Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage

Article abstract of DOI:10.1016/j.steroids.2016.08.002

An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have been synthesized via an acylation of corresponding 6,7-dihydro-1H-indazol-4(5H)-one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH₄resulted in a formation of betulinic acid-indazolone hybrids in excellent yields. The configuration of the key compounds has been fully established by X-ray and 2D NMR analysis.

Full text of DOI:10.1016/j.steroids.2016.08.002

Accepted Manuscript
Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester
linkage
Tatyana S. Khlebnicova, Yuri A. Piven, Alexander V. Baranovsky, Fedor A.
Lakhvich, Svetlana V. Shishkina, Daina Zicāne, Zenta Tetere, Irisa Rāviņa,
Viktors Kumpiņ š, Inese Rijkure, Inese Mieriņa, Uldis Peipiņ š, Māris Turks
PII:
S0039-128X(16)30098-8
http://dx.doi.org/10.1016/j.steroids.2016.08.002
STE 8006
DOI:
Reference:
To appear in:
Steroids
Received Date:
Revised Date:
Accepted Date:
26 April 2016
29 July 2016
2 August 2016
Please cite this article as: Khlebnicova, T.S., Piven, Y.A., Baranovsky, A.V., Lakhvich, F.A., Shishkina, S.V.,
Zicāne, D., Tetere, Z., Rāviņa, I., Kumpiņ š, V., Rijkure, I., Mieriņa, I., Peipiņ š, U., Turks, M., Synthesis of novel
lupane triterpenoid-indazolone hybrids with oxime ester linkage, Steroids (2016), doi: http://dx.doi.org/10.1016/
j.steroids.2016.08.002
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1
Synthesis of novel lupane triterpenoid−indazolone hybrids with
oxime ester linkage
a
a
a
Tatyana S. Khlebnicova , Yuri A. Piven , Alexander V. Baranovsky , Fedor A.
a
b
c
c
c
Lakhvich , Svetlana V. Shishkina , Daina Zicāne , Zenta Tetere , Irisa Rāviņa ,
c
c
c
c
c,
Viktors Kumpiņš , Inese Rijkure , Inese Mieriņa , Uldis Peipiņš , Māris Turks *
a
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Str.
5/2, 220141 Minsk, Belarus
b
Institute for Single Crystals, National Academy of Sciences of Ukraine, pr. Lenina 60, Kharkiv, 61001
Ukraine
c
Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry,
Riga Technical University, P. Valdena Str. 3, Riga, LV-1048, Latvia. E-mail: maris_turks@ktf.rtu.lv
Abstract
An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone
hybrids with oxime ester linkage has been developed from naturally accessible
precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have
been synthesized via an acylation of corresponding 6,7-dihydro-1H-indazol-4(5H)-
one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained
4
betulonic acid conjugates with NaBH resulted in a formation of betulinic acid -
indazolone hybrids in excellent yields. The configuration of the key compounds has
been fully established by X-ray and 2D NMR analysis.
Key words
Triterpenoid-indazolone hybrids
Betulonic acid
Betulinic acid
Indazolone oximes
X-ray structure

2
1. Introduction
The hybridization of bioactive natural and unnatural compounds is one of the
most promising for the design of new leading structures and the discovery of new and
potent drugs in the field of medicinal chemistry [1−4]. Hybrid systems (sometimes
also referred as conjugates) are defined as assembly of diverse molecular entities (in
general two), natural or synthetic, to afford functional molecules, which intrinsically
enhance or modulate the biological properties of individual components or, may
exhibit new properties. The most widely applied definition of “hybrid molecule”
defines a hybrid as a molecule that covalently connects two parent molecules that
independently act at two distinct pharmacological target structures and the hybrid
consequently is designed in a manner to maintain their activities at these two targets.
In terms of drug design these two pharmacological actions are supposed to act in an
overall synergistic manner concerning the disease to be targeted. This is why the
hybrid approach gained special attention in recent times, since the complexity of
several severe diseases, such as cancer and neurodegenerative disorders, can hardly be
effectively targeted by one [5]. While tremendous efforts have been made over the
past decades to improve the available therapeutic options, and a large number of
potent chemotherapeutic anticancer agents have been identified and successfully used
in clinical practice, cancer still remains a major cause of disease and death in most
countries. Therefore, development of potent and specific anticancer agents is well-
timed.

3
Fig. 1. Naturally occurring lupane triterpenoids 1−3 and an example of their
semisynthetic derivative 4.
Triterpenoids represent a varied class of natural products which constitute the
major components of some medicinal plants [6−8]. Among these, some pentacyclic
triterpene members have been exploited in recent past owing to their significant role
in various biological activities [9,10]. Betulin, betulonic and betulinic acids (Fig.1),
naturally occurring pentacyclic lupane triterpenoids, are common secondary
metabolites of plants, primarily from Betula species (Betulaceae), that exhibits a
variety of biological activities including an inhibition of human immunodeficiency
virus (HIV), antibacterial, antimalarial, antiinflammatory, antitumor and other
activities [11−14]. A large number of betulinic and betulonic acid derivatives have
been developed to increase its therapeutic activity [15,16]. One well-tolerated
betulinic acid derivative is NVX-207, which showed significant antitumor activity in
clinical studies in canine cancer patients with treatment-resistant malignancies [17].
Some lupane triterpene hybrids with bioactive compounds showed interesting
biological properties [18−21]. Previous studies suggested that an introduction of the
nitrogen-containing heterocyclic rings to the pentacyclic triterpenoids can
significantly improve the biological activities [15, 22−24].

4
On the other hand, indazole skeleton is an attractive structural scaffold in
medicinal chemistry and various indazole derivatives have been described to possess
useful levels of antiinflammatory, antipyretic, analgesic, antimicrobial, anticancer,
sodium channel blocker, antitubercular, antiviral, antihypertensive, antiglaucoma,
antioxidant, antidepressant, anxiolytic, neuroprotective and antidiabetic activities
[
25−28].
Fig. 2. Inhibitors of heat-shock protein 90 (HSP90).
In particular, variously substituted tetrahydroindazolones were recently recognized as
important anticancer drug candidates. Depending on structural peculiarities they were
proved to act either as excellent inhibitors of heat-shock protein 90 [29,30] or
regulators of the mitotic motor protein Eg5 [31]. The specific inhibition of the latter
prevents uncontrollable division of malignant cells. Additionally, some of
tetrahydroindazolone derivatives were shown to be active against various carcinomas
[
32] but at the same time being less toxic than other available antitumor drugs [33].
In the light of these facts, synthetic methodologies towards tetrahydroindazole analogs
continue to develop [25]. Thus, we have recently developed an efficient one-step
procedure for the synthesis of fluorine-containing 6,7-dihydro-1H-indazol-4(5H)-ones
[
34−37], which made these compounds accessible. We have also reported synthesis of
triazolyl-substituted indazolones [38] and functionalized amino-

5
tetrahydroindazolones, including enantiomerically pure analogs and their conjugation
with various carbohydrates [39−41].
The present work deals with synthesis of novel lupane triterpenoid-indazolone
hybrids. Thus, in order to search for agents with potenial antitumor activity and
selectivity, a series of lupane triterpene hybrids were synthesized by introducing
variously substituted indazolone moieties at C28 position of betulonic and betulinic
acid via oxime ester linkage. It should be noted that introduction of an oxime function
into an appropriate skeleton is a reasonable approach to the preparation of potent
cytotoxic agents and many oxime derivatives have exhibited potent inhibition
activities against human tumors [42−44].
2. Experimental
2.1. General
1
13
19
H, C, and F NMR spectra were recorded on a Bruker AVANCE 500
1
13
19
spectrometer (500 MHz for H, 125 MHz for C and 470 MHz for F) or Bruker
1
13
AVANCE 300 spectrometer (300 MHz for H and 75 MHz for C). Chemical shift
values are given in δ (ppm) relative to the residual solvent signals for δ 7.26 ppm
CDCl ), 2.05 ppm (acetone-d ), 7.16 ppm (C ) and δ 77.16 ppm (CDCl ), 29.84
ppm (acetone-d ), 128.06 ppm (C ). α,α,α-Trifluorotoluene was used as an external
standard for F NMR spectra; the chemical shifts were converted from α,α,α-
trifluorotoluene to CCl F. COSY, HSQC, HMBC, and NOESY experiments were
H
(
3
6
6
D
6
С
3
6
6 6
D
1
9
3
carried out with the use of the standard Bruker program package. Melting points were
measured on Boetius apparatus and are uncorrected. IR spectra were recorded in KBr
discs on a FT-IR Perkin Elmer Spectrum 100. High-resolution mass spectra (HRMS)

6
were recorded on a 6550 iFunnel Q-TOF LC/MS (Agilent Technologies) micromass
spectrometer by electrospray ionization (ESI). Column chromatography was
performed on 70−230 mesh silica gel. Reactions were monitored by thin layer
chromatography (TLC) on pre-coated silica gel F254 plates with a UV indicator.
Chemicals were purchased from Aldrich or Acros and used as received. Solvents were
dried and freshly distilled according to common practice.
Betulonic acid (2) with technical product quality was obtained by reported procedure
[
45]. Indazolones 7a−7n were synthesized by a condensation of 2-acylcyclohexane-
,3-diones with phenyl hydrazines by described procedure [34−37]. The analytical
1
data of indazolones 7a−7f,7h,7i were identical to those described in [34−37].
Indazolone oximes 8k,l [46] and 8m,n [33] were obtained according to previously
published procedures.
2
.2. Synthesis of the compounds
Synthesis of betulonic acid (2) from its cyclohexylammonium salt
% Aqueous solution of phosphoric acid (185 mL) was added to a stirred suspension
5
of cyclohexylammonium betulonate (5) (29.8 g, 0,053 mol, 98.7% purity by HPLC)
in DCM (900 mL). The layers were separated and the DCM layer was successively
washed with 5% aqueous solution of phosphoric acid (6 × 60 ml), water (7 × 120 ml;
until pH 5 – 6) and brine (150 ml). The organic layer was dried over anh. Na
2 4
SO ,
filtered and evaporated to provide betulonic acid with 97.8% purity by HPLC (23.7 g,
96% calculated on 100% cyclohexylammonium betulonate; or 88% calculated on the
1
initial technical betulonic acid). Mp 245−247 °C. H NMR (300 MHz, CDCl
3
) δ:
), 0.99 (s, 3H,
), 1.76−1.58 (m, 2H, CH, CH ) 1.69 (s, 3H,
1
.55−1.18 (m, 15H, CH, CH
2
), 1.06 (s, 3H, CH
3
), 1.01 (s, 3H, CH
3
CH ), 0.97 (s, 3H, CH ), 0.92 (s, 3H CH
3
3
3
2

