European Journal of Medicinal Chemistry 85 (2014) 311e340

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Progress of the synthesis of condensed pyrazole derivatives (from

2010 to mid-2013)
Meng Li, Bao-Xiang Zhao*
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Condensed pyrazole derivatives are important heterocyclic compounds due to their excellent biological
Received 5 March 2014 activities and have been widely applied in pharmaceutical and agromedical fields. In recent years,
Received in revised form numerous condensed pyrazole derivatives have been synthesized and advanced to clinic studies with
25 July 2014
various biological activities. In this review, we summarized the reported synthesis methods of condensed
Accepted 26 July 2014
Available online
pyrazole derivatives from 2010 until now. All compounds are divided into three parts according to the
rings connected to pyrazole-ring, i.e. [5, 5], [5,F 6], and [5, 7]-condensed pyrazole derivatives. The bio-
logical activities and applications in pharmaceutical fields are briefly introduced to offer an orientation
Keywords:
Condensed pyrazole derivatives
for the design and synthesis of condensed pyrazole derivatives with good biological activities.
Synthesis © 2014 Elsevier Masson SAS. All rights reserved.
Bioactivities
Progress
Review

1. Introduction reported. Furthermore, the methodology for the synthesis of pyr-

As one of the most important heterocyclic compounds, pyr-
azoles exhibit significant biological properties such as antispas-
modic [1], anti-inflammatory [2], antibacterial [3], analgesis [4],
antihyperglycemic [5], hypoglycemic [6], antineoplastic [7], anti-
depressive activities [8], and have been widely used in bio-
pharmaceutical and pesticides. Among the several FDA approved
pharmaceutical drugs, the pyrazole core was found in Celebrex [9],
Sildenafil [10] and Rimonabant (Fig. 1) [11]. As a new type of het-
erocyclic compounds, condensed pyrazole derivatives are designed
and synthesized through biomimicry or splice. Since pyrazole ring
and other important heterocyclic active structural units both exist
in these compounds, the compounds always exhibit more
outstanding biological activities. Boyer et al. have reported a series
of condensed pyrazole derivatives with four-fold of antibacterial
activities against Gram-positive as well as Gram-negative
compared with general pyrazole compounds [12].
Because of the excellent bioactivity and wide range of appli-
cation of pyrazole derivatives, thousands of papers concerning the
synthesis or bioactivities of pyrazole derivatives have been
* Corresponding author.
E-mail addresses: bxzhao@sdu.edu.cn, sduzhao@hotmail.com (B.-X. Zhao).
azole derivatives have been summarized in some reviews occa-
sionally. Makino et al. reported the synthetic progress of pyrazoles
from 1981 to 1999 in two reviews [13,14]; in 2011, Fustero et al.
reported the synthetic progress of pyrazoles from 2000 to mid-
2010 [15]; and then a mini-review involving the synthesis of
functionalized tetrasubstituted pyrazoles was reported by Dadi-
boyena et al. [16]; in 2012, Janin summarized the preparation and
chemistry of 3/5-halogenopyrazoles [17], which are usually the
precursors of various derivatives. Yet, all these papers mainly
focused on the construction of pyrazole core but the chemistry of
condensed pyrazole derivatives exhibiting more outstanding bio-
activities was less concerned. Here we briefly introduce the bio-
activities and summarize the synthesis progress of condensed
pyrazole derivatives investigated by us and others from 2010 to
mid-2013. As we know in the existing literature, common
condensed pyrazole derivatives mainly included: pyrazolopyr-
idines, pyrazolopyrimidine, pyrazolopyrazine, pyrazolopyrane,
pyrrolopyrazole and so on. In this review, all compounds are
divided into different parts according to the type of the ring
connected to the pyrazole ring. If a five-membered ring is con-
nected to the pyrazole ring, the compound belongs to [5, 5]-
condensed pyrazole derivatives, and if the connected ring is a six-
membered or seven-membered ring, the compound belongs to [5,
6]-condensed pyrazole derivatives or [5, 7]-condensed pyrazole
derivatives.

http://dx.doi.org/10.1016/j.ejmech.2014.07.102
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.
312 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340

2. [5, 5]-Condensed pyrazole derivatives

2.1. Pyrrolo[3,4-c]pyrazoles

The pyrrolopyrazole (PP), as an extension of the classic adenine

Fig. 1. Examples of several pharmaceutical drugs containing pyrazole core.
Fig. 2. Structures of compounds containing pyrrolopyrazole core.
mimetic pharmacophore presenting in several classes of kinase
inhibitors, has been exploited as a hinge binder for numbers of
protein kinase targets [18e24]. Recently, PHA-739358 (Fig. 2), an
Aurora kinase inhibitor, has advanced into phase II clinical trials for
the treatment of cancer because of the good pharmacokinetic
properties and general safety profiles in phase I clinical study [25].
Compared with other hinge binder templates, the PP core offers
efficient hydrogen bond interactions without multiple co-planar
aromatic systems, which improves the physicochemical proper-
ties greatly.
In 2010, Brasca et al. reported a potent cyclin dependent kinases
(CDK) inhibitor, PHA-793887 (Fig. 2) which shows the inhibition of
tumor growth in preclinical xenograft tumor models and was
selected for clinical evaluation as anticancer agent [21]. Shi et al.
reported the synthesis of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles
as Aurora-A kinase inhibitors and two of them were found to have

Scheme 1. Synthesis of PAK inhibitors.

Scheme 2. Synthesis of pyrazolo[1,5-a]indole framework via CuI catalyzation.

Scheme 3. Synthesis of pyrazole-condensed carbazole or azacarbazole derivatives.

 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 313

Scheme 7. Synthesis of pyrazolo[5,1-c]triazoles via pyrolysis.

Scheme 4. One-step synthesis of pyrazolo[5,1-a]isoindoles via intramolecular CeH

activation.

Scheme 8. Synthesis of pyrazolo[5,1-c]triazoles via Cu (I)-mediated [3 þ 2]

cycloadditions.

Scheme 5. Synthesis of pyrazolo[5,1-a]isoindoles from stilbene-methylene-sydnones.

the ideal anti-proliferative activities in vitro [20]. In 2011, Li et al.

reported the identification of novel pyrrolo[3,4-c]pyrazoles as
protein kinase C b II potent inhibitors with good cell permeability
[19]. Guo et al. reported the discovery of pyrroloaminopyrazoles as
p21-activated kinase (PAK) inhibitors which are orally active in
inhibiting tumor growth in vivo [18]. The construction of pyrrolo
[3,4-c]pyrazole core for all these compounds are similar and
involve the condensation of cyanoketone 2 with hydrazine. Take Fig. 3. Structures of compounds containing pyrazolo[1,2-a]pyrazolone core.

the synthesis of PAK inhibitor for example (Scheme 1) [18].

2.2. Pyrazoloindoles
Katayama et al. first reported that some pyrazolo[1,5-a]indole
derivatives have fairly powerful inhibitory activity against DNA
topoisomerases I and II, and have potent cytotoxic activity against
cancer cells [26]. Common methods for the synthesis of pyrazolo
[1,5-a]indole core in which a nitrogen atom should be connected to
the benzene ring from the starting material usually require harsh
reaction conditions and probably give poor yields. Zhu et al.
developed an efficient synthetic method via tandem Cu (I)-cata-
lyzed cyclization/condensation reaction of 1,3-diketones 5 to form
the pyrazolo[1,5-a]indole framework with high yields (Scheme 2)
[27,28]. 1,3-Diketone 5 and hydrazine monohydrate in anhydrous

Scheme 6. Synthesis of pyrazolo[5,1-a]isoindoles via N-formyl-pyrazolines and a plausible mechanism for the observed pyrazoloisoindole formation.
314 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 9. Synthesis of chiral pyrazolo[1,2-a]pyrazolones via [3 þ 2] cycloaddition.
Scheme 10. Synthesis of functionalized pyrazolo[1,2-a]pyrazolones.
1,4-dioxane was stirred at 100  C for 1 h. Then, with the presence of
CuI, 1,10-phenanthroline (PHAN) as ligand, K2CO3 as base in anhy-
drous 1,4-dioxane, the mixture was refluxed at 110  C for 20 h to
yield the final products 7. According to the author, pyrazolo[1,5-a]
quinoline can also be prepared through this method.
As the strong biological activities of pyrazole derivatives and the
discovery of cytotoxic properties in some carbazole or azacarbazole
derivatives [29], it was considered of interest to synthesize some
examples of pyrazolo-condensed carbazole or azacarbazole de-
rivatives. Singh et al. developed an efficient methodology for the
synthesis of condensed pyrazole oxocarbazoles and oxoazacarba-
zoles under the conditions of JappeKlingemann reaction, followed
by the Fischer indolization with Kent's acid (HCl:AcOH, 1:4, v/v)
Scheme 11. Synthesis of pyrazolo[5,1-b]thiazoles.
Fig. 4. Structures of compounds A02011-1 and E2508.
Scheme 12. Synthesis of tetrasubstituted thieno[3,2-c]pyrazoles.
(Scheme 3) [30,31]. The resulting products were then converted to
various biologically active compounds such as 1,4-benzodiazepine
analogs and quinoline carboxylic acid derivatives using the Pfit-
zinger reaction and the Beckmann rearrangement.
2.3. Pyrazolo[5,1-a]isoindoles
As important structural intermediates in the biogenesis of plant-
growth regulants, pyrazolo[5,1-a]isoindoles endowed with partic-
ular biological activities. Johnson et al. reported the synthesis of 2-
aryl-1,3-dihydropyrazolo[5,1-a]isoindol-8-ones and their dehy-
drated derivatives 2-arylpyrazolo[5,1-a]isoindol-8-ones with her-
bicidal activity [32]. Galliani et al. reported the antihypertensive
activity of pyrazolo[5,1-a]isoindole derivatives [33]. Multiple stra-
tegies have been developed for the synthesis of pyrazolo[5,1-a]
isoindoles including the reactions of iminophosphoranes with
acetylenic compounds [34], the intromolecular Wittig reaction of
phosphorus ylides [35], the condensation of phthalaldehydeic acid
and acetophenones followed by the reaction with hydrazine hy-
drates [36]. Other methods with the use of metal catalyst or specific
substrates have also been applied for the synthesis of these
compounds.
Heo et al. established a one-step synthesis of pyrazolo[5,1-a]
isoindoles 17 through Pd-catalyzed intramolecular CeH bond
activation with the presence of PivOH (30 mol%), LiCl (none or
3 equiv.) and K2CO3 (2 equiv.) starting from 1-(2-halobenzyl)pyr-
azoles 16 in DMA at 150  C for 6 h (Scheme 4) [37].
Marija et al. developed an efficient synthetic method with the
employment of a specific substrates, stilbene-methylene-sydnones
18 through photochemical intramolecular [3 þ 2] cycloaddition
reaction followed by aromatization with DDQ to afford pyrazolo
[5,1-a]isoindoles 20 (Scheme 5) [38]. The reaction was performed in
~103 M benzene solution in a Rayonet reactor at 300 nm under
anaerobic conditions. The specific substrates were prepared by a
sequence of reactions starting from o-cyanotoluene.
Ahmed et al. reported an alternate synthetic route for func-
tionalized pyrazolo[5,1-a]isoindoles 23 via chalcone-based N-
formyl-pyrazolines [39]. The intermediates, N-formyl-pyrazolines
22 were prepared through the reactions of chalcones 21 with hy-
drazine hydrate in the presence of formic acid. Subsequently,
intramolecular Friedel eCrafts acylation in refluxing acetonitrile
proceeded with the catalyzation of trifluoroacetic acid (TFA) to give
target product 23. A proposed mechanism is showed below
(Scheme 6). Two alternative pathways are compatible with the
observed effect of additional substituents on the aromatic rings and
Scheme 13. Synthesis of CF3-substituted furo[2,3-c]pyrazoles via Rh catalyzation.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 315

Scheme 14. Synthesis of CF3-substituted furo[2,3-c]pyrazoles without catalyst.

with the possible occurrence of competing aromatic ionization derivatives [44] or 1,2,4-triazolium salts [45,46] followed by pyro-
when electronically activated aromatic rings are present. The re- lytic desulfurization ring contractions of [1,2,4]triazolo[3,4-b]
action makes it possible to use aldehydes as acylating agents for [1,3,4]-thiadiazines which was realized upon pyrolysis at 230  C for
arenes in a straightforward synthesis of ketones. 30 min or 45 min (Scheme 7) [47,48].

