Design and synthesis of some novel 2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indoles as potential c-Met inhibitors

Article abstract of DOI:10.1002/hlca.201100226

Since deregulation of the tyrosine-kinase receptor c-Met is implicated in several human cancers and is an attractive target for small-molecule-drug discovery, we report herein the synthesis of 2,3,4,5-tetrahydro-8-[1-(quinolin- 6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-b]indoles 4a-4c and 2,3,4,5-tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b] pyridazin-6-yl]-1H-pyrido[4,3-b]indoles 5a-5c. These indole derivatives demonstrated inhibition of c-Met kinase activity. Concurrently, five key intermediates were synthesized. These compounds could be prepared in good yields. Copyright

Full text of DOI:10.1002/hlca.201100226

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Helvetica Chimica Acta – Vol. 95 (2012)
Design and Synthesis of Some Novel 2,3,4,5-Tetrahydro-1H-pyrido[4,3-
b]indoles as Potential c-Met Inhibitors
by Lianbao Ye, Yuanxin Tian, Zhonghuang Li, Jiajie Zhang*, and Shuguang Wu*
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
(
phone: þ 86-20-62789415; fax: þ 86-20-61648548; e-mail: shuguang@smu.edu.cn;
zhangjj@smu.edu.cn)
Since deregulation of the tyrosine-kinase receptor c-Met is implicated in several human cancers and
is an attractive target for small-molecule-drug discovery, we report herein the synthesis of 2,3,4,5-tet-
rahydro-8-[1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-b]indoles 4a – 4c
and 2,3,4,5-tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-pyrido[4,3-b]in-
doles 5a – 5c. These indole derivatives demonstrated inhibition of c-Met kinase activity. Concurrently,
five key intermediates were synthesized. These compounds could be prepared in good yields.
Introduction. – c-Met is a tyrosine-kinase receptor for the hepatocyte growth factor
(
HGF). Both c-Met and HGF are expressed in a number of different tissues [1].
Binding of HGF to the extracellular domain of c-Met can cause multimerization of the
receptor and phosphorylation of tyrosine residues. c-Met/HGF signaling is essential for
normal cell proliferation, migration, angiogenesis, and tissue regeneration [2]. In
addition, aberrant c-Met/HGF signaling plays a major role in tumorgenesis invasion
and metastasis in many human tumors [3]. The mutation and over-expression of c-Met
proto-oncogene and/or HGF have been detected in different types of malignant solid
tumors and correlated with advanced stays and poor prognosis [4]. Therefore, c-Met
has become an attractive therapeutic target for cancer therapy. One way to block c-Met
signaling is by inhibiting binding of aurintricarboxylic acid (ATA) to the tyrosine-
kinase domain of c-Met with small molecular inhibitors [5].
In our previous study, we discovered the structures of 2,3,4,5-tetrahydro-1H-pyrido
[
4,3-b]indoles 1 as a potent c-Met inhibitor (Fig.) [6]. In an ongoing effort to design
novel and selective inhibitors of the c-Met enzyme, we were intrigued by filed
applications from Pfizer [7] and Janssen [8] in which they claimed that a series of 1-
(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b] pyrazine derivatives and 3-(quinolin-6-
ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin derivatives of low molecular mass were potent
and selective c-Met inhibitors. The reports [7] and [8] disclosed that representative
examples, PF-04217903 (2) and JNJ-38877605 (3) (Fig.), respectively, are in phase-I
clinical trials.
Intrigued by the low molecular mass and unknown binding mode of PF-04217903
and JNJ-38877605 to c-Met and by our previous study, we introduced 2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole groups to the 6-position of 1-(quinolin-6-ylmethyl)-
1
H-1,2,3-triazolo[4,5-b]pyrazine (¼6-(1H-1,2,3-triazolo[4,5-b]pyrazin-1-ylmethyl)qui-
ꢀ
2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
321
Figure. Reported c-Met inhibitors
noline) and 3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazine (¼6-(1H-1,2,4-tri-
azolo[4,3-b]pyrazin-3-ylmethyl)quinoline) in order to reach synergy. With the assis-
1
tance of molecular docking (Table) ), we designed and synthesized the six structurally
relevant novel compounds 4a – 4c and 5a – 5c.