7
CH
3
), 2.07−1.84 (m, 3H, CH, CH
2
), 2.34−2.15 (m, 2H, CH, CH
2
), 2.56−2.34 (m, 2H,
CH, CH
2
), 3.07−2.94 (m, 1H, CH), 4.61 (brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl),
1
1
1.68−11.00 (brs, 1H, COOH). H NMR data correspond to those reported in
reference [47]. Elemental analysis, %: Found: C, 79.12; H, 10.29. C30
9.25; H, 10.20.
H
46
3
O . Calcd: C,
7
Cyclohexylammonium betulonate (5)
A solution of cyclohexylamine (6.62 mL, 0.058 mol; 1 equiv.) in TBME (90 mL) was
added to a vigorously stirred solution of technical betulonic acid [45] (92.8% purity
by HPLC) (28.3 g, 0.058 mol; 1 equiv.) in TBME (260 mL) at room temperature. The
resulting suspension was stirred for 40 min at room temperature, filtered and washed
on the filter with TBME (5 × 20 mL). The precipitate consists of
cyclohexylammonium betulonate with 96.1% purity by HPLC (31.3 g, 94%,
calculated on 100% betulonic acid). The resulting technical salt was crystallized from
a mixture of EtOAc/EtOH (400 mL : 400 mL) and the product (29.8 g, 89%
calculated on 100% betulonic acid) with 98.7% purity by HPLC was obtained. Mp
+
2
08−210 °C. IR (KBr), νmax: 2940 (CH), 2865 (CH), 2755−2610 (RN H
3
), 2215, 1710
) δ: 0.92
), 1.61−1.12 (m,
from c-hexylamine), 1.84−1.62 (m, 4H, CH, CH ), 1.70 (s, 3H,
), 1.97−1.84 (m, 3H, CH, CH from c-hexylamine), 2.10−1.99 (m, 2H, CH from
c-hexylamine), 2.29−2.18 (m, 1H, CH), 2.57−2.35 (m, 3H, CH, CH ), 2.92−2.80 (m,
H, CH or CH from c-hexylamine), 3.15−3.03 (m, 1H, CH or CH from c-
1
(
CO), 1635, 1525, 1455, 1390, 1365, 1325, 880. H NMR (300 MHz, CDCl
s, 3H, CH ), 0.99 (s, 6H, 2CH ), 1.03 (s, 3H, CH ), 1.08 (s, 3H, CH
1H, CH, CH , 3CH
CH
3
(
3
3
3
3
2
2
2
2
3
2
2
2
1
+
hexylamine), 4.60 (brs, 1H, Hvinyl), 4.72 (brs, 1H, Hvinyl), 7.45−7.26 (brs, 3H, RN H
3
).
1
3
C NMR (75 MHz, CDCl
3
) δ: 14.7, 16.15, 16.23, 19.4, 19.8, 21.2, 21.7, 24.9, 25.3,

8
2
5.8, 26.8, 30.0, 31.1, 33.1, 33.2, 33.9, 34.3, 37.0, 37.8, 38.5, 39.8, 40.8, 42.7, 47.4,
7.5, 49.4, 50.1, 50.5, 55.0, 56.9, 109.5, 151.6, 182.3, 218.4. Elemental analysis, %:
4
3
Found: C, 77.68; H, 10.79; N, 2.45. C36H59NO . Calcd: C, 78.07; H, 10.74; N, 2.53.
2
.2.1. 3-Cyclopropyl-6,6-dimethyl-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (7g)
The title compound was prepared in 59% yield according to [36] from 2-
cyclopropanecarbonyl-5,5-dimethylcyclohexane-1,3-dione as a white solid. Mp
1
1
2
1
1
43−145 °C. IR (KBr) νmax: 690, 715, 735, 755, 810, 890, 975, 1020, 1035, 1055,
115, 1290, 1365, 1375, 1390, 1415, 1450, 1470, 1495, 1510, 1535, 1600, 1660,
1
830−3085. H NMR (500 MHz, CDCl
3
) δ: 0.97−1.01 (m, 2H, CH2cyclopropyl),
.05−1.08 (m, 2H, CH2cyclopropyl), 1.09 (s, 6H, 2CH
H, CHcyclopropyl) 2.74 (s, 2H, CH ), 7.36−7.39 (m, 1H, Harom), 7.43−7.48 (m, 4H,
) δ: 8.5, 9.2, 28.5, 35.7, 37.4, 52.7, 117.1, 124.0,
28.0, 129.4, 138.9, 149.0, 155.8, 193.5. HRMS (ESI): m/z calcd for C18 N O
3 2
), 2.40 (s, 2H, CH ), 2.59−2.65 (m,
2
1
3
H
arom). C NMR (125 MHz, CDCl
3
1
H
20
2
+
(
M+H) , 295.3788; found, 295.3797.
2
.2.2 6,6-Dimethyl-3-(furan-2-yl)-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (7j)
The title compound was prepared in 58% yield according to [36] from 2-
furoyl-5,5-dimethylcyclohexane-1,3-dione as a white solid. Mp 180−182 °C. IR
KBr) νmax: 690, 705, 755, 835, 885, 975, 990, 1020, 1025, 1060, 1080, 1165, 1225,
(
1
2
2
7
285, 1305, 1370, 1390, 1410, 1425, 1460, 1475, 1500, 1510, 1525, 1600, 1660.
1
865−3150. H NMR (500 MHz, CDCl
3
3 2
) δ: 1.11 (s, 6H, 2CH ), 2.48 (s, 2H, CH ),
.80 (s, 2H, CH
.49−7.55 (m, 5H, Harom), 7.87 (d, J = 3.4 Hz, 1H, Hfuryl). C NMR (125 MHz,
) δ: 28.4, 35.4, 37.3, 53.0, 111.6, 114.0, 115.0, 124.6, 128.7, 129.5, 138.5,
2
), 6.53 (dd, J = 3.4, 1.8 Hz, 1H, Hfuryl), 7.42−7.45 (m, 1H, Hfuryl),
1
3
CDCl
3

9
+
1
42.5, 143.2, 146.8, 149.8, 191.8. HRMS (ESI): m/z calcd for C19
07.1447; found, 307.1456.
19 2 2
H N O (M+H) ,
3
2
.2.3. General procedure for the synthesis of oximes 8a−8j
To a solution of indazolone 7a−7j (1.0 mmol) in Py (5 ml), hydroxylamine
hydrochloride (4.0 mmol, 0.28 g) was added. After refluxing for 3 h, the mixture was
cooled to room temperature and poured into cold 18% hydrochloric acid (80 mL) and
3 4
extracted with CHCl (5 x 20 mL). The combined organic layers were dried (MgSO ),
filtered and concentrated in vacuum to give oximes 8a−8j. The analytical data of
indazolone oximes 8a−8f were identical to those described in [48].
2
.2.3.1. (E)-3-Cyclopropyl-6,6-dimethyl-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one
oxime (8g)
The title compound was prepared in 86% yield from indazolone 7g as a white
solid. Mp 191−194 °C. IR (KBr) νmax: 685, 695, 730, 745, 755, 760, 795, 830, 885,
9
1
2
05, 925, 935, 945, 985, 1025, 1035, 1055, 1070, 1090, 1160, 1170, 1240, 1255,
295, 1320, 1370, 1385, 1395, 1425, 1445, 1470, 1500, 1510, 1555, 1600, 1640,
1
835−3080. H NMR (500 MHz, CDCl
3
) δ: 0.96−1.04 (m, 4H, 2CH2cyclopropyl), 1.07
(
s, 6H, 2CH
3
), 2.32−2.38 (m, 1H, CHcyclopropyl), 2.63 (s, 2H, CH
2
), 2.69 (s, 2H, CH
2
),
1
3
7
8
.31−7.34 (m, 1H, Harom), 7.42−7.46 (m, 4H, Harom). C NMR (125 Hz, CDCl ) δ:
3
.1, 9.4, 28.6, 33.0, 36.4, 37.2, 112.4, 123.7, 127.3, 129.3, 139.3, 142.7, 152.1, 152.5.
+
HRMS (ESI): m/z calcd for C18
22
H N
3
O (M+H) , 296.1763; found, 296.1774.
2
.2.3.2. (E)-3-Cyclopropyl-6,6-dimethyl-1-(4-fluorophenyl)-6,7-dihydro-1H-indazol-
(5H)-one oxime (8h)
4

1
0
The title compound was prepared in 86% yield from indazolone 7h as a white
solid. Mp 232−234 °C. IR (KBr) νmax: 675, 730, 745, 790, 810, 835, 890, 915, 930,
9
1
0
45, 985, 1035, 1050, 1075, 1100, 1155, 1215, 1235, 1295, 1365, 1385, 1400, 1420,
1
450, 1515, 1555, 1610, 1640, 2870−3085. H NMR (500 MHz, acetone-d
6
) δ:
.83−0.94 м (4H, 2CH2cyclopropyl), 1.04 (s, 6H, 2CH
), 7.24−7.27 (m, 2H, Harom), 7.53−7.55 (m, 2H, Harom). C
NMR (125 MHz, acetone-d ) δ: 9.2, 9.5, 28.6, 33.2, 36.6, 37.4, 113.8, 116.6 (d, J = 23
Hz), 125.8 (d, J = 9 Hz), 136.9, 142.4, 151.3, 152.6, 162.0 (d, J = 245 Hz). F NMR
3
), 2.55−2.61 (m, 3H, CHcyclopropyl
,
1
3
CH
2
), 2.70 (s, 2H, CH
2
6
1
9
(
(
6
3
470 MHz, acetone-d ) δ: −117.2 (1F). HRMS (ESI): m/z calcd for C19H20FN O
+
M+H) , 314.1669; found, 314.1679.
2
.2.3.3. (E)-6,6-Dimethyl-3-(furan-2-yl)-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one
oxime (8i)
The title compound was prepared in 80% yield from indazolone 7i as a white
solid. Mp 200−202 °C. IR (KBr) νmax: 685, 695, 725, 740, 765, 800, 825, 885, 905,
920, 935, 945, 985, 995, 1000, 1015, 1025, 1070, 1105, 1160, 1210, 1300, 1365,
1
1
395, 1420, 1450, 1465, 1505, 1535, 1600, 1625, 2840-3070. H NMR (500 MHz,
3 3 2 2
CDCl ) δ: 1.06 (s, 6H, 2CH ), 2.65 (s, 2H, CH ), 2.68 (s, 2H, CH ), 6.48 (dd, J = 3.4,
1.8 Hz, 1H, Hfuryl), 7.36−7.39 (m, 1H, Harom), 7.44−7.53 (m, 5H, 4Harom, 1Hfuryl), 7.57
1
3
(
brs, 1H, Harom). C NMR (125 MHz, CDCl
3
) δ: 28.4, 32.5, 36.4, 37.1, 110.0, 111.3,
112.2, 124.4, 128.1, 129.3, 138.8, 140.4, 142.8, 143.7, 147.7, 151.7. HRMS (ESI):
+
20 3 2
m/z calcd for C19H N O (M+H) , 322.1556; found, 322.1565.
2
.2.3.4. (E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(furan-2-yl)-6,7-dihydro-1H-indazol-
(5H)-one oxime (8j)
4