2.4. Pyrazolo[5,1-c]triazoles

The pyrazolo[5,1-c]triazole scaffolds possess particular proper-

ties and have been widely used in azo dyes [40], inkjets and color
filters, photographic materials, antibacterial agents with reduced
human toxicity and antitumor agents [41,42]. Traditional synthetic
methods mainly include three groups: starting from substituted
pyrazolo derivatives [43], cyclic condensation of 1,2,4-triazole

Scheme 19. Synthesis of spiro pyrazolo[3,4-b]pyridines in water.

Scheme 15. Synthesis of pyrazole-condensed lactones, thiolactones and lactams.

Scheme 20. Synthesis of 2-substituted pyrazolo[1,5-a]pyridines.

Scheme 16. Synthesis of pyrazole-condensed pyrazolones.

Scheme 21. Synthesis of 3-pyrazinyl-pyrazolo[1,5-a]pyridines.

Scheme 17. Synthesis of pyrazole-condensed pyranes.

Scheme 22. Synthesis of pyrazolo[1,5-a]pyridines via Cu-mediated intramolecular

Scheme 18. Synthesis of pyrazolo[3,4-b]pyridines under ultrasound irradiation. cyclization.
316 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340

Scheme 23. Synthesis of 1-phenylpyrazolo[4,3-c]pyridines.

Scheme 24. Intramolecular cyclization of pyrazole oximes.

New approaches have also been developed for the synthesis of

pyrazolo[5,1-c]triazoles. Katritzky et al. established a regioselective
one-pot Cu (I)-mediated synthesis of pyrazolo[5,1-c]triazoles
through cycloadditions of terminal alkynes 28 to 1,2,4-triazolium
N-imides 27 (Scheme 8) [49]. Only terminal alkynes gave the
desired products in 62e78% yields, while disubstituted aromatic
alkynes failed to react.

Scheme 25. Synthesis of azo-linked pyrazolo[4,3-e]pyridines under nano-Fe3O4

catalyzation. 2.5. Pyrazolo[1,2-a]pyrazolones

N,N-Bicyclic pyrazolidin-3-ones, i.e. pyrazolo[1,2-a]pyrazolone

derivatives usually endowed with distinct bioactivity [50], and have

Scheme 28. Synthesis of pyrazolo[1,5-a]pyrimidines without catalyst.

Scheme 26. Synthesis of pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones.

Scheme 29. Synthesis of pyrazolo[1,5-a]pyrimidines catalyzed by CF3COOH.

Scheme 27. Regioselective synthesis of pyrazolo[1,5-a]pyrimidines via [3 þ 2]

cyclization. Scheme 30. Synthesis of pyrazolo[3,4-d]pyrimidines via POCl3-catalyzed reaction.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 317

Scheme 33. Synthesis of pyrazolo[3,4-d]pyrimidines via 3-CR in ionic liquid.

Fischer carbene complexes 34, a class of versatile building blocks

in organic synthesis for construction of five- or six-membered ring,
under N2 at 0e50  C in THF within 2 h. Then, oxidative demetala-
tion of the addition compounds 35 with pyridine-N-oxide (PNO)
afforded potentially bioactive functionalized N,N-bicyclic pyr-
azolidin-3-ones, i.e. pyrazolo[1,2-a]pyrazolones 36 (Scheme 10)
[67e69].

2.6. Pyrazolo[5,1-b]thiazoles
Scheme 31. Synthesis of pyrazolo[3,4-d]pyrimidines from Vilsmeier-type reagents.
Thiazole derivatives have been found in many natural products
and synthesized with a wide spectrum of biological activities, such
as antifungal, anti-inflammatory and cytotoxic activities. Yet, there
been utilized as antibacterial agents [51e53], pesticides [54], and
are not many reports about the biological activities of pyrazolo[5,1-
some of them have drawn much attention to drug development.
b]thiazole derivatives. Molina et al. reported the synthesis of 3,6-
For example, LY173013 and LY186826 (Fig. 3) have been developed
diphenyl-7-mercaptopyrazolo[5,l-b]thiazole, 7-benzoyl-3,6-
as the analogs of penicillin and cephalosporin antibiotics
diphenylpyrazolo[5,l-b]thiazole and 6-amino-3,7-
[52,53,55,56]. Nowadays, the most general route for the construc-
diphenylpyrazolo[5.1-b]thiazole from the construction of thiazole
tion of the fascinating bicyclic pyrazolo[1,2-a]pyrazolone skeleton
ring first [70]. Wang et al. reported the synthesis of pyrazolo[5,1-b]
seems to be 1,3-dipolar cycloaddition of azomethine imines with
thiazole by a new tandem reaction, in which ethyl 1-pyrazolacetate
alkynes [57e59]. To date, the synthesis of pyrazolo[1,2-a]pyr-
reacted with carbon disulfide and iodomethane [71]. Takahashi
azolones in chiral forms is in high demanded due to the important
et al. designed and synthesized a series of 7-dialkylamino-3-
biological activities of these compounds. Fu et al. firstly succeeded
phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives as selective
in the asymmetric cyclization of azomethine imines and terminal
CRF1 receptor antagonists [72]. They started with a one-pot reac-
alkynes using phosphaferrocene-oxazoline-CuI as a catalyst [60].
tion of diethyl malonate with carbon disulfide and bromoace-
Subsequently, various catalysts with different metals and ligands
taldehyde diethyl acetal in the presence of Cs2CO3 and NaI to yield
have been developed for the synthesis of these compounds
38, which was treated with hydrazine hydrate to yield pyrazolone
[61e65]. In 2011, Arai et al. reported the [3 þ 2] cycloaddition of
39. Then, intermolecular cyclization of 39 followed by methylation
azomethine imines 30 with electron-poor terminal alkynes 31 with
gave the 6-methoxy pyrazolo[5,1-b]thiazole core (Scheme 11). A
the catalyzation of chiral bis(imidazolidine)pyridine-CuOAc com-
series of reaction was carried out to obtain the final products. The
plex to give bicyclic pyrazolo[1,2-a]pyrazolone derivatives 32
most promising compound showed high affinity and functional
(Scheme 9) [66]. When the reaction was carried out at 20  C
antagonism for the human CRF1 receptor and anxiolytic activity at a
utilizing DIPEA as base, the ee value of product came to 74%.
dose of 30 mg/kg (po).
By means of 1,3-dipolar [3 þ 2] cycloaddition of azomethine
imines with electronic-poor terminal alkynes, only less substituted
pyrazolo[1,2-a]pyrazolones could be obtained. Thus, new methods 2.7. Thieno[3,2-c]pyrazoles
for the synthesis of functionalized pyrazolo[1,2-a]pyrazolones
would be welcome. Yu et al. established a highly regioselective Heterocyclo-fused thiophenes have attracted considerable
[3 þ 2] cycloaddition of azomethine imines 33 with 1-alkynyl attention because of their excellent optoelectronic properties and

Scheme 32. Synthesis of pyrazolo[3,4-d]dihydropyrimidines.

