Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV-1

Article abstract of DOI:10.1016/j.bmcl.2009.09.056

Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antivir

Full text of DOI:10.1016/j.bmcl.2009.09.056

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6399–6403
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives
with potent activity against HIV-1
a
a
a
a
Kristjan S. Gudmundsson a, , Sharon D. Boggs , John G. Catalano , Angilique Svolto , Andrew Spaltenstein ,
*
Michael Thomson b, Pat Wheelan c, Stephen Jenkinson d
a Department of Medicinal Chemistry , Metabolic and Virology Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
b Department of Virology, Metabolic and Virology Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
c Department of DMPK, Metabolic and Virology Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
d Department of Biochemical and Analytical Pharmacology, Metabolic and Virology Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development,
Five Moore Drive, Research Triangle Park, NC 27709-3398, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent
activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern
are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several
compounds with low nanomolar anti-HIV activity and oral bioavailability are described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 August 2009
Revised 8 September 2009
Accepted 14 September 2009
Available online 19 September 2009
Keywords:
CXCR4
HIV
Antiviral
Imidazopyridine
Tetrahydroquinoline
CXCR4 is a 7-transmembrane chemokine receptor.1 Unlike most
of the other receptors within the chemokine family, CXCR4 has
only one known natural ligand, stromal cell-derived factor (SDF-
1). The interaction of SDF-1 with CXCR4 has been shown to play
a role in a number of physiological processes. CXCR4 is involved
in the homing of immune cells to sites of inflammation2 and the
interaction of CXCR4 and SDF-1 helps maintain the cellular
micro-environment of the bone marrow.3 CXCR4/SDF-1 interaction
has been shown to play a role in metastatic spread and in directly
regulating the growth and/or survival of several types of cancer.4
CXCR4 is a co-receptor for some strains of HIV-1 that are associated
with late stage disease and progression to AIDS.5 The CCR5 (R5)
utilizing HIV-1 strains are generally associated with the initial
infection and asymptomatic phase. As the disease progresses
towards AIDS variant forms of the virus emerge that utilize both
CCR5 and CXCR4 chemokine receptors (dual tropic viruses) or
solely the CXCR4 chemokine receptor (CXCR4 tropic) to gain entry
and infect new host cells.6
CXCR4 antagonists have potential therapeutic uses in HIV
infection and several other indications, including mobilization of
hematopoietic stem cells from the bone marrow.7 CXCR4 antago-
nists may be of value in the treatment of rheumatoid arthritis by
blocking the homing of inflammatory cells to inflamed joints.8
Both peptidic and small molecule CXCR4 antagonists have been
described. Peptides that are CXCR4 antagonists include ALX-40-
4C,9 CTCE-9908,10 FC13111 and POL3026.12 Small molecule CXCR4
antagonists have been developed by Kureha (KRH1636)13 and
N
N
1
HN
N
N
N
* Corresponding author. Tel.: +1 919 676 6530.
E-mail address: ksgudmundsson@gmail.com (K.S. Gudmundsson).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.056

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K. S. Gudmundsson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6399–6403
AnorMED (AMD3100, Plerixafor, Mozobil14 and AMD07015).
AMD3100 was recently approved by the FDA for stem cell
mobilization.
We recently described benzimidazole analogs, such as 1 (Fig. 1),
that showed very potent anti-HIV activity (IC50 0.6 nM against HIV-
1).16
However, upon further investigation it became evident that
benzimidazole 1 was highly protein bound and suffered significant
protein shift (80-fold) in the antiviral assay (Table 1). We were
therefore interested in synthesizing compounds in which the benz-
imidazole portion of 1 was replaced with an imidazopyridine and
exploring the effect on antiviral activity and protein shift. Herein,
we describe the synthesis and antiviral activity of several imidazo-
pyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives.
For the synthesis of the desired imidazopyridine derivatives
containing the piperazine linked to the C5-position, the first steps
involved synthesis of a suitable imidazopyridine building block
(Scheme 1). Condensation of commercially available 2-amino-6-
fluoropyridine 2 and trichloroacetone gave the dichloromethyl
imidazopyridine 3. Treatment of 3 with aqueous sodium acetate
yielded the aldehyde 4.
Condensation of 4 and chiral tetrahydroquinoline amine 516 via
reductive amination gave the 5-fluoroimidazopyridine derivative
6. Treatment of 6 with N-methylpiperazine under relatively mild
Table 1
Anti-HIV activity and cytotoxicity of imidazopyridine-tetrahydro-8-quinolinamines
8
1
N
N
2
6
N
N
R1
5
R2
3
Compda
R1
R2
IC50
(l
M)
Proteinc shift
1.5
CC50
4.5
(lM)
b
d
8
Me
0.002
0.084
N
N
N
N
Me
Me
10 R
11 (rac)
12
Me
Me
Et
—
12.6
>10
8.1
0.69
N
N
O
0.002
1.5
N
Me
13 (rac)
14
CH2CF3
n-Pr
0.127
0.003
0.005
—
5
>5
N
N
N
N
N
N
Me
Me
Me
6.7
8.9
15
i-Pr
5
16
17
18
19
0.004
0.003
0.023
0.028
6
8.0
5.3
20
N
N
N
N
N
N
N
N
Me
Me
Me
Me
n-Bu
—
—
—
9.3
20
21
Me
Me
0.004
0.003
10
3.9
7.1
N
N
N
N
Et
3.3
i-Pr
N
N
N
22
23
Me
Me
0.004
0.017
—
—
3.9
2.2
N