1
1
The title compound was prepared in 92% yield from indazolone 7j as a white
solid. Mp 214−216 °C. IR (KBr) νmax: 680, 710, 720, 735, 755, 770, 795, 810, 830,
840, 845, 885, 900, 905, 915, 930, 945, 970, 990, 1020, 1065, 1110, 1160, 1225,
1
1
370, 1395, 1420, 1445, 1465, 1485, 1515, 1625, 1670, 2875−3130. H NMR (500
MHz, CDCl
3
) δ: 1.07 (s, 6H, 2CH
3
), 2.68 (s, 2H, CH
2
), 2.75 (s, 2H, CH ), 6.52 (dd, J
2
=
3.4, 1.8 Hz, 1H, Hfuryl), 7.13−7.17 (m, 2H, Harom), 7.25−7.26 (m, 1H, Hfuryl),
1
3
7
.43−7.46 (m, 2H, Harom), 7.91 (brs, 1H, Hfuryl). C NMR (125 MHz, CDCl
3
) δ: 28.2,
33.0, 36.7, 37.4, 106.5, 111.1, 111.9, 116.5 (d, J = 23 Hz), 126.3 (d, J = 9 Hz), 134.0,
1
9
1
3
40.6, 144.4, 146.0, 146.7, 152.5, 162.5 (d, J = 250 Hz). F NMR (470 MHz, CDCl )
+
3 2
δ: −111.5 (1F). HRMS (ESI): m/z calcd for C19H19FN O (M+H) , 340.1461; found,
340.1473.
2
.2.4. General procedure for the synthesis of betulonic acid hybrids 9a−9n.
To a solution of oximes 8a−8n (1 mmol) in CHCl
(10 mL), pyridine (0.1 mL)
and then dropwise a solution of betulonic acid chloride 6 [45] (1 mmol) in CHCl (10
3
3
mL) were added. After refluxing for 20 h, the mixture was cooled to room
temperature and treated with 10% hydrochloric acid (3 × 10 ml) and water (1 × 10
4
ml). The organic phase was dried (MgSO ) and filtered. After removal of the solvent
in vacuum, the residue was purified by silica gel column chromatography with
petroleum ether/ethyl acetate as eluent to give the corresponding hybrids 9a−9n.
2.2.4.1.
(E)-(6,6-Dimethyl-3-(trifluoromethyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9a)
The title compound was prepared in 48% yield from oxime 8a as a white solid.
Mp 200−204 °C. IR (KBr) νmax: 695, 715, 765, 795, 830, 860, 885, 900, 920, 940,

1
2
985, 1010, 1025, 1055, 1080, 1115, 1145, 1170, 1205, 1245, 1290, 1320, 1350, 1375,
1
1
400, 1455, 1505, 1545, 1600, 1610, 1640, 1705, 1750, 2875−3070. H NMR (500
MHz, CDCl
3
) δ: 0.79−2.53 (m, 24H, СH, CH
.00 (s, 6H, 2CH ), 1.06 (s, 3H, CH ), 1.09 (s, 3H, CH
H, CH ), 2.65 (d, J = 16.4 Hz, AB system, 1H, CH
), 2.70 (s, 2H, CH
), 3.12−3.18 (m, 1H, H19), 4.62 (brs, 1H, Hvinyl),
.74 (brs, 1H, Hvinyl), 7.45−7.54 (m, 5H, Harom). C NMR (125 MHz, CDCl
) δ: 14.7,
3
2
), 0.92 (s, 3H, CH
), 1.11 (s, 3H, CH
), 2.70 (d, J = 16.4 Hz, AB
3
), 0.98 (s, 3H, CH
3
),
1
3
3
3
3
3
), 1.71 (s,
3
2
system, 1H, CH
2
2
1
3
4
1
5.9, 19.4, 19.6, 21.0, 21.4, 25.5, 26.5, 28.3, 28.5, 29.7, 30.5, 32.3, 33.1, 33.7, 34.1,
6.6, 36.9, 37.1, 38.2, 38.3, 39.6, 40.7, 42.5, 46.8, 47.3, 50.0, 50.1, 55.0, 56.5, 109.7,
10.7, 120.7 (q, J = 269 Hz) 124.2, 128.9, 129.5, 138.0, 138.9 q (J = 39 Hz), 145.2,
3
1
1
9
1
50.4, 154.7, 171.9, 218.2. F NMR (470 MHz, CDCl
3
) δ: −63.7 (3F). HRMS (ESI):
+
m/z calcd for C46
H
60
F
3
N
3
NaO
3
(M+Na) 782.4484, found 782.4491.
2.2.4.2.
(E)-(6,6-Dimethyl-3-(perfluoroethyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9b)
The title compound was prepared in 38% yield from oxime 8b as a white
solid. Mp: 145−149 °C. IR (KBr) νmax: 695, 735, 750, 770, 790, 820, 860, 895, 940,
965, 1025, 1055, 1080, 1095, 1120, 1155, 1190, 1220, 1290, 1315, 1335, 1375, 1390,
1
1
400, 1450, 1460, 1505, 1540, 1600, 1620, 1640, 1705, 1755, 2870−3070. H NMR
(
500 MHz, CDCl
CH ), 1.01 (s, 6H, 2CH
.71 (s, 3H, CH ), 2.65 (d, J = 16.3 Hz, AB system, 1H, CH
AB system, 1H, CH ), 2.71 (s, 2H, CH ), 3.12−3.18 (m, 1H, C19-H), 4.62 (brs, 1H,
vinyl), 4.74 (brs, 1H, Hvinyl), 7.45−7.54 (m, 5H, Harom). C NMR (125 MHz, CDCl
δ: 14.8, 16.0, 16.1, 19.6, 19.8, 21.2, 21.5, 25.7, 26.7, 28.4, 28.6, 29.9, 30.7, 32.5, 33.1,
3
) δ: 0.79−2.55 (m, 24H, CH, CH
), 1.06 (s, 3H, CH ), 1.09 (s, 3H, CH
), 2.68 (d, J = 16.3 Hz,
2
), 0.92 (s, 3H, CH
3
), 0.97 (s, 3H,
3
3
3
3
), 1.10 (s, 3H, CH
3
),
1
3
2
2
2
1
3
H
3
)

1
3
3
1
1
3.8, 34.3, 36.9, 37.1, 37.2, 38.5, 39.8, 40.8, 42.6, 47.0, 47.5, 50.0, 50.1, 55.2, 56.7,
09.8, 110.9 (tq, J = 252 Hz, 39 Hz), 112.2, 119.3 (qt, J = 287 Hz, 37 Hz), 124.2,
1
9
29.0, 129.7, 138.1, 138.4 (t, J = 30 Hz), 145.2, 150.6, 154.8, 172.0, 218.3. F NMR
(
470 MHz, CDCl
3
) δ: −82.3 (3F), −110.7 (2F). HRMS (ESI): m/z calcd for
+
C
47
H
60
F
5
N
3
NaO
3
(M+Na) , 832.4453, found 832.4443.
2.2.4.3.
(E)-(6,6-Dimethyl-3-(perfluoropropyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9c)
The title compound was prepared in 35% yield from oxime 7c as a white solid.
Mp 156−160 °C. IR (KBr) νmax: 695, 715, 735, 750, 765, 820, 860, 890, 905, 935,
965, 980, 1010, 1020, 1055, 1085, 1115, 1190, 1205, 1230, 1260, 1290, 1315, 1355,
1
1
375, 1390, 1400, 1455, 1500, 1540, 1600, 1620, 1640, 1705, 1755, 2870−3070. H
NMR (500 MHz, CDCl
3
) δ: 0.80−2.55 (m, 24Н, СH, CH
), 1.00 (s, 3H, CH ), 1.01 (s, 3H, CH ), 1.06 (s, 3H, CH
.09 (s, 3H, CH ), 1.71 (s, 3H, СH ), 2.64 (d, J = 16.3 Hz, AB system, 1H, CH
.68 (d, J = 16.3 Hz, AB system, 1H, CH ), 2.70 (s, 2H, CH
2
), 0.92 (s, 3H, CH
3
), 0.97 (s,
3
1
2
H, CH
3
3
3
3
), 1.08 (s, 3H, CH
3
2
),
),
3
3
2
2
), 3.10−3.16 (m, 1H,
1
3
C19-H), 4.62 (brs, 1H, Hvinyl), 4.75 (brs, 1H, Hvinyl), 7.45−7.55 (m, 5H, Harom). C
NMR (125 MHz, CDCl ) δ: 14.8, 15.8, 16.1, 19.6, 19.8, 21.2, 21.6, 25.8, 26.7, 28.4,
8.5, 29.8, 29.9, 30.8, 32.5, 33.0, 33.9, 34.3, 36.9, 37.1, 37.2, 38.5, 39.8, 40.8, 42.7,
3
2
4
2
=
7.0, 47.5, 50.0, 50.1, 55.2, 56.8, 109.3 (tm, J = 266 Hz), 109.8, 112.6, 112.9 (tt, J =
55 Hz, 32 Hz), 118.2 (qt, J = 289 Hz, 35 Hz), 124.4, 129.1, 129.7, 138.2, 138.4 (t, J
19
30 Hz), 145.3, 150.6, 154.8, 172.0, 218.2. F NMR (470 MHz, CDCl
3
) δ: −80.3
NaO
3
(
(
3F), −108.6 (2F), −125.1 (2F). HRMS (ESI): m/z calcd for C48
H
60
F
7
N
3
+
M+Na) 882.4421, found, 882.4429.