318 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 34. Synthesis of pyrazolo[4,3-d]pyrimidines via iminophosphorane-mediated
annulation.
biological activities. For instance, thieno[3,2-c]pyrazoles have been
demonstrated as potent kinase inhibitors [73,74]. A thieno[3,2-c]
pyrazole derivative A02011-1 (Fig. 4) has been shown to be a potent
adenyl cyclase activator exhibiting an antiproliferative activities in
rat vascular smooth muscle cells [75].
The general methods for the synthesis of thieno[3,2-b]pyrazoles
include the construction of a thiophene ring on vicinally
substituted 2-formyl-3-thiomethylenethiophene derivatives
through base-induced intramolecular cyclocondensation [76e78].
Ila et al. developed an efficient, high yielding synthetic method
through a radical cyclization process involving intramolecular
addition of a carbon-centered radical to a neighboring sulfide as the
key step for the synthesis of tetrasubstituted thieno[3,2-c]pyrazoles
43 (Scheme 12) starting from acrylonitrile precursors 42 [79].
2.8. Furo[2,3-c]pyrazoles
Furo[2,3-c]pyrazoles are important structural units of pigments
and dyes, such as cyanine dyes [80], and they possess strong bio-
logical activities such as antibacterial [81] and antifungal [82] ac-
tivities. Zhang et al. developed two different methods for the
preparation of CF3-substituted furo[2,3-c]pyrazoles 46 through
[3 þ 2] cycloaddition of diazocarbonyl compounds 44 with alkynes
45 or 47 under two different conditions: use Rh2(OAc)2 as catalyst
in toluene under refluxing [83] (Scheme 13) and heat at 160  C in
1,2-dichlorobenzene without catalyst (Scheme 14) [84].
Scheme 35. Synthesis of pyrazolo[4,3-d]pyrimidines 128.
Scheme 36. Synthesis of pyrazolo[4,3-d]pyrimidines via CuI-catalyzed reaction.
2.9. Other [5, 5]-condensed pyrazole derivatives
Nowadays, 1,3-dipolar cycloaddition has become an important
strategy for the synthesis of [5, 5]-pyrazole fused ring compounds
and due to the broad spectrum of biological activities of pyrazoles,
many other kinds of [5, 5]-condensed pyrazole derivatives have
been synthesized. Franchini et al. developed a one-pot two-step
method for the regiocontrolled synthesis of pyrazoles condensed
with lactones, thiolactones and lactams through 1,3-dipolar cyclo-
addition of C-carboxymethyl-N-phenyl and N-p-OCH3-phenyl
nitrile imines 49 with the corresponding a,b-unsaturated dipolar-
philes 50 (Scheme 15) [85]. Cerium (IV) ammonium nitrate (CAN)
was employed as oxidizing agent for the aromatization of the in-
termediates. The regioisomeric ratio is influenced by the X moiety
and by the nature of nitrile imines and 5-acyl pyrazole derivative
has been found as the major product when X ¼ S and the ratio is up
to 99:1.
Abaszadeh et al. developed a convenient and straightforward
synthesis of pyrazolo[1,2-a]pyrazole-triones 55 or 56 through the
condensation of (chlorocarbonyl)phenyl ketene 54 with 5-
alkylpyrazol-3(4H)-ones 53 by intramolecular hydrogen exchange
in unstable mesoionic pyrazolo[1,2-a]pyrazol-4-ium-5-olates
(Scheme 16) [86]. In contrast, when (chlorocarbonyl)phenyl
ketene reacts with N-substituted pyrazolones in dry THF at ambient
temperature, 4-hydroxypyrano[2,3-c]pyrazol-6-ones 58 were the
only products which might be attributed to the tautomerism of N-
substituted pyrazolones (Scheme 17).
3. [5, 6]-condensed pyrazole derivatives
3.1. Pyrazolo-pyridines
Pyrazolopyridines are one of the most often studied heterocyclic
compounds due to their excellent and wide spectrum of biological
activities. Numerable pharmaceutical activities have been reported,
such as potent cyclin dependent kinase 1 (CDK1) inhibitors [87,88],
HIV reverse transcriptase inhibitors [89], phosphodiesterase 3/4
(PDE3/4) inhibitors [90e93], A1 adenosine receptor antagonists
Scheme 37. Synthesis of pyrazolo-[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 38. Synthesis of pyrazolo[3,4-b]quinolines as TPSO ligands.
[94], dual Nox4/Nox1 inhibitors [95], p110a-selective PI3 kinase
inhibitors [96,97], corticotropin-releasing factor 1 (CRF1) antago-
nists [98], Acetyl-CoA carboxylase (ACC) inhibitors [99], B-Raf ki-
nase (B-RafV600E) inhibitors [100], guanylate cyclase stimulators
[101] and some derivatives are identified with potential antibac-
terial activity [102], antitumor and antimicrobial activities [103],
antimalarial [104] and antiviral activities [105].
Pyrazolo[3,4-b]pyridines, as one class of pyrazolopyridines, are
useful for the treatment of various stressed illness, such as Alz-
heimer's disease, anorexia nervosa, drug and alcohol withdrawal
symptoms, drug addiction and fertility [106]. They also exhibit
other important biological activities, such as psychotropic [107],
cytotoxic [108], antifungal and antichagasic [109] activities. General
methods for the synthesis of pyrazolo[3,4-b]pyridines include
cycloaddition of 5-aminopyrazole with substituted a,b-unsaturated
nitriles utilizing base as catalysts, or cycloaddition of 2-
aminonicotinonitriles with hydrazines [110]. Based on these
methods, multi-component reactions (MCRs) have been developed
from 5-aminopyrazole, alkyl/aryl aldehydes and diketones or b-CN
carbonyl compounds under various conditions, such as eco-friendly
solvents, ionic liquid and water, and techniques, such as ultrasound
irradiation and microwave irradiation [111e118]. For example,
Mamaghani et al. reported a 3-component regioselective reaction
of 5-amino-3-methyl-1H-pyrazole 59, 2H-indene-1,3-dione 60 and
arylaldehydes in ethanol under ultrasound irradiation within
4e5 min to give compounds 61 in high yields (Scheme 18) [118].
Khavasi et al. reported a 3-component condensation reaction of
isatin 64, aminopyrazole 63 and alkyl cyanoacetate 62 under the
catalysis of Et3N in water giving spiro[indoline-3,40 -pyrazolo[3,4-b]
pyridine-50 -carbonitriles 65 in good yields (Scheme 19) [113].
Other catalysts have also been used for the construction of
pyrazolo[3,4-b]pyridine core. For example, Batra et al. reported
copper-mediated intramolecular amination and iodine-mediated
Scheme 39. Synthesis of pyrazolo[3,4-b]quinolines via water-mediated reaction.
Scheme 40. Synthesis of pyrazolo-spirooxindoles in water.
319
intramolecular electrophilic aromatic cyclization in allylamines
for the synthesis of pyrazolo[3,4-b]pyridines [119,120].
Pyrazolo[1,5-a]pyridines, especially substituted in 2-position,
have also been identified with various pharmaceutical activities,
such as the most well-known dopamine D3 agonists and antago-
nists [121e123], adenosine A1 receptor antagonist [124,125],
phosphodiesterase 3/4 (PDE3/4) inhibitors [90,92], and PI3 kinase
inhibitors [96,97]. Takahashi et al. reported the synthesis of 3-
dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines as selective
corticotropin-releasing factor 1 (CRF1) receptor antagonists and
one of them, E2508 (Fig. 4) has advanced into clinical trials in the
treatment of stress-related disorders such as depression and anx-
iety [98].
The most general method for the synthesis of pyrazolo[1,5-a]
pyridines involves a [3 þ 2] cycloaddition of dipolarophiles bearing
electron-withdrawing groups with N-aminopyridinium salt. And
various intramolecular cyclizations have also been employed for
the preparation of 2-substituted pyrazolo[1,5-a]pyridines from
pyridine derivatives [126e132]. For example, Charette et al. re-
ported the synthesis of 2-substituted pyrazolo[1,5-a]pyridines 68
via cascade direct Pd-catalyzed alkenylation/Ag-mediated cycliza-
tion from N-iminopyridium ylides 66 and alkenyl iodides 67
(Scheme 20) [131]. Then in 2011, they reported a tandem Pd-
catalyzed/Ag-mediated elimination/direct functionalization/cycli-
zation from pyridine which expanded the scope of substrates and
enabled a wide range of groups installed onto the heterocyclic core
[130]. Collins et al. reported the synthesis of 3-pyrazinyl-pyrazolo
[1,5-a]pyridines 71 from 4-substituted 1-aminopyridinim iodides
70 and enol ether 69 (Scheme 21) [128].
Other methods also have been applied to the preparation of
pyrazolo[1,5-a]pyridines, such as thermal cyclization of pyridinyl
aziridines and cyclization of enediynes [127,133]. For example, Wu
et al. developed a Cu-mediated cyclization reaction of hydrazine
with enediynones 72 affording 2,7-disubstituted pyrazolo[1,5-a]
pyridines 73 and many functional groups were tolerated in this
reaction (Scheme 22) [134].
Pyrazolo[3,4-c]pyridines also exhibit a diverse range of biolog-
ical properties, such as kinase inhibitors [135], xanthine oxidases
inhibitors, cholesterol formation inhibitors [136], adenosine
deaminase [137], and have been identified as potential anti-
inflammatory [138], anti-bacterial agents [102]. Klotz et al. re-
ported the preparation of 40 ,60 -dihydrospiro[piperidine-4,50 -pyr-
azolo[3,4-c]pyridine]-70 (20 H)-one-based acetyl-CoA carboxylase
Scheme 41. Synthesis of pyrazolo[3,4-b]quinolines “on-water”.
320 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 42. Synthesis of benzopyrazolo[3,4-b]quinolines under microwave irradiation.
inhibitors from ethyl 3-amino-1H-pyrazole-4-carboxylate in a
streamlined 10-step synthesis [99]. The construction of the pyr-
azolo[3,4-c]pyridine core was realized from the tert-butyl 4-((5-
bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-4-
isocyanatopiperidine-1-carboxylate in the presence of tert-butyl-
lithium at 78  C. Conventional methods for pyrazolo[3,4-c]pyri-
dine core involve either pyridine ring closure to an appropriately
functionalized pyrazolo derivatives or inversely, and have been
summarized by Holzer et al. in 2011 [139]. They also developed
Sonogashira type cross-coupling reactions from 5-chloro-1-
phenyl-1H-pyrazole-4-carbaldehydes 75 with alkynes, followed
by intramolecular cyclization in the presence of tert-butylamine
under microwave irradiation affording 1-phenylpyrazolo[4,3-c]
pyridines 77 (Scheme 23). The intramolecular cyclization of oximes
79 derived from 5-chloro-1-phenyl-1H-pyrazole-4-carbaldehydes
75 was also accessed in the presence of AgOTf (Scheme 24).
In 2012, Rostamizadeh et al. reported a magnetically recoverable
nanocatalyst, (a-Fe2O3)-MCM-41 for the synthesis of pyrazolo[4,3-
c]pyridines from pyridine a,b-unsaturated ketones with hydrazine
hydrates at room temperature [140]. No significant decrease in
activity was observed even after 5 runs.
Other important pyrazolopyridines come to pyrazolo[4,3-e]
pyridines which have been identified as anti-inflammatory
[141,142], antibacterial agents [143]. Limited literatures reported
the preparation of these kind of compounds. In 2012, Mohammad
et al. reported the regioselective synthesis of fused azo-linked
pyrazolo[4,3-e]pyridines 84 or 85 via 3-component reactions (3-
CR) of 3-amino-5-methylpyrazole 83, indan-1,3-dione 82 and
azo-linked aldehydes 81 under the catalyzation of reusable nano-
Fe3O4 in high yields (Scheme 25) [144]. The structures of the
products were influenced by the nature of substrates, when azo-
linked aldehydes 81 contain electron-withdrawing substituent,
only compounds 84 were obtained. In 2013, Khosropour et al. re-
ported a 3-component reactions of kijic acid 86, 1H-pyrazol-5-
Scheme 43. Synthesis of pyrazolo[4,3-f]quinolines.
Scheme 44. Synthesis of H-pyrazolo[5,1-a]isoquinolines via AgOTf catalyzed reaction.
amines 87 and aldehydes 88 in the presence of Zn(OTf)2 and fol-
lowed by H2O2-mediated oxidation for the preparation of pyrano
[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones (Scheme 26) [145].
3.2. Pyrazolopyrimidines
Pyrazolopyrimidines have attracted considerable attentions
over decades due to their good biological activities and three most
common structural analogs, pyrazolo[1,5-a]pyrimidines, pyrazolo
[3,4-d]pyrimidines and pyrazolo[4,3-d]pyrimidines, all exhibit
important biological activities. Pyrazolo[1,5-a]pyrimidines have
been found as purine analogs and have useful properties as anti-
metabolites in purine biochemical reactions. They have already
been identified with various other biological activities, such as
HMF-CoA reductase inhibitors [146], COX-2 selective inhibitors
[147], phosphodiesterase 4 (PDE4) inhibitors [148], 5-HT6 receptor
antagonists [149,150], CRF1 antagonists [151,152], translocator
protein (TSPO) ligands [153,154], dipeptidyl peptidase IV (DPP-IV)
inhibitors [155], neuropeptide Y1 receptor antagonists [156],
Aurora-A kinase inhibitors [157], Checkpoint kinase 1 (CHK1) in-
hibitors [158,159], Matrix metalloproteinase 13 (MMP-13) in-
hibitors [160], B-RafV600E kinase inhibitors [161], mitogen-activated
protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors
[162], and Janus kinase 2 (Jak2) inhibitors [163]. Several methods
have been established for the synthesis of pyrazolo[1,5-a]pyrimi-
dines and most of them involve the [3 þ 2] cyclization between 5-
amino-1H-pyrazoles and 1,3-bis-electrophilic reagents, such as b-
dicarbonyl, a,b-unsaturated carbonyl, alkoxymethylene-b-dicar-
bonyl, b-enaminone compounds and benzylidenemalononitriles
[164e169]. For example, Portilla et al. reported the regioselective
synthesis pyrazolo[1,5-a]pyrimidines by the reaction of 5-amino-
Scheme 45. Synthesis of H-pyrazolo[5,1-a]isoquinolines via AgOTf with co-catalyst,
dioxygen-copper system catalyzed reaction.
Scheme 46. Synthesis of H-pyrazolo[5,1-a]isoquinolines via Br2 promoted reaction.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 47. Synthesis of H-pyrazolo[5,1-a]isoquinolines from bromo-substituted
substrates.
Scheme 48. Synthesis of H-pyrazolo[5,1-a]isoquinolines via tandem 1,3-dipolar
cycloaddition/oxidative aromatization.
1H-pyrazoles 90 and b-dicarbonyl compounds under fusion or
microwave irradiation conditions (Scheme 27) [170]. And Mokhtar
et al. reported an efficient catalysts, MgeAl hydrotalcites for aza-
Micheal addition of aminopyrazoles to enaminone derivatives
without solvent under microwave irradiation for the preparation of
pyrazolo[1,5-a]pyrimidines [171].
Multi-component reactions have also been applied for the
synthesis of pyrazolo[1,5-a]pyrimidines. Rahmati et al. reported the
synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-
carbonitrile 100 via 3-CR of aldehydes 98, aminomethylpyrazoles
97 and malononitrile 99 under refluxing conditions without any
catalyst (Scheme 28) for the first time [172]. And then, Pal et al.
reported a 3-CR of aromatic aldehydes 102, terminal alkynes 103
and 5-amino-1H-pyrazolo-4-carboxylate 101 catalyzed by
CF3COOH in acetic acid in the presence of aerial oxygen (Scheme
29) affording pyrazolo[1,5-a]pyrimidines 104 as potential PDE4
inhibitors [173].
Pyrazolo[3,4-d]pyrimidines, as another structural analogs of
pyrazolopyrimidines have been identified with good biological
activities, such as cyclooxygenase-2 (COX-2) inhibitors [174], ATP-
competitive inhibitors [175], phosphatidylinositol-3-kinases
(PI3K) inhibitors [176,177], insulin-like growth factor-1 receptor
(IGF1R) inhibitors [178], p38a kinase inhibitors [179], tyrosine ki-
nase c-Src inhibitors [180], dual Src/Abl inhibitors [181], dual in-
hibitors of Aurora kinases and CDK1 [182], anti-inflammatory
activity [183], RET protein kinase inhibitors [184], PDE9A inhibitor
[185,186], anti-tubercular activities [187], casein kinase 1 (CK1)
inhibitors [188], antiamoebic activity [189], antimicrobial activity
[190e192], and anti-tumor activities [193e196].
Scheme 49. Synthesis of 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles.
321
Scheme 50. Synthesis of pyrano[2,3-c]pyrazoles through DKHDA reaction.
Scheme 51. Synthesis of pyrano[2,3-c]pyrazoles via 3-CR.
Traditional methods for the synthesis of pyrazolo[3,4-d]pyrim-
idines involve two steps from 5-amino-N-substituted-1H-pyrazole-
4-carbonitrile with esters or acyl chlorides, which need vigorous
conditions and have low yields [197]. Zhong et al. developed a
POCl3-catalyzed reactions of 5-amino-N-substituted-1H-pyrazole-
4-carbonitrile 105 with various lower aliphatic acids to give pyr-
azolo[3,4-d]pyrimidines 106 in good yields (Scheme 30) [198]. And
Capretta et al. reported a microwave-assisted synthesis of N1- and
C3-substituted pyrazolo[3,4-d]pyrimidines from 5-amino-1H-pyr-
azole-4-carbonitrile and formamide within 30 min [199].
Vilsmeier-type reagents have also been employed for the syn-
thesis of pyrazolo[3,4-d]pyrimidines. Wong et al. developed a
synthetic route from 5-amino-pyrazoles 107 or pyr-
azolylimidoformamides 109 with various halomethylenimium
salts, as Vilsmeier agents synthesized from formamide with POCl3
or PBr3, via amidination reaction followed by heterocyclization to
form the pyrazolo[3,4-d]pyrimidines 108 or 110 (Scheme 31)
[200,201].
Other methods have also been applied for the preparation of
pyrazolo[3,4-d]pyrimidines. Ryabukhin et al. reported the
condensation of 5-heterylaminnopyrazoles 113 with carbonyl
compounds facilitated by AcOH or Me3SiCl furnished pyrazolo[3,4-
d]dihydropyrimidines 114 in good yields (Scheme 32) [202]. The
reaction was proposed to undergo two steps: 5-aminopyrazoles 111
react with 2-halogenazines or azoles 112 under NaH/THF condi-
tions followed by cyclization with carbonyl compounds mediated
by Me3SiCl or AcOH.
Multi-component reactions have also been developed. Baltork
et al. reported a regioselective multi-component synthesis of 1H-
Scheme 52. Asymmetric synthesis of tetrahydropyrano[2,3-c]pyrazoles.
322 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 53. Four-component syntheses of pyranopyrazoles catalyzed by base
catalysts.
Scheme 54. Synthesis of pyrano[2,3-c]pyrazoles via catalyst-free atom-economical 4-
CRs.
pyrazolo[3,4-d]pyrimidine-6(7H)-thiones 118 via 3-component
reaction of 5-methyl-1H-pyrazol-3-amine 116, arylisothiocyanates
115 and aldehydes 117 in the presence of p-TSA in ionic liquid
[Bmim]Br at 100  C with excellent yields (Scheme 33) [203].
Another kind of important pyrazolopyrimidines comes to pyr-
azolo[4,3-d]pyrimidines which have been identified with recog-
nized pharmacological activities for the treatment of
thromboembolic disorders [204] and bronchoconstriction and
cardiac insufficiency [205]. Some have also been reported as Hsp90
inhibitors [206], potential anti-cancer agents [207], phosphodies-
terase 5 (PDE5) inhibitors [208e210], and cyclin-dependent kinases
(CDKs) inhibitors [211]. There are limited known methods for the
synthesis of pyrazolo[4,3-d]pyrimidines. The most common and
widely applicable route is the cyclization of 4-substituted-amido-
1H-pyrazole-3-carboxamide under base conditions [212]. Wu et al.
developed an iminophosphorane-mediated annulation, followed
by an intermolecular nucleophilic addition with amines or phenols/
Scheme 55. Synthesis of 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines.
alcohols for the synthesis of 5-alkylamino/arylamino-1-p-tolyl-1H-
pyrazolo[4,3-d]pyrimidine-7(6H)-ones (Scheme 34) [213,214].
When primary amine was used, 122 was the major product
(73e96%), whereas when secondary amine was used, 122 was the
sole product (70e97%).
Different substrates have also been employed for the synthesis
of pyrazolo[4,3-d]pyrimidines. Khalil et al. developed a synthetic
route from benzylidenemalononitrile 124 and the construction of
the pyrazolo[4,3-d]pyrimidine core 128 was realized from the
cyclization of NH4OAc with 3-benzyl-4-(2-(dimethylamino)vinyl)-
1-aryl-1H-pyrazole-5-carbonitrile 127 by a four-step reaction
(Scheme 35) [215].
Furthermore, limited literature have reported the metal-
catalyzed reaction for the preparation of pyrazolo[4,3-d]pyrimi-
dines. Batra et al. reported a CuI-catalyzed cascade reaction of 4-
iodopyrazoles 129 with amines 130 via condensation of the
formyl and the amino group followed by cross coupling in the
cascade cycle for the facile synthesis of substituted pyrazolo[4,3-d]
pyrimidines 131 (Scheme 36) [216].
To date, diverse classes of polyheterocyclic compounds have
been designed and discovered as potential human adenosine re-
ceptor antagonists, which is associated with numbers of patho-
physiological diseases, such as giaucoma, asthma and cancer
[217,218]. Among these derivatives, pyrazolo-triazolo-pyrimidines
(PTPs), especially pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines
have been identified as highly potent and selective human A2A and
A3 adenosine receptor antagonists [219e227] and the most potent
hA3 antagonist known to date is MRE-3005-F20 [222]. In 2012,
Moro et al. reported the synthesis of a series of 5-
alkylaminopyrazolo-[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines 135
from the well-known triazolylpyrazolamino derivative 132 and the
construction of the tricircle system was realized in two steps with a
general method (Scheme 37) [219].
3.3. Pyrazoloquinolines
Quinoline ring is a prominent moiety in numerous naturally
occurring compounds possessing excellent biological activities,
such as quinine, a well known antiptritic, antimalarial, analgesic
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 323