Table. Results of Molecular Docking
Score
Score
3
4
4
4
dkf ligand
5.86
8.73
8.18
7.14
5a
5b
5c
6.35
8.69
8.31
a
b
c
Results and Discussion. – The synthetic pathways for 4a – 4c and 5a – 5c are outlined
in Schemes 1 and 2, respectively. The reaction of tert-butyl 2,3,4,5-tetrahydro-8-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrido[4,3-b]indole-2-carboxylate (6) with 6-
bromo-1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazine (¼6-[(6-bromo-1H-
1,2,3-triazolo[4,5-b]pyrazin-1-yl)methyl]quinoline; 7) [7] or 6-chloro-3-(quinolin-6-
ylmethyl)-1,2,4-triazolo[4,3-b]pyridazine (¼6-[(6-chloro-1,2,4-triazolo[4,3-b]pyrazin-
-yl)methyl]quinoline; 8) [8], respectively, gave 2,3,4,5-tetrahydro-8-[1-(quinolin-6-
ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-b]indole (4a) and
,3,4,5-tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-py-
rido[4,3-b]indole (5a) in 80 and 78% yields, respectively, via Suzuki coupling reaction
Schemes 1 and 2). Then, 4a and 5a were transformed to 4b and 4c and to 5b and 5c,
3
2
(
respectively, by formylation and carbamoylation in 78, 82, 75, and 68% yield.
The starting material 6 was prepared from 8-bromo-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indole (11) by treatment with di(tert-butyl) dicarbonate (Boc) O and an
2
electrophilic substitution reaction in 62.4% yield via 12, while 11 was synthesized by a
modification of a reported route [9] via condensation of commercially available (4-
1)
Molecular docking was performed with Sybyl7.3. A crystal structure of the c-Met complex with
SGX523 was obtained from the protein data bank (pdb entry: 3dkf).

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1. Synthesis of 4a – 4c
a) [Pd(PPh ) ], DMF/H O, K CO , 808, 18 h. b) 4m HCl, 1,4-dioxane, CH Cl , r.t., 1 h. c) N-(3-
3
4
2
2
3
2
2
Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC · HCl), HCOOH, N,N-diisopropyl-
ethylamine, CH Cl , r.t., 2 h. d) Me SiꢀNCO, CH Cl , r.t., 16 h.
2
2
3
2
2
Scheme 2. Synthesis of 5a – 5c
a) [Pd(PPh ) ], DMF/H O, K CO , 808, 18h. b) 4m HCl, 1,4-dioxane, CH Cl , r.t., 1 h. c) EDC · HCl,
3
4
2
2
3
2
2
HCOOH, N,N-diisopropylethylamine, CH Cl , r.t., 2 h. d) Me SiꢀNCO, CH Cl , r.t., 16 h.
2
2
3
2
2
bromophenyl)hydrazine (9) and tert-butyl 4-oxopiperidine-1-carboxylate (10) in 78 %
yield (Scheme 3). Compounds 6, 7, 11, and 12 have been reported previously [6][7][9].
Molecular docking was performed with Sybyl7.3. A crystal structure of the c-Met
complex with SGX523 was obtained from the protein data bank (pdb entry: 3dkf). At
the beginning of docking, all the H O and ligands were removed, and the random H-
2
atoms were added. Then, the receptor structure was minimized in 10000 cycles with the
Powell method in sybyl7.3. After the construction of the compounds, H-atoms and the

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3. Synthesis of 6
323
a) HCl, EtOH, reflux, 3 h. b) N,N-Diisopropylethylamine, (Boc) O, CH Cl , r.t., 1 h. c) Bis(pinaco-
2
2
2
lato)diboron (¼4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane), AcOK, [PdCl (dppf)]/CH Cl
2
2
2
(
dppf ¼ 1,1’-bis(diphenylphosphino)ferrocene), DMSO, N , 808, 16 h.
2
GasteigerꢀHꢀckel charges were added. Then, their geometries were optimized by the
conjugate gradient method in the TRIPOS force field. The energy convergence
criterion was 0.001 kcal/mol. Except for some special notes, default values were chosen
to finish this work. To validate the docking reliability, the ligand SGX523 was removed
from the active site and docked back into the binding pocket. The root-mean-square
deviation (r.m.s.d.) between the predicted conformation and the actual conformation
from the crystal structure of the ligand was 0.6 ꢂ, which is smaller than the resolution of
X-ray crystallography. It indicated that the parameter set for the Surflex-dock
simulation was reasonable to reproduce the X-ray structure. So, the results of molecular
docking in the Table were reasonable.