1
4
2.2.4.4.
(E)-(6,6-Dimethyl-1-(4-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9d)
The title compound was prepared in 41% yield from oxime 8d as a white
solid. Mp: 271−275 °C. IR (KBr) νmax: 700, 720, 740, 750, 765, 845, 885, 900, 940,
980, 1015, 1055, 1080, 1095, 1120, 1150, 1170, 1205, 1235, 1290, 1350, 1380, 1405,
1
1
465, 1510, 1550, 1620, 1645, 1705, 1755, 2870−3070. H NMR (500 MHz, CDCl
3
)
δ: 0.79−2.52 (m, 24H, СH, CH
), 0.92 (s, 3H, CH
), 0.98 (s, 3H, CH
), 1.00 (s, 6H,
2
3
3
2
CH
3
), 1.06 (s, 3H, CH
3
), 1.10 (s, 3H, CH
3
), 1.11 (s, 3H, CH
3
), 1.71 (s, 3H, CH ),
3
2
.65 (s, 2H, CH
2
2
), 2.65 (d, J = 16.4 Hz, AB system, 1H, CH ), 2.69 (d, J = 16.4 Hz,
AB system, 1H, CH
2
), 3.11−3.17 (m, 1H, C19-H), 4.62 (brs, 1H, Hvinyl), 4.74 (brs,
1
3
1
H, Hvinyl), 7.19−7.24 (m, 2H, Harom), 7.44−7.48 (m, 2H, Harom). C NMR (125 MHz,
3
CDCl ) δ: 14.8, 16.1, 19.5, 19.8, 21.1, 21.5, 25.7, 26.7, 28.5, 28.6, 29.9, 30.7, 32.4,
3
3.2, 33.8, 34.3, 36.6, 37.0, 37.2, 38.3, 38.5, 39.8, 40.8, 42.6, 47.0, 47.5, 50.0, 50.1,
5.1, 56.7, 109.8, 110.9, 116.7 (d, J = 23 Hz), 120.8 (q, J = 270 Hz), 126.3 (d, J = 9
5
Hz), 134.2, 139.4, 139.4 (q, J = 39 Hz), 145.4, 150.5, 154.8, 162.6 (d, J = 260 Hz),
19
1
72.0, 218.3. F NMR (470 MHz, CDCl
) δ: −63.8 (3F), −111.7 (1F). HRMS (ESI):
3
+
59 4 3 3
m/z calcd for C46H F N NaO (M+Na) 800.4390, found 800.4399.
2.2.4.5.
(E)-(6,6-Dimethyl-1-(4-fluorophenyl)-3-(perfluoroethyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9e)
The title compound was prepared in 38% yield from oxime 8e as a white solid.
Mp: 191−195 °C. IR (KBr) νmax: 705, 735, 750, 845, 885, 895, 915, 940, 960, 985,
1015, 1055, 1080, 1095, 1120, 1140, 1155, 1185, 1220, 1290, 1320, 1335, 1380,
1
1
420, 1460, 1520, 1550, 1620, 1640, 1705, 1755, 2870−3070. H NMR (500 MHz,
CDCl
3
) δ: 0.86−2.53 (m, 24H, CH, CH
2
), 0.92 (s, 3H, CH
3
), 0.97 (s, 3H, CH ), 1.00
3

1
5
(
s, 6H, 2CH
CH ), 2.65 (d, J = 16.4 Hz, AB system, 1H, CH
Hz, AB system, 1H, CH ), 3.11−3.17 (m, 1H, C19-H), 4.62 (brs, 1H, Hvinyl), 4.74
brs, 1H, Hvinyl), 7.20−7.23 (m, 2H, Harom) 7.44−7.47 (m, 2H, Harom). C NMR (125
MHz, CDCl ) δ: 14.8, 16.0, 16.1, 19.6, 19.8, 21.2, 21.5, 25.7, 26.7, 28.4, 28.6, 29.9,
0.7, 32.5, 33.1, 33.8, 34.3, 36.8, 37.1, 37.2, 38.4, 38.5, 39.8, 40.8, 42.6, 47.0, 47.5,
0.0, 50.1, 55.2, 56.7, 109.8, 110.7 (tq, J = 252 Hz, 39 Hz), 112.3, 116.7 (d, J = 23
3
), 1.06 (s, 3H, CH
3
), 1.09 (s, 3H, CH
3
), 1.10 (s, 3H, CH
3
), 1.70 (s, 3H,
3
2
), 2.67 (s, 2H, CH
2
), 2.69 (d, J = 16.4
2
1
3
(
3
3
5
Hz), 119.2 (qt, J = 287 Hz, 37 Hz), 126.2 (d, J = 9 Hz), 134.2, 138.5 (t, J = 31 Hz),
1
9
1
3
45.2, 150.5, 154.6, 162.6 (d, J = 250 Hz), 172.0, 218.4; F NMR (470 MHz, CDCl )
59 6 3 3
δ: −82.3 (3F), −110.8 (2F), −111.8 (1F). HRMS (ESI): m/z calcd for C47H F N NaO
+
(
M+Na) 850,4358, found 850.4349.
2.2.4.6.
(E)-(6,6-Dimethyl-1-(4-fluorophenyl)-3-(perfluoropropyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9f)
The title compound was prepared in 33% yield from oxime 8f as a white solid.
Mp: 131−135 °C. IR (KBr) νmax: 665, 735, 750, 845, 890, 900, 920, 935, 965, 985,
1010, 1025, 1055, 1085, 1100, 1115, 1155, 1190, 1210, 1230, 1265, 1290, 1320,
1
1
370, 1390, 1400, 1420, 1465, 1500, 1515, 1620, 1640, 1705, 1755, 2870−3070. H
NMR (500 MHz, CDCl
3
) δ: 0.80−2.53 (m, 24Н, СH, CH
), 1.01 (s, 3H, CH ), 1.02 (s, 3H, CH ), 1.06 (s, 3H, CH
.10 (s, 3H, CH ), 1.71 (s, 3H, СH ), 2.62−2.70 (m, 4H, 2CH ), 3.10−3.15 (m, 1H,
2
), 0.93 (s, 3H, CH
3
), 0.97 (s,
3
1
H, CH
3
3
3
3
), 1.08 (s, 3H, CH
3
),
3
3
2
C19-H), 4.62 (brs, 1H, Hvinyl), 4.75 (brs, 1H, Hvinyl); 7.20−7.24 (m, 2H, Harom),
1
3
7
2
3
3
.45−7.48 (m, 2H, Harom). C NMR (125 MHz, CDCl ) δ: 14.9, 15.8, 16.1, 19.6, 19.8,
1.2, 21.6, 25.8, 26.8, 28.4, 28.6, 29.9, 30.8, 32.5, 33.0, 33.9, 34.3, 36.8, 37.1, 37.2,
8.6, 39.8, 40.8, 42.7, 47.0, 47.5, 50.0, 50.2, 55.3, 56.8, 109.3 (tm, J = 266 Hz),

1
6
1
09.8, 112.7, 112.9 (tt, J = 255 Hz, 32 Hz), 116.7 (d, J = 23 Hz), 118.2 (qt, J = 288,
4 Hz), 126.4 (d, J = 9 Hz), 134.3, 138.5 (t, J = 30 Hz), 145.3, 150.6, 154.7, 162.7 (d,
3
1
9
J = 250 Hz), 172.0, 218.2. F NMR (470 MHz, CDCl
3
) δ: −80.3 (3F), −108.7 (2F),
+
−
111.7 (1F), −125.1 (2F). HRMS (ESI): m/z calcd for C48
H
59
F
8
N
3
NaO (M+Na)
3
900.4326, found 900.4335.
2.2.4.7. (E)-3-(Cyclopropyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-
one O-(3-oxolup-20(29)-en-28-oyl) oxime (9g)
The title compound was prepared in 75% yield from oxime 8g as a white solid.
Mp 130−134 °C. IR (KBr) νmax: 695, 725, 760, 790, 820, 855, 890, 940, 985, 1025,
1035, 1055, 1095, 1105, 1135, 1170, 1255, 1295, 1320, 1350, 1370, 1385, 1405,
1
450, 1510, 1545, 1600, 1645, 1705, 1750, 2870−3070. The NMR (500 MHz, CDCl )
3
+
data were in Table 2. HRMS (ESI): m/z calcd for C48
found, 754.4930.
65 3 3
H N NaO (M+Na) 754.4924,
2.2.4.8. (E)-3-(Cyclopropyl)-6,6-dimethyl-1-(4-fluorophenyl)-6,7-dihydro-1H-indazol-
4
(5H)-one O-(3-oxo-lup-20(29)-en-28-oyl) oxime (9h)
The title compound was prepared in 68% yield from oxime 8h as a white
solid. Mp 152−156 °C. IR (KBr) νmax: 665, 725, 755, 840, 885, 940, 1015, 1035,
1055, 1080, 1100, 1135, 1155, 1170, 1225, 1295, 1320, 1370, 1380, 1385, 1400,
1
1
420, 1460, 1505, 1520, 1610, 1640, 1705, 1750, 2875−3080. H NMR (500 MHz,
CDCl
s, 6H, 2CH
CH ), 2.60 (s, 2H, CH
Hz, AB system, 1H, CH
3
) δ: 0.79−2.79 (m, 28H, CH, CH
), 1.06 (s, 3H, CH ), 1.08 (s, 3H, CH
), 2.65 (d, J = 16.5 Hz, AB system, 1H, CH
), 2.73−2.81 (m, 1H, CHcyclopropyl), 3.10−3.15 (m, 1H, C19-
2
), 0.92 (s, 3H, CH
), 1.09 (s, 3H, CH
), 2.68 (d, J = 16.5
3
), 0.99 (s, 3H, CH
3
), 1.01
(
3
3
3
3
), 1.71 (s, 3H,
3
2
2
2

