Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2014.12.027

Previously disclosed H₄ receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH₂) group. In this Letter we demonstrate that an exocyclic amine (NH₂) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH₂ azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H₄ antagonists.

Full text of DOI:10.1016/j.bmcl.2014.12.027

Bioorganic & Medicinal Chemistry Letters 25 (2015) 956–959
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Diaminopyrimidines, diaminopyridines and diaminopyridazines
as histamine H receptor modulators
4
⇑
Brad M. Savall , Steven P. Meduna, Kevin Tays, Hui Cai , Robin L. Thurmond, Patricia McGovern,
à
Michael Gaul, Bao-Ping Zhao , James P. Edwards
Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously disclosed H receptor modulators, the triamino substituted pyridines and pyrimidines, contain
4
Received 17 November 2014
Revised 8 December 2014
Accepted 9 December 2014
Available online 23 December 2014
a free primary amino (–NH
needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine
component. These des-NH azacycles also show a distinct functional spectrum, that appears to be influ-
enced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the
amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyrida-
2 2
) group. In this Letter we demonstrate that an exocyclic amine (NH ) is not
2
Keywords:
4
zines as novel histamine H antagonists.
Histamine H
Antagonists
Pyrimidine
Pyridine
4
Ó 2014 Elsevier Ltd. All rights reserved.
Pyridazine
The histamine H
pled receptor that is implicated in the treatment of inflammatory
diseases such as asthma and allergic rhinitis based on the expres-
4
receptor is a 390 amino acid G-protein cou-
Chemistry: Scheme 1 describes a representative synthetic route
used to prepare the 2,4-diamino pyridines. Commercially available
2-fluoro-4-bromopyrimidine (20) was combined with a primary
amine and stirred in THF at room temperature to provide a high
yield of the 2-amino substituted 4-bromopyridine (21). The use
of a Pd catalyzed Buchwald–Hartwig amination to install the dia-
mine component delivered the desired analogs (7–11) in moderate
to high yield. For the compounds with BOC groups, the BOC was
removed by the use of 6 N HCl in formic acid, followed by azeotro-
pic removal of the formic acid with methanol on a rotary
evaporator.
Scheme 2 outlines the syntheses of the 2,4-diamino pyrimi-
dines. Starting with commercially available 2,4-dichloropyrimi-
dine (22), the diamine component selectively added at the
4-position when heated in the presence of di-isopropyl ethylamine
in isopropyl alcohol at 160 °C in the microwave. Heating of 23 with
excess primary amine in isopropyl alcohol at 160 °C in isopropanol
under microwave irradiation provided the desired diamino substi-
tuted product. Removal of the BOC group with 4.0 M HCl in diox-
ane provided the final products (12–16).
Scheme 3 shows the synthesis of the pyridazine series of com-
pounds. Combining 3,5-dichloropyridazine (24) with a diamine in
THF at room temperature for 12 h led to very selective reaction
at the 5-position to provide intermediate 3-chloropyridazines
4
sion of the H receptor on eosinophils, mast cells, dendritic cells
1
,2
and other leukocytes. JNJ 7777120 (1), the prototypical H
4
car-
1
0
boxamide derived antagonist, has served as a useful pharmacolog-
ical tool, however the rapid metabolism makes it less than ideal as
3
,4
an in vivo tool. Recently, there have been several reports from
multiple groups on pyrimidine and pyridine based H antago-
nists, including our recent reports on several new histamine H
4
5
,6
4
antagonist chemotypes. For example, the tricyclic aminopyrimi-
dines typified by JNJ 40279486 (2), the 6-alkyl-2,4-diamino pyrim-
idines, such as JNJ 39758979 (3), and the related 2-amino
azacycles, such as the triamino pyridines (4) and pyrimidines
7
–9
(
5–6).
substituted pyridines (4) and pyrimidines (5, 6) contain a free –
NH group as a common structural motif. In this paper we disclose
a series of diamino substituted pyridine (7–11) and pyrimidines
12–16) without a free –NH group demonstrating a free –NH
group is not required for H histamine receptor modulation. In
addition we disclose a series of diamino pyridazines (17–19), a
new series of H histamine receptor modulators (Fig. 1).