Scheme 59. Synthesis of pyrazolo[5,1-c][1,2,4]triazine-(1H)-4-one via ionic-

mechanism.

Scheme 56. Synthesis of pyrazolo[3,4-e][1,2,4]triazines 209.

Fig. 5. Structures of compounds containing oxazine core.

of 2-chloro-3-formyl quinolines with hydrazines in organic solu-

tions or organic catalysts [232]. Mane et al. developed a water-
mediated synthetic route in which 2-chloro-3-formyl quinolines
139 condensed with hydrazines 140 to afford pyrazolo[3,4-b]
quinolines 141 in high yields under heated/microwave irradiation
conditions for the first time (Scheme 39) [233]. After that, many
Scheme 57. Synthesis of pyrazolo[3,4-d][1,2,3]triazin-4-ones via one-pot aqueous mediated synthetic routes for pyrazolo[3,4-b]quinolines
diazotization.
appeared. Shi et al. reported a 3-CR of isatin 143, 5-amino-3-
methylpyrazole 142 and 1,3-dicarbonyl compounds 144 in water
and anti-inflammatory agents, and camptothecin, which could catalyzed by CAN affording spirooxindole derivatives in high yields
inhibit the DNA enzyme topoisomerase I (topo I) and be used as (Scheme 40) [234]; Perumal et al. reported a four-component re-
potential anticancer drugs [228]. Some synthesized pharmaceutical action (4-CR) of phenylhydrazine 148, 3-aminocrotononitrile 147,
agents containing quinoline rings are tested with particular bio- substituted benzaldehydes 149 and 2-hydroxynaphthalene-1,4-
logical activities, such as anti-tuberculosis [229], antifungal and dione 146 catalyzed by L-proline “on water” in good to excellent
antiseptic/anti-infective activities. Cappelli et al. reported the syn- yields (Scheme 41) [235]. The proposed reason for these water-
thesis of a series of translocator protein (TPSO) ligands which are
related to host-defense response, based on pyrazolo[3,4-b]quino-
line scaffold [230]. The compounds 138 were synthesized from 2-
chloroquinoline derivative 136 in a two-step reaction (Scheme
38) and some of them were found with high TPSO affinity which
further expanded the chemical diversity in TPSO ligands and pro-
vided new templates for new TPSO modulators.
Pyrazolo[3,4-b]quinolines are one important class of pyr-
azoloquinolines with various biological activities [231] and the
widely used synthetic methods concerned with the condensation

Scheme 60. Synthesis of pyrazolo[3,4-d][1,3]oxazines 225.