K. S. Gudmundsson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6399–6403
6401
M)
Table 1 (continued)
Compda
R1
R2
IC50
(l
M)
Proteinc shift
—
CC50
6.3
(l
b
d
24
25
Me
0.004
0.004
N
NH2
Me
8
3.4
N
N
NMe2
26
27
Me
Me
0.008
0.043
3
5
2.1
4.9
NMe2
N
NMe2
Me
N
N
Me
28
Me
Me
Me
0.030
0.049
0.640
1.3
—
10.8
12.5
N
Me
N
Me
29
35e
—
>5
>5
N
N Me
1f
0.0006
80
a
Compounds have S-stereochemistry at 8-position of the tetrahydroquinoline unless otherwise noted, (rac) is racemic.
HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase), HIV-1, CXCR4-tropic strain (IIIB). Compounds were tested for their ability to block infection of the HOS
b
cell line. IC50 is the concentration at which 50% efficacy in the antiviral assay is observed.19
c
Protein shift is the shift in concentration at which 50% efficacy in the antiviral assay is observed in the presence of human serum albumin (45 mg/mL) and
a-acid
glycoprotein (1 mg/mL).
d
CC50 is the concentration at which 50% cytotoxicity is observed in the HOS cell line.
Compound 35 is methylpiperazine substituted at C-8 position (Scheme 2).
Compound 1 is benzimidazole, from Ref. 16 included for comparison.
e
f
conditions resulted in displacement of the 5-fluorine and
formation of 7.17 Displacement of the fluorine has to be carried
out under mild conditions as the 8-aminotetrahydroquinoline is
labile to racemization18 at higher temperature. Finally, removal
of the (S)-4-methoxyphenylethylgroup, followed by alkylation
under reductive amination conditions gave the desired compound
8. Alternatively, 8 could be prepared from 6 via deprotection and
alkylation to give 9, followed by displacement of the 5-fluorine
with N-methylpiperazine, again using only mildly elevated tem-
perature to avoid racemization of the 8-aminotetrahydroquinoline.
The R-enantiomer 10 was prepared in a similar fashion as the
S-enantiomer 8. The S-enantiomer 8 was about 50-fold more
potent than the R-enantiomer 10 against HIV-1 (Table 1). Replac-
ing the N-methylpiperazine with morpholine (11) resulted in
greatly reduced anti-HIV activity (345-fold reduction in activity),
highlighting the importance of the basic piperazine nitrogen. We
then explored changing the 8-aminotetrahydroquinoline alkyl
substituent, while keeping the N-methylpiperazine intact.
Compounds 12–19 were prepared from 7 in a similar fashion as
outlined in Scheme 1. In general smaller alkyl substituents gave
potent compounds, as long as they did not affect the basicity of
the 8-aminotetrahydroquinoline nitrogen. Thus, the ethylamine
12 was equipotent to the methylamine 8, whereas the trifluoroeth-
ylamine 13 showed significantly reduced anti-HIV activity (60-fold
less activity), presumably due to the altered basicity of the
8-amine. The n-propylamine 14, isopropylamine 15, cyclopropylm-
ethylamine 16 and n-butylamine 17 showed promising anti-HIV
activity while the sec-butylamine 18 and the still bulkier benzyl-
amine 19 were less preferred (about fivefold less potent). We then
looked at the effect that human serum protein would have on anti-
substituent (R1) is a small alkyl group (e.g., 8 and 12), were not
generally affected by protein addition. However, piperazine ana-
logs with larger alkyl substituents at R1 (e.g., 14–16) showed a
more significant protein shift, up to 10-fold. Next we looked at
replacing the N-methylpiperazine with N-ethylpiperazine (20)
and N-isopropylpiperazine (21). Both analogs were potent in the
anti-HIV assay, but both suffered significant protein shift (>3-fold).
We then explored replacing the piperazine with other heterocy-
cles and basic amines. The C5-fluoroderivative 9 provided easy
access to a number of nitrogen linked C5-substituted derivatives
via an addition elimination reaction and compounds 22–29 were
prepared in this fashion. The hexahydropyrrolo[1,2-a]pyrazine
derivative 22 had similar potency to 8. The trimethyl ethylenedia-
mine derivative 23, a flexible analog of 8, had almost 10-fold
reduced activity against HIV-1. The 4-aminopiperidine derivatives
24 and 25, as well as the (3R)-3-dimethylamino-1-pyrrolidinyl
derivative 26, had good anti-HIV activity. Both 25 and 26 were
more protein shifted (3–10-fold) than comparable piperazine ana-
logs. Interestingly, the (3S)-3-dimethylamino-1-pyrrolidinyl deriv-
ative 27 demonstrated fivefold less anti-HIV activity than the
closely related (3R)-3-dimethylamino-1-pyrrolidinyl derivative
26. Finally, pyrrolidinyl derivative 28 and piperidinyl derivative
29 had reduced anti-HIV activity and appeared less attractive.
Thus, while several heterocycles were identified (e.g., 25 and 26)
that could potentially replace the piperazine, none showed better
anti-HIV activity and protein shift profile than the N-methylpiper-
azines. To this point we had only looked at C-5 substituted imi-
dazopyridines, whereas the piperazine could be attached to the
C-8 position of the imidazopyridine and still occupy similar space
by rotating the imidazopyridine. To confirm that the C-5 was the
optimal site for the piperazine substituent we synthesized the
C-8 substituted imidazopyridine (Scheme 2). Condensation of
2-amino-3-bromopyridine (30) with trichloroacetone gave the
viral activity (protein shift) by adding human albumin and
a-acid
glycoprotein to the antiviral assay (Table 1). The methylpiperazine
analogs (8, 12–19), in which the 8-aminotetrahydroquinoline alkyl