1
7
H), 4.62 (brs, 1H, Hvinyl), 4.75 (brs, 1H, Hvinyl), 7.12−7.16 м (2H, Harom), 7.38−7.40
1
3
(
m, 2H, H Harom). C NMR (125 MHz, CDCl
3
) δ: 9.2, 9.7, 9.8, 14.8, 16.1, 16.3, 19.6,
1
3
1
9.8, 21.2, 21.6, 25.8, 26.8, 28.6, 28.8, 29.9, 30.8, 32.5, 33.4, 33.9, 34.3, 36.8, 37.1,
7.4, 38.6, 38.7, 39.8, 40.9, 42.7, 47.2, 47.5, 50.0, 50.1, 55.2, 56.8, 109.9, 111.4,
16.3 (d, J = 23 Hz), 125.6 (d, J = 8 Hz), 135.3, 143.6, 150.5, 154.1, 158.4, 161.8 (d,
1
9
J = 247 Hz), 172.8, 218.2. F NMR (470 MHz, CDCl
3
) δ: – 113.9 (1F). HRMS
+
(
ESI): m/z calcd for C48H N NaO (M+Na) 772.4829, found 772.4837.
64 3 3
2.2.4.9. (E)-6,6-Dimethyl-3-(furan-2-yl)-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one
O-(3-oxolup-20(29)-en-28-oyl) oxime (9i)
The title compound was prepared in 76% yield from oxime 8i as a white solid.
Mp 175−179 °C. IR (KBr) νmax: 695, 715, 745, 765, 855, 885, 910, 940, 995, 1025,
1055, 1085, 1095, 1100, 1135, 1165, 1225, 1260, 1290, 1315, 1370, 1390, 1430,
1
1
455, 1505, 1535, 1600, 1620, 1640, 1705, 1750, 2870−3145. H NMR (500 MHz,
CDCl
s, 3H, CH
CH ), 1.72 (s, 3H, CH
CH ), 2.76 (d, J = 16.4 Hz, AB system, 1H, CH
brs, 1H, Hvinyl), 4.77 (brs, 1H, Hvinyl), 6.60 (dd, J = 3.5 Hz, 1.7 Hz, 1H, Hfuryl),
3
) δ: 0.86−2.52 (m, 24H, СH, CH
), 1.02 (s, 3H, CH ), 1.06 (s, 3H, CH
), 2.72 (s, 2H, CH ), 2.73 (d, J = 16.4 Hz, AB system, 1H,
), 3.11−3.16 (m, 1H, C19-H), 4.64
2
), 0.92 (s, 3H, CH
3
), 0.99 (s, 3H, CH
3
), 1.00
(
3
3
3
), 1.10 (s, 3H, CH
3
), 1.11 (s, 3H,
3
3
2
2
2
(
7.40−7.43 (m, 1H, Harom), 7.48−7.54 (m, 5H, 4Harom, 1Hfuryl), 8.30 (d, J = 3.5 Hz, 1H,
1
3
H
3
furyl). C NMR (125 MHz, CDCl ) δ: 14.8, 16.1, 16.1, 19.5, 19.8, 21.2, 21.6, 25.7,
2
4
1
6.7, 28.5, 28.6, 29.9, 30.8, 32.7, 33.0, 33.8, 34.3, 36.9, 37.0, 37.4, 38.6, 38.9, 39.8,
0.8, 42.7, 47.1, 47.5, 49.8, 50.1, 55.1, 56.8, 109.0, 109.9, 112.0, 114.4, 124.5, 128.3,
29.4, 138.7, 141.3, 142.7, 144.4, 147.4, 150.5, 156.6, 172.8, 218.3. HRMS (ESI):
+
m/z calcd for C49
H
63
N
3
NaO
4
(M+Na) , 780.4716, found 780.4724.

1
8
2
.2.4.10. (E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(furan-2-yl)-6,7-dihydro-1H-indazol-
(5H)-one O-(3-oxolup-20(29)-en-28-oyl) oxime (9j)
4
The title compound was prepared in 64% yield from oxime 8j as a white solid.
Mp: 175−179 °C. IR (KBr) νmax: 700, 745, 830, 840, 885, 900, 910, 920, 940, 995,
1
1
0
050, 1080, 1095, 1110, 1135, 1165, 1225, 1290, 1320, 1370, 1390, 1420, 1460,
1
510, 1520, 1620, 1640, 1705, 1750, 2875−3135. H NMR (500 MHz, CDCl
3
) δ:
), 1.00 (s, 3H,
), 1.12 (s, 3H, CH ), 1.72
), 2.72 (d, J = 16.3 Hz, AB system, 1H, СH ), 2.76 (d, J
16.3 Hz, AB system, 1H, СH ), 3.11−3.16 (m, 1H, C19-H), 4.64 (brs, 1H, Hvinyl),
.86−2.52 (m, 24H, СH, CH
), 1.02 (s, 3H, CH ), 1.06 (s, 3H, CH
s, 3H, CH ), 2.67 (s, 2H, CH
), 0.92 (s, 3H, CH
3 3
), 0.98 (s, 3H, CH
2
CH
3
3
3
), 1.10 (s, 3H, CH
3
3
(
3
2
2
=
2
4.77 (brs, 1H, Hvinyl), 6.60 (dd, J = 3.5 Hz, 1.8 Hz, 1H, Hfuryl), 7.17−7.21 (m, 2H,
1
3
H
arom), 7.49−7.52 (m, 3H, 2Harom, 1Hfuryl), 8.30 (dd, J = 3.5, 0.5 Hz, 1H, Hfuryl). C
NMR (125 MHz, CDCl ) δ: 14.8, 16.1, 16.1, 19.5, 19.8, 21.2, 21.6, 25.7, 26.7, 28.5,
3
2
4
1
8.6, 29.9, 30.8, 32.7, 33.0, 33.8, 34.3, 36.8, 37.1, 37.4, 38.6, 38.8, 39.8, 40.8, 42.7,
7.1, 47.5, 49.9, 50.1, 55.1, 56.8, 109.0, 109.9, 112.1, 114.5, 116.4 (d, J = 23 Hz),
26.5 (d, J = 9 Hz), 134.9, 141.4, 142.8, 144.5, 147.3, 150.4, 156.4, 162.2 (d, J = 249
19
Hz), 172.8, 218.2. F NMR (470 MHz, CDCl
3
) δ: −112.7 (1F); HRMS (ESI): m/z
+
calcd for C49
H62FN
3
NaO
4
(M+Na) 798,4622, found 798.4629.
2.2.4.11. 6,6-Dimethyl-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one O-(3-oxolup-
20(29)-en-28-oyl) oxime (9k)
The title compound was prepared as a 80:20 mixture of Z/E isomers according
(
NMR data) in 83% yield from oxime 8k as a white solid. Mp: 170−171 °C. IR (KBr)
max: 3465, 2955 (CH), 2870 (CH), 1755 (COOR), 1705 (CO), 1630, 1600, 1505,
ν

1
9
3
1455, 1105, 1075, 1055, 895, 840, 760, 695. The NMR (500 MHz, CDCl ) data are
+
provided in Table 2. HRMS (ESI): m/z calcd for C45
found 798.4629. 692.4782.
62 4 3
H N O (M+H) 692.4786,
2.2.4.12. (E)-3,6,6-Trimethyl-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one O-(3-
oxolup-20(29)-en-28-oyl) oxime (9l)
The title compound was prepared in 63% yield from oxime 8l as a white solid.
Mp: 142−144 °C. IR (KBr) νmax: 3440, 2955 (CH), 2870 (CH), 1750 (COOR), 1705
1
(
CO), 1600, 1510, 1460, 1105, 1060, 895, 760, 695. H NMR (300 MHz, CDCl
3
) δ:
),
), 1.77−1.68 (m,
), 2.14−2.03 (m, 2H,
), 2.66 (s, 2H, C5′/7′),
.69 (s, 2H, C5′/7′), 3.14 (td, J = 11.7 Hz, J = 5.4 Hz, 1H, CH), 4.64 (brs, 1H, Hvinyl),
0
1
1
.93 (s, 3H, CH
.09 (s, 3H, CH
H, CH), 1.73 (s, 3H, CH
), 2.52−2.31 (m, 4H, CH, CH
3
), 1.01 (s, 3H, CH
), 1.08 (s, 3H, CH
), 1.98−1.85 (m, 2H, CH/CH
), 2.63 (s, 3H, C3′-CH
3
3
), 1.02 (s, 6H, C6′-Ha, C6′-Hb), 1.10 (s, 3H, CH
3
3
3
), 1.60-1.21 (m, 15H, CH, CH
2
3
2
CH/CH
2
2
2
4
1
3
.76 (brs, 1H, Hvinyl), 7.42−7.34 (m, 1H, Harom), 7.53−7.43 (m, 4H, Harom). C NMR
) δ: 14.8, 14.9, 15.3, 16.1, 16.2, 19.5, 19.8, 21.2, 21.6, 22.2, 24.6,
(
75 MHz, CDCl
3
2
4
1
7
4.9, 25.7, 26.7, 29.9, 30.7, 32.3, 33.8, 34.3, 37.1, 37.3, 38.5, 39.8, 40.8, 42.6, 47.0,
7.5, 49.98, 50.10, 55.2, 56.6, 110.1, 113.4, 115.5, 121.3, 138.7, 146.4, 147.7, 149.3,
+
50.6, 153.0, 159.5, 172.8, 218.2. HRMS (ESI): m/z calcd for C46
06.4942, found 706.4926.
64 3 3
H N O (M+H)
2
.2.4.13. 3-Methyl-1-pyrid-2-yl-6,7-dihydro-1H-indazol-4(5H)-one O-(3-oxolup-
0(29)-en-28-oyl) oxime (9m)
2
The title compound was prepared in 25% yield from oxime 8m as a white
solid. Mp: 142−144 °C. IR (KBr) νmax: 3425, 2945 (CH), 2870 (CH), 1750 (COOR),