4
Previously disclosed H receptor modulators, the triamino
2
(
2
2
4
4
⇑
Corresponding author.
E-mail address: bsavall@its.jnj.com (B.M. Savall).
Current addresses: WuXi AppTec, San Diego, CA, United States.
Current addresses: WuXi AppTec (WuHan) Co., Ltd, United States.
(25). The 3-chloro was not nearly as reactive as the 5-chloro and
the second displacement required the use of a Pd mediated cou-
pling protocol. BOC groups were removed by the use of 6 N HCl
à
http://dx.doi.org/10.1016/j.bmcl.2014.12.027
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0

B. M. Savall et al. / Bioorg. Med. Chem. Lett. 25 (2015) 956–959
957
NH
2
NH2
N
Cl
O
N
N
N
N
Me
NH
Me
N
H
N
N
NH
2
Cl
O
Me
N
N
Me
2
3
1
JNJ 40279486
hH4 Ki = 9 nM
Tricyclic
JNJ 39758979
hH4 Ki = 12 nM
6-alkyl-2,4-
JNJ 7777120
hH Ki = 5 nM
Carboxamide
4
Aminopyrimidine
diamino-pyrimidine
NH
2
NH
2
NH2
N
N
N
N
R1
R1
R1
NH
2
Azacycles
N
R
DA
N
R
N
5
DA
N
R
DA
(Previous Reports)
2
2
2
4
6
N
N
N
N
R1
R1
R1
des-NH
2
Azacycles
N
R
DA
N
R
N
DA
N
R
DA
(
Current Report)
2
2
2
7
-11
12-16
17-19
1
2
Figure 1. Selective histamine H
4
receptor antagonists. DA refers to a substituted piperazine or aminopyrrolidine. R R N and DA are defined by Figure 2 and Tables 1–6.
N
N
N
N
N
a
N
NH
Me
DA
Me
Cl
N
DA
Cl
N
Cl
S
23
26
a
b
22
b,c
N
-
no diaminetoleration
21 nM
216 nM
R1
N
R
N
DA
2
1
2-16
N
N
N
NH
Me
N
N
DA
Me
Scheme 2. Reagents and conditions: DA refers to a substituted piperazine or
aminopyrrolidine. (a) R R NH, DIEA, IPA, 100–160 °C 1–2 h microwave (
a
b
1 2
27
l
W); (b)
diamine, DIEA, IPA, 100–160 °C 1–2 h
combined steps a–c.
lW; (c) 4.0 M HCl in dioxane, MeOH, 22–54%
-
decreased potency
142 nM
97 nM
R
S
N
N
N
N
Me
NH
Me
NH
Me
N
H
DA
N
N
N
N
Me
N
Me
a
8
a
b
c
DA
Cl
Cl
Cl
-
potent with diamine
toleration
51 nM
2.0 nM
96 nM
2
4
25
N
b,c
N
1
R1
Figure 2. Lead design DA refers to a substituted piperazine or aminopyrrolidine.
N
DA
2
R
7-19
N
N
a
Scheme 3. Reagents and conditions: DA refers to a substituted piperazine or
aminopyrrolidine. (a) R R NH, THF, 23 °C 12 h; (b) diamine, DIEA, (toluene, DME or
t-BuOH), 65–100 °C 1–24 h; (c) 6.0 HCl(aq), formic acid, 16–69% combined steps a–c.
R
1
N
2
Br
1 2
F
Br
R
2
0
21
b,c
N
R1
Replacing the N-methyl piperazine (26a) with other amines, such
as (R)-aminomethyl pyrrolidine (26b), resulted in a loss of affinity.
