
Marquis, K. L.; Pausch, M. H.; Popiolek, M.; Sun, S. C.; Tseng, E.; Uveges, A. J.;
Mayer, S. C. Eur. J. Pharmacol. 2009, 605, 53; (b) Mirza, N. R.; Peters, D.; Sparks,
R. G. CNS Drug Rev. 2003, 9, 159.
1H NMR (400 MHz, DMSO-d6) d 8.56–8.43 (m, 1H), 8.30 (t, J = 6.1 Hz, 1H), 8.26–
8.13 (m, 1H), 7.53–7.47 (m, 1H), 7.46–7.36 (m, 5H), 7.25 (dd, J = 7.8, 1.8 Hz,
1H), 3.19 (d, J = 12.6 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.77–2.64 (m, 2H), 2.36 (s,
3H), 1.62–1.41 (m, 3H), 1.19–1.05 (m, 2H). MS (ES+) 343 [M+H]+.
The compounds of Figure 2, and most of the compounds of Tables 2 and 3 were