Preliminary results showed that 4a – 4c and 5a – 5c obviously inhibit the c-Met
enzyme, in which 4a had the best inhibitory effect with an IC50 of 0.0145 mm, and the
inhibitory effects were consistent with the results of molecular docking in the Table.
Thus, we could make sure that the designed compounds should be well worth studying
based on the molecular-docking theory and preliminary biological tests. Further
research on activities is currently under investigation and will be reported in due
course.
This study was supported by grants from the International Science and Technology Cooperation Base
of Guangdong Provincial Department of Science and Technology (No. 2009B050900006) and the Science
and Technology Bureau of Guangzhou (No. 2009A1-E011-8 and No. 2010 V1-E00531-3).
Experimental Part
General. All chemicals were obtained from Aladdin or J&K Science. Solvents were purified and
dried by standard procedures, and stored over 3-ꢂ molecular sieves. TLC: SILG/UV 254 silica-gel plates.
1
13
Flash chromatography (FC): silica gel (SiO ; 40 mm, 230 – 400 mesh). H- and C-NMR Spectra: Bruker
2
digital NMR spectrometer; d in ppm rel. to Me Si as internal standard, J in Hz. EI-MS: Waters ZQ4000;
4
in m/z. Elemental analyses (CHNS): PerkinꢀElmer-240-B micro-analyzer.
8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (11). A mixture of (4-bromophenyl)hydrazine
hydrochloride (9 · HCl; 224 mg, 1 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (10; 199 mg,
mmol) were dissolved under stirring in EtOH saturated with HCl (10 ml). Then, the mixture was
1
heated under reflux for 3 h under stirring (TLC control). The solvent was evaporated and the residue
treated with NaHCO soln. (10 ml) and extracted with CH Cl (3 ꢁ 20 ml). The combined org. layer was
3
2
2
dried (Na SO , 3 g) and concentrated to afford the crude product, which was purified by FC (MeOH/
2
4
1
CH Cl ): 11 [6][9] (78%). H-NMR (CD OD): 2.82 (t, J ¼ 5.6, 2 H); 3.15 (t, J ¼ 5.6, 2 H); 3.95 (s, 2 H);
2
2
3

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Helvetica Chimica Acta – Vol. 95 (2012)
7
9
þ
7
2
.11 (dd, J ¼ 1.6, 8.8, 1 H); 7.18 (d, J ¼ 8.4, 1 H); 7.46 (d, J ¼ 1.6, 1 H). EI-MS: 251.01 ([M ( Br) þ H] ),
81
þ
52.99 ([M ( Br) þ H] ).
tert-Butyl 8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carboxylate. A soln. of 11 (251 mg,
mmol), (Boc) O (262 mg, 1.2 mmol), and N,N-diisopropylethylamine (258 mg, 2 mmol) in CH Cl was
1
2
2
2
stirred for 1 h at r.t. (TLC control). The solvent was evaporated, and the crude product purified by FC
(
2
3
MeOH/CH Cl ): 12 [6][9] (78%). H-NMR (CDCl ): 1.50 (s, 9 H); 2.83 (t, J ¼ 5.2, 2 H); 3.81 (t, J ¼ 5.2,
2
2
3
H); 4.58 (s, 2 H); 7.17 (d, J ¼ 8.4, 1 H); 7.24 (d, J ¼ 8.4, 1 H); 7.57 (s, 1 H); 7.92 (br. s, 1 H). EI-MS:
79 81 þ
þ
50.99 ([M ( Br) þ H] ), 352.97 ([M ( Br) þ H] ).
tert-Butyl 2,3,4,5-Tetrahydro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrido[4,3-b]in-
dole-2-carboxylate (6). [PdCl (dppf)CH Cl ] (20.4 mg, 0.025 mmol) was added portion-wise to a soln.
2
2
2
of 12 (175 mg, 0.5 mmol), bis(pinacolato)diboron (140 mg, 0.55 mmol), and AcOK (147 mg, 1.5 mmol)
in DMSO (5 ml), and N was bubbled through the mixture for 2 min. Then, the mixture was stirred for
2
1
6 h at 808 (LC/MS control). After cooling to r.t., H O (2 ml) was added, and the mixture was extracted
2
with CH Cl (3 ꢁ 5 ml). The org. layer was dried (Na SO , 1 g) and concentrated: 6 [6][9] (80%).