This lack of ‘tolerance’ for diamines other than N-methyl pipera-
N
R
DA
2
7
-11
4
zine has been previously noted with other histamine H receptor
Scheme 1. Reagents and conditions: DA refers to a substituted piperazine or
ligands such as JNJ 7777120. Replacement of the thiophene with
a piperidine led to a reduction of potency for the N-methyl piper-
1
2
aminopyrrolidine. (a) R R NH, THF, 23 °C 1–2 h; (b) diamine, LiHMDS, Pd
2
(DBA)
3
,
X-PHOS, THF, 60 °C 1–2 h microwave (lW), (c) 4.0 M HCl/dioxane; 27–84%
combined a and b steps.
azine derivative (27a, K
of the 3-aminomethylpyrrolidine (27b, K
our previously reported observations in the containing pyrimidine
series containing an –NH (5–6), we investigated the secondary
i
= 142 nM), but a slight increase in the case
i
= 97 nM). Prompted by
in formic acid, followed by azeotropic removal of the formic acid
with methanol on a rotary evaporator to provide the final products
2
amines that provided an H-bond donor at the 2-position (e.g.,
(
17–19).
During the follow up efforts to our initial screening campaign,
we identified the thiophene substituted pyridine (26a), as a rea-
sonably potent histamine H receptor ligand (21 nM) (Fig. 2).
8a–c). This change resulted in an ꢀ3 fold boost in affinity for the
piperazine (8a, K
i
= 51 nM) and an ꢀ20 fold boost for the amino
pyrrolidine (8b, K
i
= 2.0 nM). This series was further explored with
other alkyl groups and diamines (Table 1) and continued the
4

9
58
B. M. Savall et al. / Bioorg. Med. Chem. Lett. 25 (2015) 956–959
Table 1
Table 4
Functional activity of the N-methylpiperazine compounds
X
Y
N
N
R
S
N
N
N
R1
R
NH
Me
NH
Me
N
N
N
R
DA
Me
2
#
N
Me
a
7
-11
b
c
1
2
a
b
c
pA2d
—
#
R R N
X
Y
K
i
(nM)
EC50 (nM)
a
7
N
H
19 nM
1
2a
N
H
CH
CH
N
117
146
112
—
0.67
0.50
N
H
8
9
51 nM
2 nM
7 nM
96 nM
N
8a
CH
—
H
N
H
176 nM
16 nM
109 nM
33 nM
N
H
13a
14a
CH
CH
N
N
69
33
84
91
0.69
0.71
—
—
N
H
1
1
0
1
4 nM
N
H
HN
10a
N
CH
CH
25
—
0.80
—
—
1.0 nM
6 nM
H
1
1
5a
6a
N
H
HN
CH
CH
N
N
63
31
75
20
0.72
0.63
DA refers to a substituted piperazine or aminopyrrolidine.
—
Table 2
a
3
Displacement of [ H]histamine from the recombinant histamine H
4
receptor. K
i
values are the geometric mean of three or more independent determinations and
8
calculated according to Cheng and Prusoff.
N
N
R
S
b
N
N
Compounds with K
>100 nM not tested in functional assays.
Compounds with a >0.40 were not tested in the pA2 assay.
Antagonism of histamine inhibition of forskolin-stimulated cAMP-mediated
i
NH
Me
NH
Me
N
c
R
N
DA
Me
#
d
a
1
2-16
b
reporter gene activity in SK-N-MC cells expressing the human histamine H
receptor. Detailed experimental for EC50 and pA determinations included in Ref. 9.
c
4
2
1
2
N
H
117 nM
8 nM
118 nM
134 nM
This trend of amino pyrrolidines being more potent than the
piperazines translated to the pyrimidine series (Table 2). This ser-
ies had similar trends to the pyridine series in terms of overall
potency and also in the trends of the diamines. Specifically, the
N
H
1
1
3
4
69 nM
55 nM
2 nM
3 nM
N
H
(
R)-aminopyrrolidine was more potent than the (S)-enantiomer,
1
1
5
6
63 nM
86 nM
2 nM
45 nM
8 nM
N
H
though the inclusion of a lipophilic secondary amine resulted in
enhanced affinity for both the (R)- and (S)-aminopyrrolidines
HN
(16b and 16c, respectively).