2
0
1
1
705 (CO), 1590, 1470, 1445, 1390, 1135−1085, 880, 780, 700. H NMR (300 MHz,
CDCl ) δ: 0.92 (s, 3H, CH ), 1.00 (s, 9H, 3CH ), 1.06 (s, 3H), 1.10−0.89 (m, 2H,
CH/CH ), 1.56−1.23 (m, 15H, CH, CH ), 1.81−1.65 (m, 1H, CH), 1.70 (s, 3H, С30-
H), 2.10−1.85 (m, 5H, CH, CH ), 2.61 (s, 3H,
), 2.53−2.31 (m, 4H, C5′-H, CH/CH
C3′-CH
), 2.89−2.68 (m, 2H, C6′-H), 3.13 (td, J = 11.2 Hz, J = 4.3 Hz, 1H, CH), 3.33
t, J = 6.0 Hz, 1H, C7′-H), 4.61 (bs, 1H, Hvinyl), 4.75 (bs, 1H, Hvinyl), 7.20−7.14 (m,
3
3
3
2
2
2
2
3
(
1
H, Harom), 7.80 (td, 1H, J = 8.1 Hz, J = 1.8 Hz, Harom), 7.92 (d, J = 8.1 Hz, 1H,
1
3
H
3
arom), 8.40 (d, J = 3.8 Hz, 1H, Harom). C NMR (75 MHz, CDCl ) δ: 14.8, 15.3, 16.1,
1
3
1
6.2, 19.5, 19.8, 21.2, 21.6, 22.2, 24.6, 24.9, 25.7, 26.7, 29.9, 30.7, 32.3, 33.8, 34.3,
7.1, 37.3, 38.4, 39.8, 40.8, 42.3, 47.0, 47.5, 50.0, 50.1, 55.2, 56.6, 110.1, 113.4,
15.5, 121.3, 138.7, 146.4, 147.7, 149.3, 150.6, 152.9, 159.5, 172.8, 218.4. HRMS
+
(
ESI): m/z calcd for C43
H
59
N
4
O
3
(M+H) 679.4582, found: 679.4580.
2
.2.4.14. 6,6-Dimethyl-1-pyrid-2-yl-6,7-dihydro-1H-indazol-4(5H)-one O-(3-oxolup-
0(29)-en-28-oyl) oxime (9n)
2
The title compound was prepared in 45% yield from oxime 8n as a white
solid. Mp: 139-141 °C. IR (KBr) νmax: 3440, 2955 (CH), 2870 (CH), 1760 (COOR),
1705 (CO), 1635, 1590, 1475, 1445, 1400, 1385, 1105, 1075, 1055, 915, 885, 840,
1
7
80, 720. H NMR (300 MHz, CDCl
3
) δ: 0.92 (s, 3H, CH
), 1.05 (s, 3H, CH ), 1.12 (s, 3H, CH
.16−0.81 (m, 1H, CH), 1.47−1.23 (m, 12H, CH, CH
3
), 1.00 (s, 6H, C6′-Ha, C6′-
Hb), 1.01 (s, 3H, CH
3
3
3
), 1.14 (s, 3H, CH
3
),
),
1
1
2
), 1.72−1.55 (m, 3H, CH, CH
2
.70 (s, 3H, C30-H), 2.30−1.74 (m, 5H, CH, CH
2
2
), 2.58−2.41 (m, 3H, CH, CH ) 2.53
(
(
s, 2H, C5′-H), 3.11 (td, 1H, J = 11.3 Hz, J = 5.1 Hz, CH), 3.21 (s, 2H, C7′-H), 4.62
brs, 1H, Hvinyl), 4.76 (bs, 1H, Hvinyl), 7.29−7.23 (m, 1H, Hpyridyl (overlaping with
CHCl )), 7.86 (td, J = 8.1 Hz, J = 1.7 Hz, 1H, Hpyridyl), 7.95 (d, J = 8.1 Hz, 1H,
3

2
1
1
3
H
pyridyl), 8.34 (s, 1H, C3′-H), 8.47 (d, J = 4.3 Hz, 1H, Hpyridyl). C NMR (75 MHz,
CDCl ) δ: 14.8, 16.1, 16.2, 19.5, 19.8, 21.2, 21.8, 25.7, 26.7, 28.1, 28.3, 29.9, 30.6,
2.4, 33.6, 33.8, 34.3, 37.1, 37.3, 37.9, 39.4, 39.8, 40.8, 42.4, 42.7, 46.5, 47.5, 50.17,
3
3
5
1
6
0.19, 55.2, 55.3, 109.9, 112.2, 115.8, 122.1, 138.9, 142.0, 145.9, 147.9, 150.5, 152.9,
+
53.5, 172.9, 218.4. HRMS (ESI): m/z calcd for C44
93.4752.
H
61
N
4
O
3
(M+H) 693.4738, found
2.2.5. Synthesis of hybrids 9m,n by condensation with EDCI
A mixture of betulonic acid 2 (0.45 g, 1 mmol), selected oxime 8m or 8n (1 mmol), 1-
ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (EDCI) (0.38 g, 2
mmol) and DMAP (catalytic amount) in dichloromethane (15 mL) was stirred for 20 h
at room temperature, followed by addition of water (20 mL). The resulting layers
were separated and the aqueous phase was extracted with dichloromethane (3 × 5
mL). The combined organic layer was washed with brine (10 mL), dried over
anhydrous Na
2
SO , filtered and evaporated under reduced pressure. The solid residue
4
was purified by column chromatography on silica gel (eluent – Hex:EtOAc 9:1 and
6
:1).
2.2.6. General procedure for the synthesis of betulinic acid hybrids 10a−10j.
To a solution of betulonic acid hybrids 9a−9j (1.0 mmol) in isopropanol (20
mL), NaBH
4
(4.0 mmol) was added. After mixing for 18 h at room temperature, the
o
solvent was removed in vacuum, cooled (0 C) 3% hydrochloric acid (20 ml) was
added to the residue and extracted with CHCl
phase was dried (MgSO ) and filtered. A removal of the solvent in vacuum led to the
corresponding hybrids 10a−10j.
3
(5 × 10 ml). The combined organic
4

2
2
2.2.6.1.
(E)-(6,6-Dimethyl-3-(trifluoromethyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10a)
The title compound was prepared in 95% yield from hybrid 9a as a white
solid. Mp 171−175 °C. IR (KBr) νmax: 695, 715, 765, 795, 830, 860, 885, 900, 940,
980, 1015, 1025, 1055, 1085, 1095, 1120, 1150, 1170, 1205, 1290, 1320, 1350, 1375,
1
1
390, 1400, 1450, 1470, 1505, 1545, 1600, 1620, 1645, 1755, 2875−3075. H NMR
(
500 MHz, CDCl
CH ), 0.93 (s, 3H, CH
s, 3H, CH ), 1.69 (s, 3H, CH
16.4 Hz, AB system, 1H, CH
H), 4.61 (brs, 1H, Hvinyl), 4.73 (brs, 1H, Hvinyl), 7.44−7.53 (m, 5H, Harom). C NMR
125 MHz, CDCl ) δ: 14.9, 15.5, 16.3, 18.4, 19.5, 21.0, 25.7, 27.5, 28.1, 28.5, 28.6,
9.9, 30.7, 32.5, 33.2, 34.5, 36.7, 37.2, 37.3, 38.4, 38.5, 38.9, 39.0, 40.9, 42.6, 47.0,
0.1, 50.7, 55.5, 56.8, 79.1, 109.8, 110.9, 120.9 (q, J = 270 Hz), 124.3, 129.0, 129.7
3
) δ: 0.67−2.46 (m, 24H, СH, CH
), 0.95 (s, 3H, CH ), 0.99 (s, 3H, CH
), 2.65 (d, J = 16.4 Hz, AB system, 1H, CH
), 2.69 (s, 2H, CH ), 3.11−3.20 (m, 2H, C3-H, C19-
2
), 0.73 (s, 3H, CH
), 1.08 (s, 3H, CH
), 2.69 (d, J
3
), 0.80 (s, 3H,
3
3
3
3
3
), 1.10
(
3
3
2
=
2
2
1
3
(
3
2
5
1
9
1
38.1, 139.3 (q, J = 39 Hz), 145.3, 150.6, 154.9, 172.1. F NMR (470 MHz, CDCl )
3
+
δ: −114.0 (3F). HRMS (ESI): m/z calcd for C46
H F N NaO (M+Na) 784.4641;
62 3 3 3
found 784.4650.
2.2.6.2.
(E)-(6,6-Dimethyl-3-(perfluoroethyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10b)
The title compound was prepared in 97% yield from hybrid 9b as a white
solid. Mp 142−146 °C. IR (KBr) νmax: 695, 725, 735, 750, 765, 795, 820, 860, 895,
9
45, 960, 980, 1010, 1025, 1055, 1085, 1100, 1120, 1155, 1190, 1220, 1290, 1315,
330, 1375, 1390, 1400, 1450, 1465, 1500, 1543, 1600, 1620, 1645, 1755,
1

2
3
1
2
3
1
875−3070. H NMR (500 MHz, CDCl
H, CH ), 0.81 (s, 3H, CH ), 0.93 (s, 3H, CH
.09 (s, 3H, CH ), 1.10 (s, 3H, CH ), 1.71 (s, 3H, CH
), 2.70 (d, J = 16.4 Hz, AB system, 1H, СH
.12−3.20 (m, 2H, C3-H, C19-H), 4.61 (brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl),
3
) δ: 0.67−2.37 (m, 24H, СH, CH
), 0.96 (s, 3H, CH ), 1.00 (s, 3H, CH
), 2.66 (d, J = 16.4 Hz, AB
), 2.70 (s, 2H, CH ),
2
), 0.74 (s,
3
3
3
3
3
),
3
3
3
system, 1H, СH
2
2
2
3
7
1
3
1
3
.45−7.54 (m, 5H, Harom). C NMR (125 MHz, CDCl
) δ: 14.9, 15.5, 16.2, 16.3, 18.5,
3
9.6, 21.1, 25.8, 27.6, 28.1, 28.4, 28.6, 30.0, 30.8, 32.6, 33.1, 34.6, 36.9, 37.3, 37.4,
8.5, 38.6, 38.9, 39.0, 40.9, 42.6, 47.1, 50.1, 50.8, 55.5, 56.8, 79.2, 109.8, 110.9 (tq, J
=
252 Hz, 39 Hz), 112.3, 119.3 (qt, J = 287 Hz, 37 Hz), 124.3, 129.0, 129.7, 138.2,
1
9
1
3
38.4 (t, J = 30 Hz), 145.2, 150.6, 154.8, 172.1. F NMR (470 MHz, CDCl ) δ: −82.0
+
(
62 5 3 3
3F), −110.3 (2F). HRMS (ESI): m/z calcd for C47H F N NaO (M+Na) 834.4609;
found, 834.4616.
4.1.6.3.
(E)-(6,6-Dimethyl-3-(perfluoropropyl)-1-phenyl-6,7-dihydro-1H-indazol-
4
(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10c)
The title compound was prepared in 97% yield from hybrid 9c as a white
solid. Mp: 199−204 °C. IR (KBr) νmax: 660, 675, 695, 715, 735, 750, 765, 820, 860,
890, 920, 935, 985, 1010, 1020, 1055, 1085, 1110, 1190, 1210, 1230, 1320, 1355,
1
1
375, 1390, 1400, 1450, 1465, 1500, 1545, 1600, 1620, 1645, 1755, 2870−3070. H
NMR (500 MHz, CDCl
3
) δ: 0.67−2.36 (m, 24H, СH, CH
), 0.93 (s, 3H, CH ), 0.96 (s, 3H, CH ), 1.00 (s, 3H, CH
.09 (s, 3H, CH ), 1.71 (s, 3H, CH ), 2.65 (d, J = 16.3 Hz, AB system, 1H, СH
), 2.70 (s, 2H, CH ), 3.10−3.20 (m, 2H, C3-H,
C19-H), 4.62 (brs, 1H, Hvinyl), 4.75 (brs, 1H, Hvinyl), 7.45−7.54 (m, 5H, Harom).
NMR (125 MHz, CDCl ) δ: 15.0, 15.5, 16.3, 18.5, 19.6, 21.1, 25.8, 27.6, 28.1, 28.4,
2
), 0.75 (s, 3H, CH
), 1.08 (s, 3H, CH
), 2.68
3
), 0.82 (s,
3
1
H, CH
3
3
3
3
3
),
3
3
2
(
d, J = 16.3 Hz, AB system, 1H, СH
2
2
1
3
C
3