2
2
2
4
1
H-NMR (CDCl ): 1.50 (s, 9 H); 2.82 (t, J ¼ 5.2, 2 H); 3.82 (t, J ¼ 5.2, 2 H); 4.60 (s, 2 H); 7.17 (d, J ¼ 8.4,
3
þ
1
H); 7.23 (dd, J ¼ 2.0, 8.0, 1 H); 7.62 (s, 1 H); 7.96 (br. s, 1 H). EI-MS: 399.14 ([M þ H] ).
6
-[(6-Bromo-1H-1,2,3-triazolo[4,5-b]pyrazin-1-yl)methyl]quioline (7) [7]. Yield 60%. 1H-NMR
(
(
(
(D )DMSO): 6.28 (s, 2 H); 7.61 (dd, J ¼ 8.34, 4.55, 1 H); 7.83 (dd, J ¼ 8.72, 1.89, 1 H); 7.94 (s, 1 H); 8.02
6
d, J ¼ 8.84, 1 H); 8.74 (d, J ¼ 8.08, 1 H); 8.95 (dd, J ¼ 4.42, 1.64, 1 H); 9.34 (s, 1 H). EI-MS: 341.01 ([M
79
þ
81
þ
Br) þ H] ), 342.97 ([M ( Br) þ H] ).
6
-[(6-Chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline (8) [8]. Yield 70%. 1H-NMR
(
CDCl ): 4.74 (s, 2 H); 7.10 (d, J ¼ 10.0, 1 H); 7.39 (dd, J ¼ 4.0, 8.0, 1 H); 7.80 (dd, J ¼ 2.0, 8.4, 1 H);
3
7.85 (s, 1 H); 8.05 – 8.08 (m, 2 H); 8.11 (dd, J ¼ 0.8, 8.4, 1 H); 8.88 (dd, J ¼ 1.6, 4.0, 1 H). EI-MS: 296.02
35 37 þ
þ
(
[M ( Cl) þ H] ), 297.99 ([M ( Cl) þ H] ).
,3,4,5-Tetrahydro-8-[1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-
b]indole (4a). [Pd(PPh ) ] (11.6 mg, 0.01 mmol) was added portion-wise to a soln. of 7 (68.2 mg,
2
3
4
0
.2 mmol) [7], 6 (95.6 mg, 0.24 mmol), and K CO (82.9 mg, 0.6 mmol) in DMF/H O 4 :1 (2.0 ml), and
2
3
2
N was bubbled through the mixture for 2 min. The mixture was stirred for 18 h at 808 (LC/MS control)
2
and then cooled to r. t. H O (5 ml) was added, and the mixture was extracted with CH Cl (3 ꢁ 10 ml).
2
2
2
The org. layer was dried (Na SO , 1 g), and concentrated. The obtained solid was dissolved in CH Cl
2
2
4
2
(
(
5 ml), and a 4m 1,4-dioxane soln. of HCl was added. The mixture was stirred for 1 h at r.t. and filtered: 4a
1
80 mg, 80%). H-NMR (CD OD): 2.91 (t, J ¼ 5.6, 2 H); 3.27 (t, J ¼ 5.2, 2 H); 4.15 (s, 2 H); 6.24 (s, 2 H);
3
7
.45 (d, J ¼ 8.8, 1 H); 7.56 (dd, J ¼ 4.4, 8.4, 1 H); 7.94 (dd, J ¼ 2.0, 8.8, 1 H); 8.01 (dd, J ¼ 2.0, 8.8, 1 H); 8.05
(d, J ¼ 8.8, 1 H); 8.10 (s, 1 H); 8.29 (d, J ¼ 2.0, 1 H); 8.39 (d, J ¼ 8.4, 1 H); 8.85 (dd, J ¼ 2.0, 4.4, 1 H); 9.37
13
(s, 1 H). C-NMR ((D )DMSO): 31.5; 43.4; 45.7; 53.1; 110.2; 112.3; 116.8; 120.3; 122.2; 127.1; 128.5;
6
1
29.3; 131.1; 131.9; 133.7; 135.7; 136.9; 137.1; 137.7; 138.1; 145.9; 147.5; 148.6; 149.7; 155.4. EI-MS: 433.10
þ
(
[M þ H] ). Anal. calc. for C H N (432.48): C 69.43, H 4.66, N 25.91; found: C 69.42, H 4.68, N 25.90.