Scheme 58. Synthesis of pyrazolo[5,1-c][1,2,4]triazines through thermal cyclization. Scheme 61. Synthesis of 5H-benzopyrazolo[5,1-b][1,3]oxazines.
324 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 62. Synthesis of 2-hydroxypyrazolo[5,1-b][1,3]oxazine-7-ones.
mediated heterogeneous reactions would be that the unbound
hydroxyl groups in water interact with organic reactants and the
transition states, which would lower the activation energies, enable
reaction rates and enhance yields.
Tu et al. established a three-component domino reaction from
aldehydes 152, 2-hydroxynaphthalene-1,4-dione 151 and 5-amino-
3-methylpyrazole 153 with HOAc as catalyst under microwave
irradiation to afford benzopyrazolo[3,4-b]quinolines 154 with high
regioselectivity and a broad substrates scope (Scheme 42) [236].
The generated o-diketone unit would serve as important building
blocks for further reactions with nucleophilic agents, such as o-
phenylenediamine.
Pyrazolo[4,3-f]quinolines are another important
azoloquinolines possessing significant biological activities, such as
antibacterial [237] and antiviral activities [238]. Tu et al. reported a
general synthetic route for pyrazolo[4,3-f]quinolines 159 from ar-
omatic aldehydes 157, 5-aminoindazole 156, and various cyclic 1,3-
dicarbonyl compounds 158 under microwave irradiation in high
yields (Scheme 43) [239,240].
Another important type of pyrazoloquinolines is the pyrazolo
[4,3-c]quinoline ring system. As a review by Ramadan A.
Mekheimer published in 2012 [241] is describing this system in
detail, so we did not undertook this in the present review.
3.4. Pyrazolo[5,1-a]isoquinolines
Isoquinoline nucleus is identified to be one of the most abun-
dant structural motifs in numerous naturally occurring alkaloids,
which exhibit strong biological activities such as topoisomerase I
Scheme 63. Synthesis of several series of 2-hydroxypyrazolo[5,1-b][1,3]oxazine-7-
ones.
Scheme 64. Synthesis of indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-ones.
inhibitor [242] and anti-HIV activity [243], and synthetic com-
pounds possessing a broad spectrum of pharmacological activities,
such as antifungal, antimalarial, antihypertensive, antitumor and
antihistaminic activities [244,245]. Furthermore, H-pyrazolo[5,1-a]
isoquinoline core which combined both isoquinoline and pyrazolo
[1,5-a]pyridine skeletons exhibit notable biological activities for the
inhibition of CDC25B, TC-PTP and PTP1B leading to the great de-
mand for more diverse H-pyrazolo[5,1-a]isoquinolines [246].
The general synthetic methodology of H-pyrazolo[5,1-a]iso-
quinolines has been developed by Wu et al. starting from 2-
alkynylbenzaldehyde or N0 -(2-alkynylbenzylidene)hydrazide with
various catalysts. Silver triflate (AgOTf) is the most common cata-
pyr-
lyst employed in these reactions which promotes the 6-endo
cyclization to form the isoquinolinium-2-yl amide intermediates. If
substrates permitted, inter/intramolecular nucleophilic addition or
[3 þ 2] cycloaddition would take place and followed by aromati-
zation to complete the reaction for H-pyrazolo[5,1-a]isoquinolines
164 (Scheme 44) [246e250]. Yet, if conditions were not satisfied for
the subsequent reactions, co-catalysts would be needed. CuI and
CuBr were employed via CeH activation mechanism by oxidative
addition and reductive elimination to realize the reaction
[251,252]; dioxygen-copper systems were also employed to active
the CeH bond via oxidation to accomplish the reactions (Scheme
45) [253,254]; PPh3 as Lewis base to facilitate allenoates [255],
PhI(OAc)2 or Fe(acac)2 as oxidant [256] and RhCl(PPh3)3 as co-
catalyst [257] for the introduction of formyl group were also
employed to promote the reaction. Further investigation revealed
that the 6-endo cyclization could also be promoted by Br2 or I2 to
form the isoquinolinium-2-yl amide intermediate and the reaction
would be accomplished under general conditions (Scheme 46), i.e.
with appropriate base and solutions [258,259]. This strategy
afforded halo-containing H-pyrazolo[5,1-a]isoquinolines 169
which could be further decorated to functionalize H-pyrazolo[5,1-
a]isoquinoline derivatives.
Other substrates were also employed for the synthesis of H-
pyrazolo[5,1-a]isoquinolines. Fu et al. developed a one-pot CuI-
catalyzed 3-CRs of 1-(2-bromoaryl)-3-arylprop-2-yn-1-one 170,
hydrazine hydrochloride and ethyl 2-cyanoacetate or malononitrile
for the synthesis of functionalized H-pyrazolo[5,1-a]isoquinoline
derivatives 172 or 173 in moderate to good yields (Scheme 47)
[256].
Shibata et al. reported the synthesis of pyrazolo[5,1-a]iso-
quinoline triflones 176 for the first time via regioselective, tandem
1,3-dipolar cycloaddition/oxidative aromatization of triflyl alkynes
174 and azomethine imines 175 (Scheme 48) [260].
3.5. Pyrano[2,3-c]pyrazoles
Pyranopyrazoles are important fused heterocyclic compounds
with rich bioactivity profile, such as antibacterial [261], anti-
inflammatory [262], and molluscicidal activities [263], and have
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 65. Synthesis of pyrazolo[3,4-b]pyrazines through
cyclocondensation.
been widely used as medicinal agents, such as analgesic agents
[264]. Furthermore, dihydropyrano[2,3-c]pyrazoles were identified
as a screening hit for Chk1 kinase inhibitors [265]. Due to their
significant biological activities, it would be of interest to develop
efficient synthetic strategy for the construction of pyrano[2,3-c]
pyrazoles. Literature perusal reveals that three strategies are usu-
ally employed for the synthesis: simple reactions with two different
substrates, three-component synthetic reactions and four-
component synthetic reactions.
Appropriate catalysts and substrates are crucial for the simple
reactions with two substrates. Zhao et al. reported an enantiose-
lective tandem Michael additionecyclization reaction from 3-
methyl-2-pyrazolin-5-one 177 and benzylidenemalononitriles 178
with modularly designed organocatalysts (MDOs) as catalyst to
yield 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles 179 in high
yields and moderate to good enantioselectivities (Scheme 49)
[266]. The MDO performed as a Lewis base catalyst and the struc-
ture is shown.
Parmar et al. reported a tetrabutylammonium hydrogen sulfate
(TBA-HS) mediated procedure to afford benzopyran-annulated
pyrano[2,3-c]pyrazoles 183 through domino/Knoevenagel-hetero-
Diels-Alder (DKHDA) reaction from substituted salicylaldehydes
180 and 5-pyrazolones 181 (Scheme 50) [267].
As for three-component reactions, Rani et al. [268] and Azarifar
et al. [269] reported the synthesis of pyrano[2,3-c]pyrazoles 186
from substituted pyrazolone 184, malononitrile and aryl/alkyl al-
dehydes 185 catalyzed with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and recyclable magnetic La0.7Sr0.3MnO3 nanoparticles,
respectively (Scheme 51). The former reaction was carried out
under solvent-free conditions within 5 min in good yields and the
latter was confirmed with better generality. Based on this reaction,
Zhao et al. developed an enantioselective synthesis of chiral fluo-
rinated dihydropyrano[2,3-c]pyrazoles with diaminocyclohexane-
thiourea as catalyst in high yields (up to 98%) [270]. The bifunc-
tional thiourea catalyst performs as a base to deprotonate the
Scheme 66. Synthesis of pyrazolo[1,5-a]pyrazines.
325
MW-assisted
Scheme 67. Synthesis of several series of pyrazolo[1,5-a]pyrazin-4(5H)-ones.
malononitrile by the tertiary moiety, as well as activating the
carbonyl group of 4-aryliden-5-pyrazolnes, the reaction products of
184 and 185, by hydrogen bonds with the N-Hs.
In 2012, Ender et al. reported an efficient organocatalytic one-
pot asymmetric synthesis of 4H,5H-pyrano[2,3-c]pyrazoles 190
from crotonaldehyde 187, 3-trifluoro-N-substituted-pyrazolone
188 and Wittig reagent 189 via Michael/Wittig/oxa-Michael reac-
tion sequence in very good yields and enantioselectivities (Scheme
52) [271]. This is the first asymmetric synthesis of a tetrahy-
dropyrano[2,3-c]pyrazoles.
Four-component syntheses pyranopyrazoles using ethyl ace-
toacetate, hydrazine hydrate, aldehydes or ketones and malononi-
trile have been reported in the presence of base catalysts such as b-
cyclodextrin [272], triethylamine [273], cinchona alkaloid de-
rivatives [274], and imidazole (Scheme 53) [275]. Recently, various
catalysts and conditions have also been employed to realize this
transformation, such as catalyzed by piperidine under ultrasound
irradiation condition [276], catalyzed by biocatalyst, lipase from
Aspergillus niger (ANL) in ethanol at 30  C [277].
In 2012, Zonouz et al. reported a catalyst-free atom-economical
4-CRs of aldehyde, malononitrile, hydrazine hydrate and dimethyl
acetylenedicarboxylate 195 in water for the synthesis of pyrano
[2,3-c]pyrazoles 196 in good yields (Scheme 54) [278].
3.6. Pyrazolotriazines
The biological activities of pyrazolotriazines have been carefully
studied since these moieties are bioisosteric with purine, a mo-
lecular which endowed with broad spectrum of biological activ-
ities. Pyrazolo[1,5-a][1,3,5] triazines, one class of pyrazolotriazines,
have been identified as CDKs inhibitors which exhibit high anti-
proliferative activity in tumor cell lines [279], PDE4 inhibitors
Scheme 68. Synthesis of pyrazolo[3,4-d]pyridazines 261.
326 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 69. Synthesis of pyrazolo[3,4-d]pyridazines from hydrazonoyl halides.
which are potential therapeutic agents for inflammatory disease
[280]. Furthermore, a well-known CRF1 receptor antagonist, Pex-
acerfont has been tested as potential agent for the control and
treatment of some disease related to stress such as anxiety and
depression [281]. In 2012, Insuaaty et al. reported three practical
methods for the synthesis of 4,7-dihetarylpyrazolo[1,5-a][1,3,5]
triazines 200/205 starting from isothiocyanates 201 with 5-amino-
3-furyl-1H-pyrazoles 202 under conventional heating conditions in
DMF giving moderate to good yields (59e71%); starting from S,S-
diethyl hetaroylimidodithiocarbonates 197 with 5-amino-3-furyl-
1H-pyrazoles 198 in the absence of solvent employing microwave
irradiation gave an overall yields in 75e84%; reactions performed
in two steps, first under microwave irradiation and second under
conventional heating conditions in DMF gave overall yields in
68e78% (Scheme 55) [282]. The microwave-assisted reactions
seem to be more efficient.
Pyrazolo[4,3-e][1,2,4]triazines have been less studied in com-
parison with other pyrazolotriazines, yet some of naturally pro-
duced pyrazolo[4,3-e][1,2,4]triazines exhibit anticancer and
antibacterial activities [283] and some synthesized compounds
have been described as moderate purine nucleoside phosphorylase
inhibitors [284], and CDKs inhibitors which may be considered as
new scaffold for the development of antiproliferative agents [285].
Al-Matar et al. developed an efficient route for the synthesis of
pyrazolo[3,4-e][1,2,4]triazines 209 from arylhydrazonomalononi-
triles 206 as starting materials (Scheme 56) [286]. The starting
material is also versatile for the synthesis of a new ring system,
[1,2,4]triazino[5,6-d][1,2,3]triazines.
Pyrazolo[3,4-d][1,2,3]triazines have also been identified as
important heterocyclic compounds because of their various bio-
logical activities, such as anticonvulsant [287], antifungal, antiviral
and anticancer activities [288]. In 2011, Moyano et al. established an
efficient one-pot diazotization of 5-amino-1H-pyrazole-4-
carbonitriles 210 for the synthesis of pyrazolo[3,4-d][1,2,3]triazin-
4-ones 211 in good to very good yields (Scheme 57) [289]. The
Scheme 70. Synthesis of pyrazolo[1,2-a]pyridazines via 3-CR.
Scheme 71. Synthesis of pyrazolo[4,3-c]pyridazines.
reaction is assumed to take place through the intermediate of a
diazocarboxamide or a diazoic acid. Further detection revealed that
electron-withdrawing or alkyl substitutes did not facilitate such
kind of reactions and obtained lower yields of desired products.
Pyrazolo[5,1-c][1,2,4]triazines have also been prepared for their
potential biological activity investigation and some displayed
antimicrobial activities [290]. In addition, Guerrini et al. reported a
pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide system as a GABAA re-
ceptor ligand with selective anxiolytic-like effects and might be
novel subtype as new agents for pain relief [291e293]. In 2011,
Cankar et al. established an efficient approach for the synthesis of
pyrazolo[5,1-c][1,2,4]triazines 216 through thermal cyclization of
1H-pyrazol-5-yl hydrazones 215 in boiling ethanol (Scheme 58)
[294]. Further investigation of the reaction revealed that the reac-
tion was directed by both the substitution of the pyrazole ring and
the cyclization medium. Nader et al. reported a two-step ionic-
mechanism involving initial nucleophilic addition followed by
cyclization reaction from 3-diazo-5-methyl-4-phenyl-1H-pyrazole
217 with [11C]lithium trimethylsilylynolate 218 for the synthesis of
7-methyl-8-phenyl-3-trimethylsilylpyrazolo[5,1-c][1,2,4]triazine-
(1H)-4-one 220 (Scheme 59) [295].
3.7. Pyrazoleoxazines
Compounds containing oxazines have been widely studied due
to their remarkable biological activities against different diseases.
An imidazo[2,1-b][1,3]oxazine derivative, PA-824 (Fig. 5) has been
demonstrated to have a novel mechanism against Mycobacterium
tuberculosis and Helicobacter pylori, comparable with isoniazid
[296,297] and analogs have also been synthesized with excellent
activities against M. tuberculosis [298]. Since the discovery of tri-
fluoromethyl-1,3-oxazin-2-one (Fig. 5) [299], known as Efavirenz, a
non-nucleoside reverse-transcriptase inhibitor and selective anti-
HIV drug, much attention has been paid on the synthesis of ben-
zooxazines and anologues. Though only a few literature reported
the biological activities of pyrazolecondensed 1,3-oxazines, many
synthetic methods have been established. For example, an anti-
microbial agent 5-amino-2-methyl-pyrazolo[5,1-b][1,3]oxazine-7-
one was prepared with ethyl acetate and cyanoacetohydrazide as
starting materials [300].
Fig. 6. Structures of compounds containing benzothiazine core.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 327

Scheme 72. Synthesis of pyrazolo[3,4-c][1,2]benzothiazines with anti-oxidant and

anti-bacterial activity.