0.8 nM
Finally, we investigated the pyridazine series (Table 3); which
was unique in several respects. In all three series, the piperazines
were less active than the pyrrolidine counterparts, however in
the pyridazine series the discrepancy was more dramatic and none
of the piperazine derivatives (17–19a) were under 100 nM, with
most being in the micromolar range. For example, with isobutyl-
amine at the 3-position and an N-Me piperazine at the 5 position
(20a), the affinity is >10,000 nM, while the corresponding N-Me
pyrrolidine (17b) is 55 nM. This series overall was less potent than
the other two series, though the combination of a lipophilic amine
at the 3 position with either an (R)- or (S)-aminomethyl pyrrolidine
at the 5 position delivered single digit nanomolar compounds
(19b, c).
Thus far we have only focused on the affinity of the various ser-
ies without discussing the functional activity of the ligands. At this
point, it is more instructive to look at the diamines and how they
impact the functional activity. As such, Tables 4–6 are configured
to compare the effect of the diamines across the various series.
Table 4 shows that the pyridine derivatives (8a, 10a) tested as par-
DA refers to a substituted piperazine or aminopyrrolidine.
Table 3
N
R
S
N
N
N
N
NH
Me
NH
Me
N
Me
#
R
DA
a
b
1
7-19
c
N
H
1
7
10,000 nM
824 nM
55 nM
6 nM
389 nM
240 nM
1
8
9
N
H
HN
1
2
365 nM
8 nM
5 nM
DA refers to a substituted piperazine or aminopyrrolidine.
tial agonists with
was noticed for the pyrimidines (12a–16a) where all of the piper-
azines tested behaved as partial agonists with -values between
a-values between 0.5 and 0.8. A similar trend
a
diamine trends. Specifically, the (R)-amino pyrrolidine derivatives
7–11b) were nearly an order of magnitude more potent relative
to the corresponding piperazines (7–11a). Although the (R)-enan-
tiomer was more potent than the (S)-enantiomer, at least one
derivative (11c) with an (S)-pyrrolidine was under 10 nM.
0.6 and 0.7. As mentioned above, the piperazine derivatives in
the pyridazine series did not possess sufficient potency to be tested
in the functional assays.
Looking at the aminopyrrolidines, there was a range of
functional activity across the series. In the aminopyridines, the
(

B. M. Savall et al. / Bioorg. Med. Chem. Lett. 25 (2015) 956–959
959
Table 5
Table 6
Functional activity of (R)-3-aminomethyl pyrrolidine compounds
Functional activity of (S)-3-aminomethyl pyrrolidine compounds
X
N
X
N
R1
R
H
N
R1
R
H
N
N
Y
N
N
Y
N
2
Me
2
Me
1
2
a
b
c
pA2d
8.5
1
2
a
i
b
c
pA2d
#
R R N
X
Y
K
i
(nM)
EC50 (nM)
a
#
R R N
X
Y
K
(nM)
EC50 (nM)
a
7
b
N
H
CH
CH
N
19
3162
25
—
10c
11c
N
H
CH
CH
34
>10,000
—
7.4
HN
N
H
CH
8.0
0.70
—
CH
CH
N
CH
N
5.6
>10,000
>10,000
>10,000
—
—
—
9.0
8.1
1
2b
HN
HN
1
1
6c
9c
8.3
5.0
N
8
1
b
CH
CH
CH
N
2.0
3.4
—
—
9.2
—
H
CH
8.1
N
H
3b
15
0.42
a
3
Displacement of [ H]histamine from the recombinant histamine H
values are the geometric mean of three or more independent determinations and
calculated according to Cheng and Prusoff.