25
20
8
2
,3,4,5-Tetrahydro-8-[1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-
b]indole-2-carboxaldehyde (4b). N,N-Diisopropylethylamine (38 mg, 0.296 mmol) was added portion-
wise to a soln. of HCOOH (6.8 mg, 0.148 mmol) and EDC · HCl (28.4 mg, 0.148 mmol) in CH Cl (4/1,
2
2
2
0 ml). The mixture was stirred for 0.5 h at r.t., then 4a was added and the mixture stirred for 2 h at r.t.
The solvent was evaporated and the crude product purified by FC (MeOH/CH Cl ): 4b (26.5 mg, 78%).
2
2
1
H-NMR (CD OD): 2.98 (t, J ¼ 5.6, 2 H); 3.89 (t, J ¼ 5.6, 2 H); 4.80 (s, 2 H); 6.25 (s, 2 H); 7.47 (d, J ¼ 8.4,
3
1
H); 7.56 (dd, J ¼ 4.8, 8.8, 1 H); 7.95 (dd, J ¼ 2.0, 8.8, 1 H); 8.03 (d, J ¼ 8.4, 1 H); 8.08 (d, J ¼ 8.8, 1 H);
.14 (s, 1 H); 8.27 (s, 1 H); 8.37 (s, 1 H); 8.42 (d, J ¼ 8.8, 1 H); 8.85 (d, J ¼ 4.4, 1 H); 9.40 (s, 1 H).
8
13
C-NMR ((D )DMSO): 29.1; 42.3; 47.7; 52.5; 111.4; 113.1; 117.1; 119.7; 123.1; 126.9; 129.1; 129.6; 130.1;
6
1
31.5; 132.7; 135.1; 135.9; 136.1; 136.7; 138.1; 146.1; 147.3; 148.2; 149.1; 153.4; 162.5. EI-MS: 461.00 ([M þ
þ
H] ). Anal. calc. for C26
20 8
H N O (460.49): C 67.81, H 4.38, N 24.33; found: C 67.83, H 4.36, N 24.33.
2
,3,4,5-Tetrahydro-8-[1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-
b]indole-2-carboxamide (4c). N,N-Diisopropylethylamine (64.2 mg, 0.5 mmol) and Me SiꢀNCO
3
(
28.8 mg, 0.25 mmol) were added portion-wise to a soln. of 4a (25 mg, 0.05 mmol) in CH Cl (2 ml).
2 2
The mixture was stirred for 16 h at r.t. The solvent was evaporated and the crude product purified by FC
1
(
MeOH/CH Cl ): 4c (19.5 mg, 82%). H-NMR (CD OD): 2.88 (t, J ¼ 4.8, 2 H); 3.85 (t, J ¼ 5.2, 2 H); 4.70
2
2
3

Helvetica Chimica Acta – Vol. 95 (2012)
325
(
s, 2 H); 6.23 (s, 2 H); 7.45 (d, J ¼ 8.4, 1 H); 7.55 (dd, J ¼ 4.4, 8.4, 1 H); 7.94 (dd, J ¼ 2.0, 8.8, 1 H); 8.01 (d,
J ¼ 8.4, 1 H); 8.06 (d, J ¼ 8.8, 1 H); 8.09 (s, 1 H); 8.32 (s, 1 H); 8.39 (d, J ¼ 8.0, 1 H); 8.84 (d, J ¼ 4.0, 1 H);
13
9
1
4
2
.36 (s, 1 H). C-NMR ((D )DMSO): 28.3; 44.9; 51.3; 52.5; 110.8; 112.9; 116.8; 119.7; 122.1; 126.8; 129.1;
6
29.8; 130.4; 131.3; 132.5; 135.3; 135.7; 136.3; 136.7; 137.9; 146.3; 146.9; 147.8; 149.2; 152.9; 163.3. EI-MS:
þ
76.08 ([M þ H] ). Anal. calc. for C H N O (475.5): C 65.67, H 4.45, N 26.51; found: C 65.65, H 4.47, N
26
21
9
6.49.
