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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


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
Condensed pyrazole derivatives
for the design and synthesis of condensed pyrazole derivatives with good biological activities.
Synthesis © 2014 Elsevier Masson SAS. All rights reserved.

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

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

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

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
Fig. 1. Examples of several pharmaceutical drugs containing pyrazole core. 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.
Fig. 2. Structures of compounds containing pyrrolopyrazole core.
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


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


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].

[1,5-a]indole core in which a nitrogen atom should be connected to
2.2. Pyrazoloindoles the benzene ring from the starting material usually require harsh
reaction conditions and probably give poor yields. Zhu et al.
Katayama et al. first reported that some pyrazolo[1,5-a]indole developed an efficient synthetic method via tandem Cu (I)-cata-
derivatives have fairly powerful inhibitory activity against DNA lyzed cyclization/condensation reaction of 1,3-diketones 5 to form
topoisomerases I and II, and have potent cytotoxic activity against the pyrazolo[1,5-a]indole framework with high yields (Scheme 2)
cancer cells [26]. Common methods for the synthesis of pyrazolo [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 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-
Scheme 10. Synthesis of functionalized pyrazolo[1,2-a]pyrazolones. 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
1,4-dioxane was stirred at 100  C for 1 h. Then, with the presence of
activity of pyrazolo[5,1-a]isoindole derivatives [33]. Multiple stra-
CuI, 1,10-phenanthroline (PHAN) as ligand, K2CO3 as base in anhy-
tegies have been developed for the synthesis of pyrazolo[5,1-a]
drous 1,4-dioxane, the mixture was refluxed at 110  C for 20 h to
isoindoles including the reactions of iminophosphoranes with
yield the final products 7. According to the author, pyrazolo[1,5-a]
acetylenic compounds [34], the intromolecular Wittig reaction of
quinoline can also be prepared through this method.
phosphorus ylides [35], the condensation of phthalaldehydeic acid
As the strong biological activities of pyrazole derivatives and the
and acetophenones followed by the reaction with hydrazine hy-
discovery of cytotoxic properties in some carbazole or azacarbazole
drates [36]. Other methods with the use of metal catalyst or specific
derivatives [29], it was considered of interest to synthesize some
substrates have also been applied for the synthesis of these
examples of pyrazolo-condensed carbazole or azacarbazole de-
rivatives. Singh et al. developed an efficient methodology for the
Heo et al. established a one-step synthesis of pyrazolo[5,1-a]
synthesis of condensed pyrazole oxocarbazoles and oxoazacarba-
isoindoles 17 through Pd-catalyzed intramolecular CeH bond
zoles under the conditions of JappeKlingemann reaction, followed
activation with the presence of PivOH (30 mol%), LiCl (none or
by the Fischer indolization with Kent's acid (HCl:AcOH, 1:4, v/v)
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,
Scheme 11. Synthesis of pyrazolo[5,1-b]thiazoles. 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

Fig. 4. Structures of compounds A02011-1 and E2508. 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)

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 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-
Scheme 34. Synthesis of pyrazolo[4,3-d]pyrimidines via iminophosphorane-mediated
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)
biological activities. For instance, thieno[3,2-c]pyrazoles have been was employed as oxidizing agent for the aromatization of the in-
demonstrated as potent kinase inhibitors [73,74]. A thieno[3,2-c] termediates. The regioisomeric ratio is influenced by the X moiety
pyrazole derivative A02011-1 (Fig. 4) has been shown to be a potent and by the nature of nitrile imines and 5-acyl pyrazole derivative
adenyl cyclase activator exhibiting an antiproliferative activities in has been found as the major product when X ¼ S and the ratio is up
rat vascular smooth muscle cells [75]. to 99:1.
The general methods for the synthesis of thieno[3,2-b]pyrazoles Abaszadeh et al. developed a convenient and straightforward
include the construction of a thiophene ring on vicinally synthesis of pyrazolo[1,2-a]pyrazole-triones 55 or 56 through the
substituted 2-formyl-3-thiomethylenethiophene derivatives condensation of (chlorocarbonyl)phenyl ketene 54 with 5-
through base-induced intramolecular cyclocondensation [76e78]. alkylpyrazol-3(4H)-ones 53 by intramolecular hydrogen exchange
Ila et al. developed an efficient, high yielding synthetic method in unstable mesoionic pyrazolo[1,2-a]pyrazol-4-ium-5-olates
through a radical cyclization process involving intramolecular (Scheme 16) [86]. In contrast, when (chlorocarbonyl)phenyl
addition of a carbon-centered radical to a neighboring sulfide as the ketene reacts with N-substituted pyrazolones in dry THF at ambient
key step for the synthesis of tetrasubstituted thieno[3,2-c]pyrazoles temperature, 4-hydroxypyrano[2,3-c]pyrazol-6-ones 58 were the
43 (Scheme 12) starting from acrylonitrile precursors 42 [79]. only products which might be attributed to the tautomerism of N-
substituted pyrazolones (Scheme 17).
2.8. Furo[2,3-c]pyrazoles