2
4
2
4
2
=
−
8.5, 29.9, 30.8, 32.6, 33.0, 34.6, 37.0, 37.3, 37.4, 38.5, 38.6, 38.9, 39.0, 40.9, 42.6,
7.1, 50.1, 50.8, 55.6, 56.8, 79.2, 109.3 (tm, J = 266 Hz), 109.8, 112.6, 112.9 (tt, J =
55 Hz, 32 Hz), 118.2 (qt, J = 289 Hz, 35 Hz), 124.4, 129.0, 129.7, 138.2, 138.5 (t, J
1
9
30 Hz), 145.3, 150.7, 154.8, 172.0. F NMR (470 MHz, CDCl
108.6 (2F), −125.1 (2F). HRMS (ESI): m/z calcd for C48
84.4577; found, 884.4588.
3
) δ: −80.3 (3F),
+
H
62
F
7
N
3
NaO (M+Na)
3
8
2.2.6.4.
(E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10d)
The title compound was prepared in 96% yield from hybrid 9d as a white
solid. Mp > 245 °C (decomp.). IR (KBr) νmax: 700, 720, 740, 765, 845, 885, 895, 940,
985, 1010, 1035, 1055, 1085, 1095, 1120, 1150, 1170, 1205, 1235, 1290, 1350, 1375,
1
1
390, 1405, 1420, 1455, 1465, 1510, 1550, 1620, 1645, 1755, 2875−3075. H NMR
(
500 MHz, CDCl
CH ), 0.93 (s, 3H, CH
s, 3H, CH ), 1.70 (s, 3H, CH
2H, CH ), 2.69 (d, J = 16.3 Hz, AB system, 1H, CH
3
) δ: 0.67−2.36 (m, 24H, СH, CH
), 0.95 (s, 3H, CH ), 0.99 (s, 3H, CH
), 2.62 (d, J = 16.3 Hz, AB system, 1H, CH
), 3.11−3.20 (m, 2H, C3-H,
2
), 0.74 (s, 3H, CH
), 1.09 (s, 3H, CH
), 2.65 c
3
), 0.80 (s, 3H,
3
3
3
3
3
), 1.10
(
(
3
3
2
2
2
C19-H), 4.61 (brs, 1H, Hvinyl), 4.73 (brs, 1H, Hvinyl), 7.19−7.22 (m, 2H, Harom),
1
3
7
2
3
3
.44−7.47 (m, 2H, Harom). C NMR (125 MHz, CDCl ) δ: 14.9, 15.5, 16.3, 18.4, 19.5,
1.0, 25.7, 27.5, 28.1, 28.5, 28.6, 29.9, 30.7, 32.5, 33.2, 34.5, 36.7, 37.2, 37.3, 38.4,
8.5, 38.9, 39.0, 40.9, 42.6, 47.0, 50.1, 50.7, 55.5, 56.8, 79.1, 109.8, 110.9, 120.9 (q, J
=
270 Hz), 124.3, 129.0, 129.7 138.1, 139.3 (q, J = 39 Hz), 145.3, 150.6, 154.9, 162.6
19
(
3
d, J = 250 Hz), 172.1. F NMR (470 MHz, CDCl ) δ: −114.0 (3F). HRMS (ESI):
+
m/z calcd for C46
H
61
F
4
N
3
NaO
3
(M+Na) 802.4547; found 802.4540.

2
5
2.2.6.5.
(E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(perfluoroethyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10e)
The title compound was prepared in 95% yield from hybrid 9e as a white
solid. Mp: > 210 °C (decomp.). IR (KBr) νmax: 705, 720, 735, 750, 765, 790, 830, 845,
8
1
1
85, 900, 945, 960, 985, 1010, 1035, 1055, 1085, 1100, 1120, 1150, 1190, 1225,
285, 1315, 1335, 1380, 1390, 1400, 1420, 1450, 1465, 1500, 1515, 1545, 1620,
1
645, 1755, 2875−3075. H NMR (500 MHz, CDCl
3
) δ: 0.67−2.37 (m, 24H, СH,
), 0.93 (s, 3H, CH ), 0.96 (s, 3H, CH ), 1.00
), 1.10 (s, 3H, CH ), 1.71 (s, 3H, CH ), 2.65 (d, J = 16.2
), 2.66 (s, 2H, CH ), 2.70 (d, J = 16.4 Hz, AB system, 1H,
), 3.12−3.20 (m, 2H, C3-H, C19-H), 4.62 (brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl),
CH
s, 3H, CH
Hz, AB system, 1H, СH
СH
2
), 0.75 (s, 3H, CH
3
), 0.81 (s, 3H, CH
3
3
3
(
3
), 1.09 (s, 3H, CH
3
3
3
2
2
2
1
3
7
1
3
5
3
.20−7.24 (m, 2H, Harom). 7.45−7.54 (m, 2H, Harom). C NMR (125 MHz, CDCl ) δ:
5.0, 15.5, 16.2, 16.3, 18.5, 19.6, 21.1, 25.8, 27.6, 28.2, 28.5, 28.6, 30.0, 30.8, 32.6,
3.1, 34.6, 36.8, 37.3, 37.4, 38.5, 38.6, 38.9, 39.0, 40.9, 42.6, 47.1, 50.1, 50.8, 55.6,
6.8, 79.2, 109.8, 110.9 (tq, J = 252 Hz, 39 Hz), 111.0, 116.7 (d, J = 23 Hz), 119.3
(
qt, J = 287 Hz, 37 Hz), 126.3 (d, J = 23 Hz), 134.2, 138.4 (t, J = 30 Hz), 145.3,
1
9
1
50.6, 154.6, 162.6 (d, J = 250 Hz), 172.1. F NMR (470 MHz, CDCl
3
) δ: −82.0
NaO
3
(
(
3F), −110.4 (2F), −111.5 (1F). HRMS (ESI): m/z calcd for C47
H
61
F
6
N
3
+
M+Na) 852.4515; found 852.4527.
2.2.6.6.
(E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(perfluoropropyl)-6,7-dihydro-1H-
indazol-4(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10f)
The title compound was prepared in 95% yield from hybrid 9f as a white solid.
Mp: > 210 °C (decomp.). IR (KBr) νmax: 700, 710, 735, 750, 765, 830, 845, 920, 935,
985, 1015, 1025, 1055, 1085, 1095, 1115, 1125, 1155, 1190, 1210, 1230, 1285, 1350,

2
6
1
1
375, 1390, 1400, 1420, 1455, 1465, 1500, 1515, 1620, 1645, 1755, 2870−3080. H
NMR (500 MHz, CDCl ) δ: 0.66−2.36 (m, 24H, СH, CH ), 0.75 (s, 3H, CH ), 0.81 (s,
), 0.92 (s, 3H, CH ), 0.96 (s, 3H, CH ), 0.99 (s, 3H, CH ), 1.08 (s, 3H, CH ),
.09 (s, 3H, CH ), 1.71 (s, 3H, CH ), 2.65 (d, J = 16.3 Hz, AB system, 1H, СH ), 2.66
), 2.68 (d, J = 16.3 Hz, AB system, 1H, СH
), 3.10−3.20 (m, 2H, C3-H,
C19-H), 4.62 (brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl), 7.20−7.24 (m, 2H, Harom).
3
2
3
3
1
H, CH
3
3
3
3
3
3
3
2
(
s, 2H, CH
2
2
1
3
7
2
3
1
.44−7.48 (m, 2H, Harom). C NMR (125 MHz, CDCl
3
) δ: 15.0, 15.5, 16.3, 18.5, 19.6,
1.1, 25.8, 27.6, 28.1, 28.4, 28.5, 30.0, 30.8, 32.6, 33.0, 34.6, 36.8, 37.3, 37.4, 38.5,
8.9, 39.0, 40.9, 42.6, 47.0, 50.0, 50.8, 55.5, 56.8, 79.2, 109.3 (tm, J = 266 Hz),
09.8, 112.7, 112.9 (tt, J = 255 Hz, 32 Hz), 116.7 (d, J = 23 Hz), 118.2 (qt, J = 289
Hz, 35 Hz), 126.4 (d, J = 9 Hz), 134.3, 138.5 (t, J = 30 Hz), 145.4, 150.6, 154.6, 162.6
1
9
(
d, J = 250 Hz), 172.0. F NMR (470 MHz, CDCl
3
) δ: −80.0 (3F), −108.3 (2F),
+
−111.4 (1F), −124.8 (2F). HRMS (ESI): m/z calcd for C48
61 8 3 3
H F N NaO (M+Na)
902.4483 found, 902.4492.
2.2.6.7. (E)-3-(Cyclopropyl)-6,6-dimethyl-1-phenyl-dihydro-1H-indazol-4(5H)-one O-
[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10g)
The title compound was prepared in 95% yield from hybrid 9g as a white
solid. Mp 169−173 °C. IR (KBr) νmax: ): 675, 695, 735, 790, 820, 855, 885, 895, 910,
9
1
1
42, 975, 980, 1010, 1025, 1035, 1055, 1085, 1100, 1105, 1130, 1160, 1170, 1190,
250, 1295, 1320, 1370, 1375, 1390, 1405, 1450, 1465, 1510, 1545, 1600, 1620,
1
645, 1745, 2870−3070. H NMR (500 MHz, CDCl
3
) δ: 0.67−2.38 (m, 28H, CH,
), 0.95 (s, 3H, CH ), 0.96 (s, 3H, CH ), 1.00
), 1.09 (s, 3H, CH ), 1.71 (s, 3H, CH ), 2.65 (s, 2H,
), 2.65 (d, J = 16.5 Hz, AB system, 1H, CH ), 2.69 (d, J = 16.5 Hz, AB system,
CH
s, 6H, 2CH
CH
2
), 0.75 (s, 3H, CH
3
), 0.81 (s, 3H, CH
3
3
3
(
3
), 1.08 (s, 3H, CH
3
3
3
2
2