Scheme 74. Synthesis of pyrazolo[4,3-c][1,2]benzothiazines with FAK inhibitory

Abonia et al. developed a selective approach for the synthesis of activity.
7-(arylmehthyl)-3-tert-butyl-1-phenyl-6,7-dihydro-1H,4H-pyr-
azolo[3,4-d][1,3]oxazines 225 through a three-step reaction pro-
diseases that are related to bone metabolism [308], such as rheu-
moted by acetic acid starting from aminopyrazole 221 and
matoid arthritis, osteoporosis, Psget's disease. Some reports also
arenealdehydes (Scheme 60) [301]. During the reaction, a dihy-
indicated their diversiform biological activities, such as anti-
droxy intermediate 224 was obtained and then intramolecular
inflammatory [309], anti-aggregations of blood platelets, antitu-
etherification took place to obtain the final product.
moral [310,311], antibacterial [312] and antifungal activities [313].
Kurth et al. developed a base-mediated one-pot N,N-bond
There are rather limited literature focused on the synthesis of
forming heterocyclization reaction of o-nitroarylmethylamines 228
pyrazolo[3,4-b]pyrazines in spite of their multifold biological ac-
for the synthesis of 5H-benzopyrazolo[5,1-b][1,3]oxazines 229
tivities. Kashef et al. reported the construction of pyrazolo[3,4-b]
(Scheme 61) [302]. Several unique pyrazole-based heterocycles
pyrazine core from 5-amino-3-methyl-4-nitroso-l-phenylpyrazole
including benzo-1,3-dioxolopyrazoles, benzothiazolopyrazoles,
243 and benzoylacetonitile 244 in refluxing pyridine [313]. Intra-
pyridopyrazoles, were synthesized through this method, except for
molecular FriedeleCrafts reaction was applied in the synthetic
thiophene-fused pyrazoles, which may attribute to the weak acidity
process and novel indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-ones 248
of the sp3 hybridized proton next to N of the intermediate leading to
possessing antibacterial and antifungal activities were easily syn-
the 1,4-elimination of water.
thesized (Scheme 64) [314].
Petina et al. reported the synthesis of 2-hydroxypyrazolo[5,1-b]
Microwave-assisted chemistry has become an effective tech-
[1,3]oxazine-7-ones 232 from the reaction of arylpropynehy-
nique to simplify and improve classic organic reactions which can
drazides with substituted malonyl chlorides through 6-endo-dig
dramatically reduce the reaction time, increase product yields and
cyclization (Scheme 62) [303]. Furthermore, a mesoionic pyrazolo
control the reaction conditions. Quiroga et al. reported the prepa-
[5,1-b][1,3]oxazine (234) was obtained through thermolysis of 4,4-
ration of pyrazolo[3,4-b]pyrazines 251 through microwave-assisted
dimethyl-1-(3-phenylprop-2-inoyl)pyrazolidine-3,5-dione
cyclocondensation reaction of o-aminonitrosopyrazoles 249 and
(Scheme 62).
cyclic b-diketones 250 in DMF as an extension of EhrlicheSachs
Zhao et al. reported another several series of pyrazolooxazines,
reaction (Scheme 65) [315].
2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-ones 236 via lacto-
Another pyrazolopyrazines derivatives, pyrazolo[1,5-a]pyr-
nization of 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-5-
azines also exhibit interesting pharmaceutical properties, such as
carboxylic acids in the presence of AcOH with good yields [304];
vasodilators, vitronectin-receptor antagonists. Gentile et al. syn-
6-(aroxymethyl)-2-aryl-6,7-dihydropyrazolo[5,1-c][1,4]oxazin-4-
thesized a series of pyrazolo[1,5-a]pyrazines 255 identified as
one derivatives 239 were synthesized under microwave irradiation
potent and selective Vasopressin1b receptor antagonists which
with no solvent in good yields and a tandem reaction mechanism
have been suggested as potential agents in the treatment of dis-
was proposed [305]; 2-ferrocenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-
eases characterized of excessive cortisol secretion [316], such as
one derivatives 242 were synthesized by the intra-esterification
major depression [317] and stress-related disorders [318]. The
reaction in the presence of MgBr2$Et2O and diisopropylethyl-
construction of the pyrazolo[1,5-a]pyrazine was realized by the
amine in one-pot process (Scheme 63) [306]. The biological activ-
cyclization of compound 253with ammonium acetate (Scheme 66).
ities evaluation of these compounds is undergoing.
Zhao et al. synthesized several series of pyrazolo[1,5-a]pyrazin-
4(5H)-one derivatives under conventional organic synthesis con-
3.8. Pyrazolopyrazines ditions or microwave irradiation as lung cancer cell growth in-
hibitors. The construction of pyrazolo[1,5-a]pyrazin-4(5H)-one core
Pyrazolopyrazines, as an important class of pyrazolo-fused were realized via intramolecular aminolysis (Scheme 67)
compounds, have been widely employed in the treatment of [310,311,319e322].
depression, dementia, Parkinson's disease, anxiety, cerebrovascular
disease, which are related to adenosine receptors [307] and