Furo[2,3-c]pyrazoles are important structural units of pigments 3. [5, 6]-condensed pyrazole derivatives
and dyes, such as cyanine dyes [80], and they possess strong bio-
logical activities such as antibacterial [81] and antifungal [82] ac- 3.1. Pyrazolo-pyridines
tivities. Zhang et al. developed two different methods for the
preparation of CF3-substituted furo[2,3-c]pyrazoles 46 through Pyrazolopyridines are one of the most often studied heterocyclic
[3 þ 2] cycloaddition of diazocarbonyl compounds 44 with alkynes compounds due to their excellent and wide spectrum of biological
45 or 47 under two different conditions: use Rh2(OAc)2 as catalyst activities. Numerable pharmaceutical activities have been reported,
in toluene under refluxing [83] (Scheme 13) and heat at 160  C in such as potent cyclin dependent kinase 1 (CDK1) inhibitors [87,88],
1,2-dichlorobenzene without catalyst (Scheme 14) [84]. HIV reverse transcriptase inhibitors [89], phosphodiesterase 3/4
(PDE3/4) inhibitors [90e93], A1 adenosine receptor antagonists

Scheme 35. Synthesis of pyrazolo[4,3-d]pyrimidines 128. 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 319

Scheme 38. Synthesis of pyrazolo[3,4-b]quinolines as TPSO ligands.