2
7
1
H, CH
brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl), 7.33−7.47 (m, 5H, Harom). C NMR (125 MHz,
CDCl ) δ: 9.2, 9.8, 9.9, 14.9, 15.5, 16.3, 16.5, 18.5, 19.5, 21.1, 25.7, 27.6, 28.1, 28.6,
8.7, 29.9, 30.8, 32.6, 33.3, 34.6, 36.9, 37.3, 37.5, 38.6, 38.8, 38.9, 39.0, 40.9, 42.6,
2
), 2.75−2.80 (m, 1H, CHcyclopropyl) 3.10−3.20 (m, 2H, C3-H, C19-H), 4.62
1
3
(
3
2
4
1
7
7.2, 50.0, 50.7, 55.5, 56.9, 79.2, 109.8, 111.4, 123.8, 127.6, 129.4, 139.0, 143.6,
+
50.6, 154.0, 158.4, 172.9. HRMS (ESI): m/z calcd for C48
56.5080, found 756.5091.
H
67
N
3
NaO (M+Na)
3
4
.1.6.8.
(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10h)
The title compound was prepared in 96% yield from hybrid 9h as a white
solid. Mp 182-186 °C. IR (KBr) νmax: 665, 725, 755, 840, 890, 940, 985, 1110, 1035,
(E)-3-(Cyclopropyl)-6,6-dimethyl-1-(4-fluorophenyl)-dihydro-1H-indazol-
4
1054, 1100, 1295, 1320, 1370, 1380, 1390, 1400, 1420, 1455, 1465, 1520, 1605,
1
1
615, 1645, 1745, 2870−3070. H NMR (500 MHz, CDCl
3
) δ: 0.66−2.37 (m, 28H,
), 0.94 (s, 3H, CH ), 0.95 (s, 3H, CH ),
), 1.08 (s, 3H, CH ), 1.70 (s, 3H, CH ), 2.60 (s,
), 2.64 (d, J = 16.4 Hz, AB system, 1H, CH ), 2.68 (d, J = 16.4 Hz, AB
), 2.73−2.79 (m, 1H, CHcyclopropyl) 3.09−3.19 (m, 2H, C3-H, C19-H),
.61 (brs, 1H, Hvinyl), 4.74 (brs, 1H, Hvinyl), 7.12−7.15 (m, 2H, Harom), 7.37−7.40 (m,
CH, CH
2
), 0.74 (s, 3H, CH
.00 (s, 6H, 2CH ), 1.07 (s, 3H, CH
H, CH
3
), 0.80 (s, 3H, CH
3
3
3
1
2
3
3
3
3
2
2
system, 1H, CH
2
4
2
1
3
1
1
3
3
H, Harom). C NMR (125 MHz, CDCl ) δ: 9.2, 9.7, 9.8, 14.9, 15.5, 16.3, 16.5, 18.4,
9.5, 21.1, 25.7, 27.5, 28.1, 28.6, 28.7, 29.9, 30.8, 32.6, 33.3, 34.6, 36.8, 37.3, 37.4,
8.6, 38.7, 38.9, 39.0, 40.9, 42.6, 47.2, 50.0, 50.7, 55.5, 56.8, 79.1, 109.8, 111.4,
16.2 (d, J = 23 Hz), 125.6 (d, J = 8 Hz), 135.2, 143.6, 150.6, 154.0, 158.3, 161.7 (d,
1
9
J = 248 Hz), 172.8. F NMR (470 MHz, CDCl
) δ: −113.8 (1F). HRMS (ESI): m/z
3
+
calcd for C48
H66FN
3
NaO
3
(M+Na) 774.4986, found 774.4972.

2
8
2.2.6.9. (E)-6,6-Dimethyl-1-phenyl-3-(furan-2-yl)-dihydro-1H-indazol-4(5H)-one O-
[(3β)-3-hydroxy-lup-20(29)-en-28-oyl] oxime (10i)
The title compound was prepared in 96% yield from hybrid 9i as a white solid.
Mp: 196−200 °C; IR (KBr) νmax: 675, 700, 720, 745, 765, 795, 820, 830, 855, 995,
1025, 1035, 1050, 1060, 1085, 1100, 1135, 1165, 1225, 1240, 1315, 1370, 1390,
1
1
435, 1455, 1470, 1485, 1505, 1540, 1600, 1625, 1640, 1750, 2870−3070. H NMR
(
500 MHz, CDCl
CH ), 0.95 (s, 3H, CH
s, 3H, CH ), 1.72 (s, 3H, CH
H, CH ), 2.76 (d, J = 16.4 Hz, AB system, 1H, CH
H), 4.63 (brs, 1H, Hvinyl), 4.77 (brs, 1H, Hvinyl), 6.60 (dd, J = 3.5, 1.7 Hz, 1H, Hfuryl),
.40−7.43 (m, 1H, Harom), 7.48−7.54 (m, 5H, 4Harom, 1Hfuryl), 8.30 (d, J = 3.5 Hz, 1H,
3
) δ: 0.67−2.40 (m, 24H, СH, CH
), 1.01 (s, 3H, CH ), 1.01 (s, 3H, CH
), 2.71 (s, 2H, CH ), 2.73 (d, J = 16.4 Hz, AB system,
), 3.11−3.19 (m, 2H, C3-H, C19-
2
), 0.74 (s, 3H, CH
3
), 0.81 (s, 3H,
3
3
3
3
), 1.10 (s, 3H, CH
3
), 1.11
(
3
3
2
1
2
2
7
1
3
H
furyl). C NMR (125 MHz, CDCl ) δ: 14.9, 15.5, 16.2, 16.3, 18.4, 19.6, 21.1, 25.8,
3
2
3
1
7.5, 28.1, 28.5, 28.6, 29.9, 30.8, 32.8, 33.0, 34.5, 37.0, 37.4, 37.5, 38.6, 38.8, 38.9,
9.0, 40.9, 42.7, 47.2, 49.9, 50.7, 55.5, 56.9, 79.1, 109.0, 109.9, 112.1, 114.4, 124.6,
28.3, 129.4, 138.8, 141.4, 142.7, 144.4, 147.4, 150.6, 156.5, 172.9. HRMS (ESI):
+
m/z calcd for C49
H
65
N
3
NaO
4
(M+Na) 782.4873, found 782.4882.
2.2.6.10.
(E)-6,6-Dimethyl-1-(4-fluorophenyl)-3-(furan-2-yl)-dihydro-1H-indazol-
4
(5H)-one O-[(3β)-3-hydroxylup-20(29)-en-28-oyl] oxime (10j)
The title compound was prepared in 94% yield from hybrid 9j as a white solid.
Mp 192−196 °C. IR (KBr) νmax: 705, 730, 745, 765, 830, 840, 885, 895, 905, 920,
9
40, 985, 995, 1010, 1035, 1055, 1085, 1100, 1110, 1130, 1165, 1185, 1230, 1290,
320, 1375, 1390, 1415, 1455, 1465, 1485, 1510, 1515, 1620, 1640, 1750,
1

2
9
1
2
3
1
1
870−2135. H NMR (500 MHz, CDCl
H, CH ), 0.81 (s, 3H, CH ), 0.95 (s, 3H, CH
.10 (s, 3H, CH ), 1.12 (s, 3H, CH ), 1.72 (s, 3H, CH
6.3 Hz, AB system, 1H, CH ), 2.76 (d, J = 16.3 Hz, AB system, 1H, CH
m, 2H, C3-H, C19-H), 4.64 (brs, 1H, Hvinyl), 4.77 (brs, 1H, Hvinyl), 6.61 (dd, J = 3.5,
.7 Hz, 1H, Hfuryl), 7.17−7.21 (m, 2H, Harom), 7.49−7.52 (m, 3H, 2Harom, 1Hfuryl), 8.30
3
) δ: 0.67−2.40 (m, 24H, СH, CH
), 0.96 (s, 3H, CH ), 1.01 (s, 3H, CH
), 2.67 (s, 2H, CH ), 2.72 (d, J =
), 3.10−3.20
2
), 0.74 (s,
3
3
3
3
3
),
3
3
3
2
2
2
(
1
1
3
(
d, J = 3.5 Hz, 1H, Hfuryl). C NMR (125 MHz, CDCl
3
) δ: 14.9, 15.5, 16.2, 16.3, 18.4,
1
3
1
1
9.6, 21.1, 25.7, 27.5, 28.1, 28.5, 28.6, 29.9, 30.8, 32.8, 33.0, 34.5, 36.8, 37.4, 37.5,
8.6, 38.9, 39.0, 40.9, 42.7, 47.2, 49.9, 50.7, 55.5, 56.9, 79.1, 109.1, 109.9, 112.1,
14.6, 116.4 (d, J = 23 Hz), 126.5 (d, J = 9 Hz), 134.9, 141.4, 142.8, 144.5, 147.3,
19
3
50.5, 156.4, 162.2 (d, J = 249 Hz), 172.9. F NMR (470 MHz, CDCl ) δ: −112.7
+
(
1F). HRMS (ESI): m/z calcd for C49
H64FN
3
NaO
4
(M+Na) 800.4779, found
800.4783.
2.2.7. (E)-3-Cyclopropyl-6,6-dimethyl-1-phenyl-1,5,6,7-tetrahydro-4H-indazol-4-one
O-ethyl oxime (11)
To a solution of oxime 8g (0.15 mmol, 0.05 g) in 5 ml of DMF, sodium
hydroxide (0.3 mmol, 0.012 g) was added and the mixture was stirred at room
temperature for 30 min. Then ethyl iodide (0.3 mmol, 0.048 g, 0.025 ml) was added,
the reaction mixture was stirred for 24 h, treated with 50 ml of 3% aqueous HCl and
4
extracted with ether (3 x 15 ml). The combined organic phase was dried (MgSO ) and
filtered. After removal of the solvent in vacuum, the residue was purified by silica gel
column chromatography with petroleum/ethyl acetate as eluent to give the O-ethyl
oxime 11 in 75% yield as white solid. Mp 127−129 °C. IR (KBr) νmax: 670, 680, 695,
725, 740, 765, 790, 810, 830, 875, 910, 940, 980, 1030, 1035, 1045, 1065, 1090,