4
receptor. K
i
N
H
1
9
1
7b
b
N
CH
CH
N
55
18
3.4
3160
48
0.22
0.60
0.62
7.8
—
8
b
N
H
Compounds with K
Compounds with
>100 nM not tested in functional assays.
a >0.40 were not tested in the pA2 assay.
CH
CH
i
c
d
N
H
Antagonism of histamine inhibition of forskolin-stimulated cAMP-mediated
4b
4.0
—
reporter gene activity in SK-N-MC cells expressing the human histamine H
receptor. Detailed experimental for EC50 and pA determinations included in Ref. 9.
4
2
1
1
1
0b
5b
8b
N
CH
CH
N
CH
N
1.2
2.0
6.0
>10,000
—
9.0
—
H
N
H
86
—
0.53
—
There have been several reports of exocyclic NH
cycles as ligands for the histamine H receptor. In this Letter we
demonstrate that the NH can be replaced with hydrogen if a free
NH is available on the opposite side of the basic heterocyclic nitro-
gen and maintain H receptor affinity. We further elaborated these
des-NH ’ series to show that N-methyl piperazine derivatives
behaved as partial agonists while (R)- and (S)-amino pyrrolidine
provided for a range of functional activity. Interestingly, the com-
bination of the lipophilic [2.2.1]-bicycloheptyl amine and an (S)-
aminopyrrolidine provided potent antagonists in all three series.
This provides a range of functional activity across multiple chem-
otypes each of which are undergoing additional profiling.
2
-amino hetero-
4
2
N
H
CH
8.0
HN
HN
HN
4
1
1
1
1b
6b
9b
CH
CH
N
CH
N
0.4
0.8
8.5
>10,000
3162
—
11.2
10.1
‘
2
—
CH
1000
0.14
8.0
a
3
Displacement of [ H]histamine from the recombinant histamine H
values are the geometric mean of three or more independent determinations and
calculated according to Cheng and Prusoff.
4
receptor. K
i
8
b
Compounds with K
Compounds with
i
>100 nM not tested in functional assays.
>0.40 were not tested in the pA2 assay.
c
a
References and notes
d
Antagonism of histamine inhibition of forskolin-stimulated cAMP-mediated
reporter gene activity in SK-N-MC cells expressing the human histamine H
receptor. Detailed experimental for EC50 and pA determinations included in Ref. 9.
4
1
2
3
.
.
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Jablonowski, J. A.; Carruthers, N. I.; Thurmond, R. L. Mini-Rev. Med. Chem. 2004,
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R)-enatiomer provided antagonists with the branched isopropyl-
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4, 993.
4. Jablonowski, J. A.; Grice, C. A.; Chai, W.; Dvorak, C. A.; Venable, J. D.; Kwok, A.
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[
of the linear n-butylamine (9b). In the case of the pyrimidines,
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.
Schreeb, A.; Lazewska, D.; Dove, S.; Bushcauer, A.; Kiec-kononowicz, K.; Stark,
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a
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bicycloheptyl amine (16b). In the pyridazine series, only the
2.2.1]-bicycloheptyl amine derivative (19b) had sufficient potency
and functionally behaved as an antagonist of the H receptor.
[
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P. M. Bioorg. Med. Chem. Lett. 2011, 21, 3113.
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R.; Thurmond, R. L.; Edwards, J. P. J. Med. Chem. 2014 Accepted.
4
8
.
Although the (S)-aminomethyl pyrrolidines were generally less
potent than the (R)-aminopyrrolidines, in the limited number of
examples where the potency warranted functional testing, all (S)-
aminomethyl pyrrolidines behaved as antagonists. It is interesting
that for all three cores, the combination of [2.2.1]-bicycloheptyl
amine and an (S)-aminopyrrolidine provided functional antago-
nists (11c, 16c, 19c).
9. Savall, B. M.; Gomez, L.; Chavez, F.; Curtis, M.; Meduna, S. P.; Kearney, A.;
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