6402
K. S. Gudmundsson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6399–6403
Table 2
Pharmacokinetics in rats
O
a
Cl
Cl
1
N
8
F
Parameter
8
14
16
21
25
26
2
Cl
Cl
7
6
Cl
Cl (mL/min/kg)
Vdss (L/kg)
T1/2 (h)
14
8.9
6.2
10.7
41
9.9
6.0
8.8
31
31
5.7
5.1
10
7
9.5
4.5
7.9
2
N
4
b
F
N
NH2
4.9
5.5
11
10.6
3.9
29
3
5
2
3
F (%, solution)
Clearance (Cl), volume of distribution (Vdss) and half life (T1/2) calculated following
a 1 mg/kg iv dose. Oral bioavailability (F) calculated following solution doses of
3 mg/kg.
OMe
N
6
N
OMe
5
N
N
H
O
N
N
N
H
c
Table 3
Pharmacokinetics of 8
N
4
F
F
Parameter
Rat
Dog (beagle)
Monkey (cynomolgus)
Cl (mL/min/kg)
Vdss (L/kg)
T1/2 (h)
14
18
6
OMe
4.9
5.5
11
8.5
7.6
13
3.7
10
10
N
7
N
8
N
F (%, solution)
N
Clearance (Cl), volume of distribution (Vdss) and half life (T1/2) calculated following
a 1 mg/kg iv dose. Oral bioavailability (F) calculated following solution doses of
3 mg/kg.
d
e and f
N
N
N
N
N
N
N
N
dichloromethyl derivative 31. Aqueous base treatment of 31
yielded aldehyde 32. Reductive amination of aldehyde 32 and
(8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine 33 gave 34.
The C8-bromine in 34 could not be replaced via treatment of 34
with N-methylpiperazine at elevated temperature but required
coupling under Buchwald amination conditions to give the desired
C-8 N-methylpiperazine substituted 35. Compound 35 was over
300-fold less potent than the corresponding C-5 substituted deriv-
ative 8, highlighting the importance of the position of the imidazo-
pyridine N1-nitrogen in relation to the piperazine.
N
9
N
6
8
g and h
i
N
N
F
Scheme 1. Reagents and conditions: (a) trichloroacetone, DME, 80 °C, 12 h (63%);
(b) NaOAc, EtOH, H2O, 60 °C, 12 h (55%); (c) NaBH(OAc)3, AcOH, ClCH2CH2Cl, rt, 18 h
(64%); (d) N-methylpiperazine, 100 °C, 72 h (93%; >20:1 de as determined by
HNMR); (e) CF3COOH, CH2Cl2, rt, 4 h; (f) CH2O (aq), NaBH(OAc)3, AcOH, ClCH2CH2Cl,
rt, 18 h, (64% for two steps); (g) CF3COOH, CH2Cl2, rt, 4 h; (h) CH2O (aq),
NaBH(OAc)3, AcOH, ClCH2CH2Cl, rt, 18 h (60% for two steps); (i) N-methylpipera-
zine, 100 °C, 72 h (90%, 100% ee as determined by chiral supercritical fluid
chromatography).
A set of potent analogs were chosen for rat pharmacokinetic
studies (Table 2).
With regard to bioavailability and half life, compounds 8, 14 and