Compounds 5a – 5c were prepared in analogy to 4a – 4c.
2
,3,4,5-Tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-pyrido[4,3-
1
b]indole (5a). Yield 78%. H-NMR (CD OD): 3.22 (t, J ¼ 5.6, 2 H); 3.65 (t, J ¼ 5.6, 2 H); 4.58 (s, 2 H);
3
5
8
1
1
7
.13 (s, 2 H); 7.56 (d, J ¼ 8.0, 1 H); 8.03 (d, J ¼ 8.0, 1 H); 8.13 (t, J ¼ 8.0, 1 H); 8.32 (d, J ¼ 7.6, 1 H); 8.36 –
.41 (m, 2 H); 8.52 – 8.57 (m, 3 H); 8.22 – 8.23 (m, 2 H). 13C-NMR ((D )DMSO): 30.2; 31.3; 42.8; 45.5;
6
09.5; 112.1; 116.7; 120.0; 121.7; 125.6; 127.1; 127.8; 128.1; 129.3; 129.7; 131.2; 135.7; 136.1; 136.4; 136.9;
þ
43.5; 145.3; 147.2; 149.1; 160.3; 162.1. EI-MS: 432.08 ([M þ H] ). Anal. calc. for C H N (431.49): C
26
21
7
2.37, H 4.91, N 22.72; found: C 72.39, H 4.89, N 22.72.
2
,3,4,5-Tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-pyrido[4,3-
1
b]indole-2-carboxaldehyde (5b). Yield 75%. H-NMR (CD OD): 2.94 (t, J ¼ 5.6, 2 H); 3.86 (t, J ¼ 5.6,
3
2
7
1
1
H); 4.73 (s, 2 H); 4.83 (s, 2 H); 7.38 (d, J ¼ 8.4, 1 H); 7.53 (dd, J ¼ 4.4, 8.8, 1 H); 7.78 (d, J ¼ 8.4, 1 H);
.84 – 7.91 (m, 2 H); 7.99 (s, 1 H); 8.03 – 8.04 (m, 2 H); 8.10 (d, J ¼ 10.0, 1 H); 8.27 (s, 1 H); 8.36 (d, J ¼ 8.8,
13
H); 8.78 (d, J ¼ 2.8, 1 H). C-NMR ((D )DMSO): 27.9; 29.8; 41.7; 46.9; 110.1; 111.9; 117.1; 120.5; 122.1;
6
25.9; 126.9; 128.1; 128.4; 129.8; 130.3; 133.1; 136.3; 136.5; 136.7; 137.1; 144.0; 145.5; 147.2; 149.1; 161.1;
þ
1
62.7; 164.5. EI-MS: 460.05 ([M þ H] ). Anal. calc. for C H N O (459.51): C 70.57, H 4.61, N 21.34;
27
21
7
found: C 70.57, H 4.63, N 21.33.
2
,3,4,5-Tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-pyrido[4,3-
1
b]indole-2-carboxamide (5c). Yield 68%. H-NMR (CD OD): 2.88 (t, J ¼ 4.8, 2 H); 3.84 (t, J ¼ 5.6, 2 H);
3
4
.68 (s, 2 H); 4.87 (s, 2 H); 7.42 (d, J ¼ 8.8, 1 H); 7.53 (dd, J ¼ 4.4, 8.4, 1 H); 7.81 (d, J ¼ 8.4, 1 H); 7.91 (d,
J ¼ 8.4, 1 H); 7.96 (d, J ¼ 9.6, 1 H); 8.01 – 8.05 (m, 3 H); 8.17 (d, J ¼ 10.0, 1 H); 8.34 (d, J ¼ 7.6, 1 H); 8.80
13
(
d, J ¼ 2.8, 1 H). C-NMR ((D )DMSO): 27.6; 29.8; 45.1; 50.4; 110.1; 112.5; 116.9; 120.7; 123.3; 124.4;
6
1
1
6
26.9; 127.8; 128.3; 128.9; 131.7; 132.9; 136.1; 136.5; 136.9; 137.4; 144.2; 145.8; 146.9; 148.8; 161.2; 163.1;
þ
65.1. EI-MS: 475.06 ([M þ H] ). Anal. calc. for C H N O (474.52): C 68.34, H 4.67, N 23.61; found: C
27
22
8
8.35, H 4.68, N 23.57.
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Received June 2, 2011