Scheme 73. Synthesis of pyrazolo[3,4-c][1,2]benzothiazine 5,5-dioxide analogs. Scheme 75. Synthesis of 3-amino-5,8-dichloroflavazoles.
328 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 76. Synthesis of pyrazolo[1,5-a]quinoxalines.
3.9. Pyrazolopyridazines
Pyrazolopyridazines are reported as important organic com-
pounds because of their wide application in pharmaceuticals and
agrochemicals. For example, several pyrazolo[3,4-d]pyridazines
exhibit antifungal [323] and antibacterial activities [324], and some
pyrazolo[1,2-a]pyridazine-5,8-diones were reported as anti-
inflammatory, analgesic, anti-hypoxic and anti-pyretic agents
[325]. Due to their potential biological activities, various pyr-
azolopyridazines have been designed and synthesized.
Pyrazolo[3,4-d]pyridazines were usually constructed from
cyclization of 4-aroyl/acyl-1H-pyrazole-3-carboxylic acid or -acid
chloride 260 with 2-hydroxyethyl hydrazine (Scheme 68) [326].
Giovannoni et al. reported the synthesis of pyrazolo[3,4-d]pyr-
idazinones as potential phosphodiesterase 4 (PDE4) inhibitors,
which are widely applied in therapeutic treatment of inflammatory
and immune disorders with the aforesaid method [327]. Shawali
et al. established a convenient synthetic procedure with the utility
of hydrazonoyl halides as precursors for the synthesis of pyrazolo
[3,4-d]pyridazines (Scheme 69) [328e330]. Based on this method, a
series of 3-arylazo-8H-imidazo[1,2-b]pyrazolo[3,4-d]pyridazines
264 were synthesized and realized the site-selectivity in the reac-
tion of hydrazine hydrate with 3,40 -bis-(functionalized carbonyl)-
4,30 -bis(pyrazol)ketones 265 and cyanoacetic hydrazides with
hydrazonoyl chlorides.
Multicomponent reactions (MCRs) are attractive to organic and
pharmaceutical chemists since these reactions effectuate the con-
struction of basic and important compounds possessing unique
biological activities in a single step [331]. Teimouri et al. reported a
one-pot three-component condensation reaction of isocyanides
267 with dialkyl acetylenedicarboxylates 268 and 3,6-
dihydroxypyridazine 269 for the synthesis of dialkyl 3-(alkyl/ary-
lamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-
dicarboxylates 270 (Scheme 70) [332]. The three-component re-
action was quite general with the reactants, dialkyl acetylenedi-
carboxylates affording moderate to good yields of final products,
and diverse alkyl or aryl isocyanides were used in the reaction with
satisfactory results.
Another pyrazolopyridazine derivative, pyrazolo[4,3-c]pyr-
idazines has also been reported. Mojahidi et al. reported the syn-
thesis of 5-(4-fluorophenyl)-6-methyl-2H-pyrazolo[4,3-c]
pyridazin-3(5H)-one 272 with an important cytotoxic activity
against cell line P815 from b-ketone carboxylic acid 271 and hy-
drazine hydrate as reactants (Scheme 71) [333].
Scheme 77. Synthesis of pyrazolo[1,5-a]quinoxalines oxides.
Scheme 78. Synthesis of pyrazolo[3,4-g]quinoxalines.
3.10. Pyrazolo[3,4-c][1,2]benzothiazines
Benzothiazines are known as potential biological agents, for
example, 1,2-benzothiazine-3-carboxamide 1,1-dioxide derivatives
(Meloxicam and Piroxicam) are famous as analgesic and anti-
inflammatory agents (Fig. 6). Furthermore, benzothiazines are re-
ported as potent calpain I inhibitors [334] and antifungal agents
against Bacillus subtilis [335]. They have also been reported as po-
tential antibacterial and anti-oxidants agents [336]. In recent years,
pyrazolo[3,4-c][1,2]benzothiazines have also been synthesized
with important biological activities, such as anti-oxidants, anti-
bacterial and antitumor [337e339].
Siddiiqui et al. reported the synthesis of a series of potential
anti-oxidant and anti-bacterial N0 -arylmethylidene-2-(3,4-
dimethyl-5,5-dioxidopyrazolo[3,4-c][1,2]benzothiazin-2(4H)-yl)
acetohydrazides 276 starting from saccharine 273 and ultrasonic
irradiation was employed for the construction of the pyrazolo[3,4-
c][1,2]benzothiazine core in high yields (Scheme 72) [337]. Another
series of chalcone-based pyrazolobenzothiazines were also syn-
thesized with potent anti-bacterial activity by them [340].
In 2012, Sabatini et al. synthesized a new class of pyrazolo[3,4-c]
[1,2]benzothiazine 5,5-dioxide analogs 281 performed as Staphy-
lococcus aureus NorA multidrug efflux pump inhibitors [338].
Saccharin sodium salt 273 was also employed as starting materials
and the construction of pyrazolo[3,4-c][1,2]benzothiazine core was
realized from the condensation of key intermediate 279 with
phenylhydrazines hydrochloride in refluxing EtOH with conc H2SO4
as dehydrating agent (Scheme 73).
In 2013, Tomita et al. reported a series of 1,5-dimethyl-1,5-
dihydropyrazolo[4,3-c][1,2]benzothiazine derivatives 284 which
could selectively inhibit kinase activity of focal adhesion kinase
(FAK) without affecting other kinases and could be developed as
Fig. 7. Structures of compounds containing pyrazolo[4,3-h]quinazoline core.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 79. Synthesis of PHA-848125.
antitumor agents [339]. The pyrazolo[4,3-c][1,2]benzothiazine
scaffold was synthesized from methyl anthranilates 283 and N,N-
dimethylformamide dimethylacetal (DMFDMA) and hydrazines
were employed for the construction of pyrazole ring (Scheme 74).
The structure was fully modified with different groups leading to an
optimized compound N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-
dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide
which possessed FAK inhibitory activities both in cell-free
(IC50 ¼ 0.64 mM) and in cellular assays (IC50 ¼ 7.1 mM).
3.11. Pyrazoloquinoxalines
Quinoxaline derivatives are widely used in pharmaceutical in-
dustry because of their broad spectrum biological activities, such as
antiviral, antidiabetic and anti-inflammatory [341]. Additionally,
nitrogen-containing tricyclic compounds have been demonstrated
with various applications in pesticide and are potential enzyme
inhibitors. Most common structures of the pyrazoloquinoxalines
are 1H-pyrazolo[3,4-b]quinoxalines, known as flavazoles, which
can be readily synthesized by oxidative cyclization of the corre-
sponding quinoxalines hydrazones [342]. In 2011, Guirado et al.
developed a general method for the synthesis of 3-amino-5,8-
dichloroflavazoles from the key intermediate, 5,8-dichloro-2,3-
Scheme 80. Synthesis of pyrazolo[1,5-c]quinazolines as PDE10A inhibitors.
329
Scheme 81. Synthesis of pyrazolo[1,5-c]quinazolines via Cu-mediated reaction.
dicyanoquinoxaline 287 which was easily obtained from 3,3,6,6-
tetrachloro-1,2-cyclohexanodione 285 with diaminomaleonitrile
286, alkylhydrazines through first substitution followed by the
intramolecular addition in near quantitative yield (Scheme 75)
[343]. However, when hydrazine (ratio: 1:1) was employed, only
substitution reaction occurred owing to the relatively weaker
nucleophilic activity of hydrazine. The targeted product was finally
obtained by increasing the hydrazine amount (ratio 2:1) followed
by pyrolysis of the intermediate.
Pyrazolo[1,5-a]quinoxalines were studied less intensively in
spite of their important properties as HIV integrase inhibitors and
in vivo antitumor activities [344]. And they were firstly obtained as
byproducts from the photodecomposition of azides [345,346]. In
2009, Linker et al. synthesized a series of pyrazolo[1,5-a]quinoxa-
lines 293 from aryloxymethylquinoxaline oximes 291 in the pres-
ence of acetic anhydride through a proposed formal [3,5]-
sigmatropic rearrangement process (Scheme 76) [347]. In 2010,
Reeves et al. established a CuI-catalyzed annulation of o-amino-
iodoarene with formylpyrazole in high yields [348]. And in 2013,
Wu et al. developed a two-step procedure from 2-
methylthiosubstituted 1,4-enediones 294 and substituted o-phe-
nylenediamines 295 forming the key intermediate dihy-
droquinoxalines 296 for the synthesis of pyrazolo[1,5-a]
quinoxalines oxides 297 in excellent yields (Scheme 77) [349].
Also, another pyrazoloquinoxaline derivatives, pyrazolo[3,4-g]
quinoxalines have been synthesized as particular kinases in-
hibitors, such as Akt inhibitors [350], tyrosine kinase or PKC in-
hibitors [351]. In 2010, Moreau et al. reported the synthesis of
pyrazolo[3,4-g]quinoxaline derivatives 301 as in vivo Pim-3 kinase
inhibitors and some have demonstrated favorable antiproliferative
potencies [352]. The synthesis of these compounds was carried out
starting from 1H-indazole-5,6-diamine 300 which was obtained
from 6-nitroindazole 298 through nitration with H2SO4 and KNO3
followed by reduction of nitro groups. Condensation of 1H-inda-
zole-5,6-diamine 300 with various 1,2-diketones or a-chlor-
oketones gave targeted products in moderate to good yields
(Scheme 78).
3.12. Pyrazoloquinazolines
Quinazoline derivatives endowed with various biological and
medicinal properties and have been developed as potent cellular
phosphorylation and tyrosine kinase inhibitors [353], DNA binders
Scheme 82. Synthesis of pyrazolo[4,3-f]quinazolin-9-ones.
330 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 83. Synthesis of pyrazolo[1,2-b]phthalazines through 3-CRs.
[354], antiviral [355], anticancer [356], and antitubercular agents
[357]. Recently, the synthesis of pyrazoloquinazolines has drawn
considerable attention due to their good biological activities. Pyr-
azolo[4,3-h]quinazoline derivatives have been demonstrated as
inhibitors of several cell cycle kinases which might be developed as
potential antineoplastic agents. Traquandi et al. reported the
identification of pyrazolo[4,3-h]quinazoline-3-carboxamides as
cyclin-dependent kinases (CDKs) inhibitors, and one of the deriv-
ative PHA-848125 (Fig. 7), mainly targeting CDK2 and TRKA, is
advanced in phase II clinical trials [358,359]. Beria et al. identified a
series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as
Polo-like-kinase 1 (PLK1) inhibitors and one of the derivative, NMS-
P937 (Fig. 7) is presently in phase I clinical trials evaluation
[360e362]. Caldarelli et al. developed a series of 4,5-dihydro-pyr-
azolo[4,3-h]quinazoline-3-carboxamide derivatives 308 as potent
and selective Monopolar Spindle-1 kinase (MPS1) inhibitors and
identified NMS-P715 (Fig. 7) with favorable pharmacokinetic pa-
rameters, good potency and selectivity profile [363]. The con-
struction of the pyrazolo[4,3-h]quinazoline core was commonly
realized through condensation of enaminone with dinucleophile,
as illustrated by the synthesis of PHA-848125 (Scheme 79) [359].
N-Fused heterocycles of pyrazoles and quinazolines, pyrazolo
[1,5-c]quinazolines have been demonstrated as potent IkB kinase
inhibitors [364], AMPA and kainate receptor [365] and NMDA re-
ceptor antagonists [366]. In 2011, Asproni et al. identified a series of
potent phosphodiesterases 10A (PDE10A inhibitors) by combining
the pyrazolo[1,5-c]quinazoline system with a phenylimidazole
fragment and the most potential derivative was demonstrated with
an IC50 value of 16 nM [367]. The synthetic procedure is shown
(Scheme 80).
In 2011, Fu et al. established an efficient one-pot synthesis of
pyrazolo[1,5-c]quinazoline derivatives 316 under mild CuI-
catalyzed condition from substituted 1-(2-halophenyl)-3-
alkylprop-2-yn-1-ones 314, hydrazine hydrochloride and amidine
hydrochlorides in good to excellent yields (Scheme 81) [368]. This
method provides diverse and useful pyrazolo[1,5-c]quinazoline
derivatives for medicinal chemistry.
In 2012, Demeunynck et al. established a catalyst-free synthesis
of quinazolin-4-ones in two steps, guanidine formation and cycli-
zation, from (hetero)aryl-guanidines and the intramolecular cycli-
zation was realized by catalyst-free thermolysis at 130  C in water
Scheme 84. Synthesis of spiro[indoline-pyrazolo[1,2-b]phthalazine] derivatives.
Scheme 85. Synthesis of pyrazolo[1,2-b]phthalazines through 4-CRs in ionic liquid.
under microwave irradiation [369]. The pyrazolo[4,3-f]quinazolin-
9-ones 319, which were demonstrated as DYRK1A inhibitors at
submicromolar concentrations, were synthesized under the same
condition (Scheme 82).
3.13. Pyrazolo[1,2-b]phthalazines
Phthalazine derivatives have attracted increasing attention in
recent years due to their excellent pharmacological and biological
activities [370,371], such as anticonvulsant [372], cardiotonic [373],
and vasorelaxant activities [374]. Pyrazolo[1,2-b]phthalazine-dione
is identified as anti-inflammatory, analgesic, anti-hypoxic and anti-
pyretic agent [375]. In 1937, Drew and Hart initially reported the
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione skeleton
from phthalhydrazide and cinnamaldehyde [376]. Until now, most
of pyrazolo[1,2-b]phthalazines were synthesized by one-pot multi-
component reactions in various different conditions as summarized
below.
As for the three-component reactions (3-CRs) of phthalhy-
drazide 320, malononitrile or ethyl cyanoacetate or 1,3-diketones
322/323, and aromatic aldehydes 321(Scheme 83), various
methods were developed: 1) in the presence of p-TSA at 100  C in
ionic liquid [bmim]Br [377]; 2) with Et3N (20 mol%) as catalyst in
ethanol at 50  C under ultrasonic irradiation [378]; 3) without
catalyst in ionic liquid [bmim]OH under microwave irradiation at
45  C [379]; 4) with mesoporous aluminosilicates (Al-KIT-6) as
heterogeneous catalyst in ethanol under refluxing conditions, Al-
KIT-6 was found to be a good recyclable solid catalyst [380]; 5)
with (S)-camphorsulfonic acid as catalyst under solvent-free con-
ditions at 80  C as well as under solvent-free conditions at room
temperature, and this method was quite tolerated to aldehydes and
cyclic or acyclic 1,3-diketones, yet when cyclic 1,3-diketones were
treated with phthalhydrazide and aldehyde failed to give the tar-
geted product [381]. These reactions are proposed to be realized
through domino Knoevenagel condensation/Michael addition/
intramolecular cyclodehydration sequence.
By reacting isatin or acenaphthylene-1,2-dione with either
phthalhydrazide, malononitrile or ethyl cyanoacetate, spiro com-
pounds were obtained. Shi et al. reported the synthesis of spiro
[indoline-pyrazolo[1,2-b]phthalazine] derivatives 327 catalyzed by
piperidine (10 mol%) in CH3CN under refluxing conditions or ul-
trasound irradiation conditions (Scheme 84) [382,383]; the
Scheme 86. Synthesis of functionalized 1H-pyrazolo[1,2-b]phthalazine-1,2-
dicarboxylates.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 87. Synthesis of pyrazolo[1,2-b]phthalazines through NiCl2-catalyzed 4-CR.
synthesis of spirowiacenaphthylene derivatives with Et3N as cata-
lyst under ultrasound irradiation conditions [384] and the syn-
thesis of pyrazolophthalazinyl spirooxindoles catalyzed by NiCl2
(20 mol%) in polyethylene glycol 600 at 100  C were also reported
[385].
Pyrazolo[1,2-b]phthalazines were also prepared through four-
component reactions (4-CRs) which could improve the diversity
of the available starting materials and obtained fairly good
combinatorial libraries. Dabiri et al. reported a one-pot four-
component condensation reaction of phthalhydrazide 320, (prop-
argyloxy)benzaldehyde 328, malononitrile or ethyl cyanoacetate,
and an azide in the presence of Cu(OAc)2/sodium L-ascorbate as
catalyst in ionic liquid [Hmim](CF3COO) for the synthesis of pyr-
azolo[1,2-b]phthalazine derivatives 330. Knoevenagel condensa-
tion and click reaction, and subsequent Michael-type addition were
proposed to effectuate this reaction (Scheme 85) [386]. Shaabani