16 appeared promising. While compounds 14 and 16 showed better
pharmacokinetic properties in rat studies than compound 8, this
benefit was outweighed by the higher protein shift of both 14 and
16 (>5-fold for both). Compound 21 showed good bioavailability
but shorter half life and greater protein shift than 8. Compounds 25
and 26 were less bioavailable and more protein shifted than 8. This
resulted in 820 being chosen as the first compound for more detailed
pharmacokinetic studies in dog and cynomolgus monkey (Table 3).
Compound 8 showed oral bioavailability in both dog and mon-
key. Furthermore, it displayed suitable cytochrome P450 profile
and screening against a panel of enzymes and receptors (PanLab)
revealed little risk of unwanted enzyme and receptor inhibition
at concentrations close to those demonstrating anti-HIV activity
(selectivity over 100-fold).
Br
Br
NH2
N
Cl
Cl
N
b
a
N
31
30
Br
N
33
N
N
O
N
H
N
N
34
Because of the promising anti-HIV potency and oral bioavail-
ability, 8 was progressed into toxicology studies and served as a
template for the synthesis of additional analogs.
N
H
c
32
N
Br
Acknowledgements
N
N
35
We thank David McCoy, Richard Hazen and Wendell Lawrence
for providing HIV-1 and protein shift data.
d
N
N
References and notes
N
N Me
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Scheme 2. Reagents and conditions: (a) trichloroacetone, DME, 15 h, rt. Then,
precipitate collected by filtration, EtOH, 4 h, reflux (45%); (b) aq CaCO3, 1.5 h, reflux
(91%); (c) NaBH(OAc)3, AcOH, ClCH2CH2Cl, rt, 15 h (89%); (d) N-methylpiperazine,
Pd(OAc)2, BINAP, Cs2CO3, toluene, reflux, 12 h (27%).

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20. Compound 8 is a pale yellow oil: 1H NMR (CDCl3): d 8.52 (d, 1H), 7.70 (s, 1H),
7.34 (d, 1H), 7.28 (d, 1H), 7.10 (m, 1H), 7.06 (m, 1H), 6.23 (dd, 1H), 4.12 (m, 1H),
3.96 (s, 2H), 3.14 (m, 4H), 2.86–2.78 (m, 2H), 2.71–2.65 (m, 4H), 2.41 (s, 3H),
2.39 (s, 3 H), 2.16 (m, 1H), 2.06–1.97 (m, 2H), 1.68 (m, 1H); MS m/z 391 (M+1).
13C NMR (CDCl3): d 158.0, 147.0, 146.2, 145.5, 145.2, 136.4, 134.1, 124.7, 121.4,
111.9, 107.9, 98.9, 62.5, 55.0, 55.0, 53.1, 49.5, 49.5, 46.1, 39.0, 29.2, 24.2, 21.1;
HRMS: Calculated Mass: 391.2610; Found Mass: 391.2614; Formula: C23H31N6.
Anal. Calcd for C23H30N6: C, 70.74; H, 7.74; N, 21.52. Found: C, 70.36; H, 7.77;
N, 21.53.