et al. reported an isocyanide-based 4-CRs of various cyclic anhy-
drides 331, hydrazine hydrate, isocyanides 332 and dialkyl acety-
lenedicarboxylates 333 in EtOH/acetone (1:1) at room temperature
for the synthesis of highly functionalized 1H-pyrazolo[1,2-b]
phthalazine-1,2-dicarboxylates 334 in good to moderate yields
(Scheme 86) [387]. He et al. reported a NiCl2-catalyzed 4-CR of
phthalimide 335, hydrazine, malononitrile or ethyl cyanoacetate
322, and aromatic aldehydes 336 in ethanol under refluxing con-
ditions (Scheme 87) [388]. The Lewis acid NiCl2$6H2O showed an
excellent catalytic activity leading to high yields of target products.
Shaterian et al. reported a 4-CRs of hydrazine monohydrate,
phthalic anhydride, malononitrile or ethyl cyanoacetate, and aro-
matic aldehydes employing three weak basic ionic liquids, DBU
[CH3COO], [Pyrr][HCOO] and [Pyrr][CH3COO] as efficient catalysts
under ambient and solvent-free conditions in excellent yields
[389]. These reusable ionic liquids played crucial roles in these
reactions and proposed to be the most efficient catalyst respect to
the less reaction time and the higher yields.
3.14. Other [5, 6]-condensed pyrazole derivatives
3.14.1. Pyrazolo[4,3-c]cinnolines
Cinnoline has been developed as potent anti-inflammatory
agents [390], such as cinnopentazone, cinoxacin (Fig. 8) and anti-
bacterial agents [391]. Furthermore, some cinnoline derivatives
have been reported as dual anti-inflammatory-antibacterial agents
possessing improved safety profile for improved therapeutic ben-
efits and better patient compliance [392]. Bawa et al. synthesized a
Fig. 8. Structures of compounds containing cinnoline core.
331
Scheme 88. Synthesis of pyrazolo[4,3-c]cinnolines.
series of pyrazolo[4,3-c]cinnoline derivatives 340 and a useful
model of a new class of dual non-acidic anti-inflammatory-anti-
bacterial agents was developed [393]. The construction of the
pyrazolo[4,3-c]cinnoline framework was realized through
condensation of 3-acetyl-7-chloro-6-fluorocinnolin-4(1H)-one 338
with acid hydrazides 339 in 1,4-dioxane containing a catalytic
amount of conc. HCl (Scheme 88).
3.14.2. Pyrazolo[1,5-f]phenanthridines
Apart from the attractive applications of phenanthridine-fused
heterocycles in organic diodes and discotic liquid crystals owing
to the electroluminescent properties of the compounds, phenan-
thridine moiety has been suggested as an effective pharmacophore
as DNA-intercalating antitumor agents [394,395]. In 2010, Martin
et al. reported the synthesis of a series of pyrazolo[1,5-f]phenan-
thridine derivatives 344 by a straightforward sequence. First, a
tandem amine-exchange/heterocyclization of enaminones was
carried out for the preparation of 1,5-diarylpyrazole intermediates
343; second, cyclization by intramolecular biaryl bond formation
was accomplished by two alternative methods: free-radical SRN1
coupling employing tris(trimethysilyl)silane (TTMSS) and AIBN or
catalytic direct arylation via CeH activation (Scheme 89) [396].
3.14.3. Pyrazolo[1,5-a][1,4]benzoxazines
As a key structural component in many biological and thera-
peutic compounds, such as the anticancer agent actinomycin D
[397], benzoxazinorifamycin KRM-1648 known as antitubercular
agent [398], flumioxazin and thidiazimin used as herbicides [399],
1,4-benzoxazines have attracted considerable interest of organic
and pharmaceutical chemists and Zhao et al. have explored the
important biological activity of 2,3-dihydro-3-hydroxymethyl-1,4-
benzoxazines as HUVEC (human umbilical vein endothelial cell)
apoptosis inhibitors [400e405]. Also, pyrazolobenzoxazines have
been demonstrated as inhibitor of the mitotic kinesin spindle
protein [406] and viral replications in recent years. In spite of the
good biological activities of pyrazolobenzoxazines, only a few
synthetic methods are available for them. Garati et al. reported the
synthesis of pyrazolo[5,1-c][1,4]benzoxazines through the intra-
molecular cycloaddition of nitrilimines with terminal alkynes,
substituted ethylenes and acetylenes [407,408]. Shimizu et al. re-
ported the synthesis of pyrazolo[5,1-c][1,4]benzoxazines through
1,3-dipolar cycloaddition reaction from 2-(allyloxy)phenyl-
hydrazine with arylaldehydes in the presence of HCl [409].
Scheme 89. Synthesis of pyrazolo[1,5-f]phenanthridine.
332 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 90. Synthesis of 3-substituted pyrazolo[5,1-c][1,4]benzoxazines.
In 2011, Chowdhury et al. established an efficient strategy for the
general synthesis of 3-substituted pyrazolo[5,1-c][1,4]benzox-
azines 347 through 1,3-dipolar cycloaddition of hydrazonoyl chlo-
ride intermediate obtained by a two-step one-pot reaction (Scheme
90) [410]. Furthermore, the results revealed that the reaction pro-
tocol could also be applied in bis-heteroannulation and the syn-
thesis of uracil derivatives.
3.14.4. Pyrazolo[3,4-h][1,6]naphthyridines
1,6-Naphthyridine derivatives have been developed as lumi-
nescence materials in molecular recognition [411] and anticancer
agents, such as HIN-1 integrase inhibitors [412,413], FGF receptor-1
tyrosine kinase inhibitors [414] and acetylcholinesterase inhibitors
[415].
Jachak et al. established a general method for the synthesis of
pyrazolo[3,4-h][1,6]naphthyridines 350/351 through Friedla €nder
condensation of 4-amino-3-(4-aryl)-1-phenyl-1H-pyrazolo[3,4-b]
pyridine-5-carbaldehyde 349, which was easily obtained through
diazotization, reduction, and oxidation from ethyl 4-chloro-1-
phenyl-3-aryl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 348,
with active methylenes or cyclic ketones in high yields (Scheme 91)
[416]. Furthermore, more angular tricyclic and tetracyclic hetero-
annulated compounds could be synthesized by the condensation of
4-aminopyrazolo[3,4-b]pyridine-5-carbaldehyde (Scheme 91). All
the synthesized compounds have potential applications in opto-
electronic devices because of their efficient blue light emission
and thermostability.
Bernardino et al. reported the synthesis of two series of 3H-
benzolo[3,4-h][1,6]naphthyridines as potent anti-HSV-1 agents. A
general approach was employed for preparing the targeted prod-
ucts from 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate 354 (Scheme 92), which was prepared from 5-qmino-
Scheme 91. Synthesis of pyrazolo[3,4-h][1,6]naphthyridines 350, 351.
Scheme 92. Synthesis of 3H-benzolo[3,4-h][1,6]naphthyridines as potent anti-HSV-1
agents.
1-phenyl-1H-pyrazole through condensation with diethyl ethox-
ymethylenemalonate followed by cyclization [417,418].
3.14.5. Pyrazolo[5,1-d][1,2,3,5]tetrazines
In 2010, Lam et al. reported a solid-phase synthesis (SPS) of 5-
aminopyrazole and the application to the preparation of pyrazolo
[5,1-d][1,2,3,5]tetrazine-4(3H)-ones 359 (Scheme 93) [419]. The
SPS allows convenient handling and distribution of the synthetic
intermediates and offers an alternative pathway for organic
synthesis.
4. [5, 7]-Condensed pyrazole derivatives
4.1. Pyrazolo-1,4-benzodiazepines
1,4-Benzodiazepine moieties are important skeletons in natu-
rally occurring as well as synthetic products with a wide range of
biological activities. For example, Deoxyharringtonine displays the
lowest IC50 against leukemic cells [420,421]. They are also reported
as potential antitumor agents [422], anti-inflammatory [423], anti-
HIV agents [424], anxiolytics [425], antibiotics [426] and potent
arginine vasopressin antagonists [427].
Due to their remarkable biological activities, various synthetic
methods have been developed. In 2010, Khodairy reported the
synthesis of 1,4-diphenyl-1,10-dihydrobenzopyrazolo[3,4-e][1,4]
diazepine 362 from 3-dimethylaminomethyleno-4-phenyl-1H-1,5-
benzodiazepin-2-one 361 with hydrazines (Scheme 94) [428].
Abonia et al. developed a radical mediated intramolecular
alkylation from ethyl pyrazolylbenzylaminoxanthates 365 for the
synthesis of 4H-benzopyrazolo[1,5-a][1,3]diazepin-5(6H)-ones 366
in moderate yields (Scheme 95) [429]. Dilauroyl peroxide (DLP) was
employed for the generation of a-alkylcarbonyl radicals.
Scheme 93. Synthesis of pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 94. Synthesis of 1,4-diphenyl-1,10-dihydrobenzopyrazolo[3,4-e][1,4]
diazepine.
Scheme 95. Synthesis of 4H-benzopyrazolo[1,5-a][1,3]diazepin-5(6H)-ones.
In spite of the conventional methods, metal-catalysts were also
employed in these reactions. Batra et al. established a CuI-catalyzed
cascade reactions via intermolecular condensation followed by a
copper-mediated intramolecular CeN or CeO coupling reaction
from substituted 4-iodopyrazolecarbaldehydes 367 with 1,2-
phenylenediamines 368 or 2-aminophenols 370 to obtain dihy-
drobenzopyrazolo [4,3-e] [1,4]diazepines 369 or benzopyrazolo
[3,4-f][1,4]-oxazepines 371, respectively (Scheme 96) [430].
Beccalli et al. reported Pd-catalyzed amination/1,3-dipolar
cycloaddition as the key reaction steps for the synthesis of tetra-
cyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazepine-5,8-
diones 375 (Scheme 97) [431]. The construction of pyrazolo ring
was realized via 1,3-dipolar cycloaddition.
In 2011, Martin et al. developed a straightforward entry for
pyrazolodibenzo[1,4]diazepines 377 prepared by a tandem
sequence amine-exchange/heterocyclization with Pd-catalyzed
intramolecular N-arylation as key step, from enaminones and
arylhydrazines (Scheme 98) [432]. Heterogeneous catalyst,
Scheme 96. Synthesis of dihydrobenzopyrazolo [4,3-e] [1,4]diazepines through CuI-
catalyzed reactions.
333
Scheme 97. Synthesis of tetracyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazepine-
5,8-diones.
FibreCat™ catalyst was also examined without notable progress in
yields.
In 2013, Zhao et al. reported the synthesis of chiral ferroce-
nylpyrazolo[1,5-a][1,4]diazepin-4-one derivatives 380 as lung
cancer cells inhibitors under microwave-assisted condition
(Scheme 99) [433]. The anti-tumor activities of these compounds
were related to the nature of substituents in benzene moiety. Three
conditions were tested and the microwave irradiation seemed to be
the most efficient method.
4.2. Pyrazolo-1,4-thiazepines
1,4-Thiazepines are important heterocyclic compounds existing
both in natural products and synthetic compounds with various
biological activities [434,435], such as anticonvulsant, analgesic,
antifeedant activities. Among them, heteroaryl-fused derivatives
are proved to be an important class of compounds exhibiting
interesting pharmaceutical properties, such as HIV-1 enzyme
integrase [436] and reverse transcriptase inhibitors [437] and cal-
cium channel antagonists [438].
In recent years, many approaches have been developed for the
synthesis of pyrazolothiazepines. In 2011, Mohamed reported a
simple condensation of benzo[1,5]thiazepines with phenyl-
hydrazine for the synthesis of phenyl-2H-pyrazolo[3,4-b][1,5]ben-
zothiazepine 382 as a general method for the construction of the
condensed pyrazolo-1,4-thiazepine ring (Scheme 100) [439]. Shi
et al. reported a one-pot 3-CRs of 5-amino-3-methylpyrazole 383,
isatin 384 and thioacid 385 through 3-(5-aminopyrazol-3-yl)-3-
hydroxy-2-oxindoline intermediate (Baylis-Hillman type adduct)
for the synthesis of spiro[indoline-3,4-pyrazolo[3,4-e][1,4]thiaze-
pine] dione derivatives 386 in high yields (Scheme 101) [440].
Scheme 98. Synthesis of pyrazolodibenzo[1,4]diazepines through Pd-catalyzed
reaction.
334 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 99. Synthesis of chiral ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-ones.
Scheme 100. Synthesis of phenyl-2H-pyrazolo[3,4-b][1,5]benzothiazepines.
Scheme 101. Synthesis of spiro[indoline-3,4-pyrazolo[3,4-e][1,4]thiazepine] dione
derivatives.
4.3. Pyrazolo-1,4-oxazepines
1,4-Oxazepine unit is an important moiety for psychoactive
pharmaceuticals, for example Oxazepam, a drug which is a short-
to-intermediate-acting 3-hydroxy benzodiazepine derivative. In
addition, aryl-fused 1,4-oxazepines have been described as potent
non-peptidergic GPCR inhibitors, squalene synthase inhibitors,
reverse transcriptase inhibitors, and integrin antagonists [441]. In
2013, Liu et al. reported the synthesis of a series of pyrazolo[1,5-d]
[1,4]oxazepin-8(7H)-one derivatives 391 as telomerase inhibitors
[442]. The products were prepared in general way (Scheme 102).
4.4. Other [5, 7]-condensed pyrazole derivatives
Other kinds of [5, 7]-condensed pyrazole derivatives have also
been reported. In 2011, Sackus et al. reported the construction of a
Scheme 102. Synthesis of pyrazolo[1,5-d][1,4]oxazepin-8(7H)-ones.
Scheme 103. Synthesis of 5-chloro-8H-dibenzo[c,f]pyrazolo[1,5-a]azepin-8-ones.
tetracyclic system, 5-chloro-8H-dibenzo[c,f]pyrazolo[1,5-a]azepin-
8-ones 394 from 5-(3-chlorophenyl)-1-phenyl-1H-pyrazole-4-
carboxylic acid under the catalyzation of TfOH in 85% yield
(Scheme 103) [443]. The proposed reaction mechanism might
involve the COOH transfer from pyrazolo ring to chlorophenyl ring
via ring closing/opening process followed by condensation with the
N-phenyl ring.
In 2012, Zhao et al. reported the synthesis of pyrazolo[5,1-d]
[1,2,5]triazepin-4-ones 396 from pyrazolo[5,1-c][1,4]oxazin-4-one
395 via a facile ring-enlargement reaction in refluxing BuOH
(Scheme 104) [444].
In 2012, Prasad et al. reported the synthesis of pyr-
azolocycloheptaindoles 399 from the condensation of substituted
7-(hydroxymethylene)-7,8,9,10-tetrahydrocycloheptaindol-6(5H)-
ones 398 with phenylhydrazine (Scheme 105) [445]. The primary
pharmacological property evaluation indicates that the compounds
substituted with chloride exhibit antitubercular activity and the
bioavailability and initial toxicity test of the compounds permit
further testing as potential drug candidates.
5. Conclusion
In conclusion, we have summarized the reported synthetic
methods of various condensed pyrazole derivatives including [5, 5],
[5, 6], and [5, 7]-condensed pyrazole derivatives and introduced
their multiplicate biological activities and applications in pharma-
ceutical fields briefly. People have paid much attention to the
synthesis of [5, 5] or [5, 6]-condensed pyrazole derivatives, yet little
attention has been paid to [5, 7]-condensed pyrazole derivatives or
other macrocyclic condensed pyrazole derivatives and polycyclic
condensed pyrazole derivatives which might be due to their poor
stability. With the development of organic synthesis chemistry,
various atom economy and eco-friendly methods have been
applied, such as multicomponent reactions and the utilization of
environment benign solvents, such as ionic liquids and water. Also,
the technology of microwave assisted or ultrasound irradiation
remarkably improves the reaction yields and shortens the reaction
time which may provide abundant compounds for high throughput
screening of drugs with satisfactory biological activities. The ap-
plications and advantages of microwave assisted synthesis of het-
erocyclic compounds have been summarized by Kumar V.
Srinivasan et al. [446]. Due to the excellent performance in phar-
maceutical and agromedical fields of condensed pyrazole
Scheme 104. Synthesis of pyrazolo[5,1-d][1,2,5]triazepin-4-ones.
 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340
Scheme 105. Synthesis of pyrazolocycloheptaindoles.
derivatives and the rapidly growing needs for medicines, the design
and synthesis of condensed pyrazoles with structural diversity
would be welcome.
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