[94], dual Nox4/Nox1 inhibitors [95], p110a-selective PI3 kinase intramolecular electrophilic aromatic cyclization in allylamines
inhibitors [96,97], corticotropin-releasing factor 1 (CRF1) antago- for the synthesis of pyrazolo[3,4-b]pyridines [119,120].
nists [98], Acetyl-CoA carboxylase (ACC) inhibitors [99], B-Raf ki- Pyrazolo[1,5-a]pyridines, especially substituted in 2-position,
nase (B-RafV600E) inhibitors [100], guanylate cyclase stimulators have also been identified with various pharmaceutical activities,
[101] and some derivatives are identified with potential antibac- such as the most well-known dopamine D3 agonists and antago-
terial activity [102], antitumor and antimicrobial activities [103], nists [121e123], adenosine A1 receptor antagonist [124,125],
antimalarial [104] and antiviral activities [105]. phosphodiesterase 3/4 (PDE3/4) inhibitors [90,92], and PI3 kinase
Pyrazolo[3,4-b]pyridines, as one class of pyrazolopyridines, are inhibitors [96,97]. Takahashi et al. reported the synthesis of 3-
useful for the treatment of various stressed illness, such as Alz- dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines as selective
heimer's disease, anorexia nervosa, drug and alcohol withdrawal corticotropin-releasing factor 1 (CRF1) receptor antagonists and
symptoms, drug addiction and fertility [106]. They also exhibit one of them, E2508 (Fig. 4) has advanced into clinical trials in the
other important biological activities, such as psychotropic [107], treatment of stress-related disorders such as depression and anx-
cytotoxic [108], antifungal and antichagasic [109] activities. General iety [98].
methods for the synthesis of pyrazolo[3,4-b]pyridines include The most general method for the synthesis of pyrazolo[1,5-a]
cycloaddition of 5-aminopyrazole with substituted a,b-unsaturated pyridines involves a [3 þ 2] cycloaddition of dipolarophiles bearing
nitriles utilizing base as catalysts, or cycloaddition of 2- electron-withdrawing groups with N-aminopyridinium salt. And
aminonicotinonitriles with hydrazines [110]. Based on these various intramolecular cyclizations have also been employed for
methods, multi-component reactions (MCRs) have been developed the preparation of 2-substituted pyrazolo[1,5-a]pyridines from
from 5-aminopyrazole, alkyl/aryl aldehydes and diketones or b-CN pyridine derivatives [126e132]. For example, Charette et al. re-
carbonyl compounds under various conditions, such as eco-friendly ported the synthesis of 2-substituted pyrazolo[1,5-a]pyridines 68
solvents, ionic liquid and water, and techniques, such as ultrasound via cascade direct Pd-catalyzed alkenylation/Ag-mediated cycliza-
irradiation and microwave irradiation [111e118]. For example, tion from N-iminopyridium ylides 66 and alkenyl iodides 67
Mamaghani et al. reported a 3-component regioselective reaction (Scheme 20) [131]. Then in 2011, they reported a tandem Pd-
of 5-amino-3-methyl-1H-pyrazole 59, 2H-indene-1,3-dione 60 and catalyzed/Ag-mediated elimination/direct functionalization/cycli-
arylaldehydes in ethanol under ultrasound irradiation within zation from pyridine which expanded the scope of substrates and
4e5 min to give compounds 61 in high yields (Scheme 18) [118]. enabled a wide range of groups installed onto the heterocyclic core
Khavasi et al. reported a 3-component condensation reaction of [130]. Collins et al. reported the synthesis of 3-pyrazinyl-pyrazolo
isatin 64, aminopyrazole 63 and alkyl cyanoacetate 62 under the [1,5-a]pyridines 71 from 4-substituted 1-aminopyridinim iodides
catalysis of Et3N in water giving spiro[indoline-3,40 -pyrazolo[3,4-b] 70 and enol ether 69 (Scheme 21) [128].
pyridine-50 -carbonitriles 65 in good yields (Scheme 19) [113]. Other methods also have been applied to the preparation of
Other catalysts have also been used for the construction of pyrazolo[1,5-a]pyridines, such as thermal cyclization of pyridinyl
pyrazolo[3,4-b]pyridine core. For example, Batra et al. reported aziridines and cyclization of enediynes [127,133]. For example, Wu
copper-mediated intramolecular amination and iodine-mediated 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 39. Synthesis of pyrazolo[3,4-b]quinolines via water-mediated reaction.

Scheme 40. Synthesis of pyrazolo-spirooxindoles in water. 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 amines 87 and aldehydes 88 in the presence of Zn(OTf)2 and fol-
streamlined 10-step synthesis [99]. The construction of the pyr- lowed by H2O2-mediated oxidation for the preparation of pyrano
azolo[3,4-c]pyridine core was realized from the tert-butyl 4-((5- [3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones (Scheme 26) [145].
isocyanatopiperidine-1-carboxylate in the presence of tert-butyl- 3.2. Pyrazolopyrimidines
lithium at 78  C. Conventional methods for pyrazolo[3,4-c]pyri-
dine core involve either pyridine ring closure to an appropriately Pyrazolopyrimidines have attracted considerable attentions
functionalized pyrazolo derivatives or inversely, and have been over decades due to their good biological activities and three most
summarized by Holzer et al. in 2011 [139]. They also developed common structural analogs, pyrazolo[1,5-a]pyrimidines, pyrazolo
Sonogashira type cross-coupling reactions from 5-chloro-1- [3,4-d]pyrimidines and pyrazolo[4,3-d]pyrimidines, all exhibit
phenyl-1H-pyrazole-4-carbaldehydes 75 with alkynes, followed important biological activities. Pyrazolo[1,5-a]pyrimidines have
by intramolecular cyclization in the presence of tert-butylamine been found as purine analogs and have useful properties as anti-
under microwave irradiation affording 1-phenylpyrazolo[4,3-c] metabolites in purine biochemical reactions. They have already
pyridines 77 (Scheme 23). The intramolecular cyclization of oximes been identified with various other biological activities, such as
79 derived from 5-chloro-1-phenyl-1H-pyrazole-4-carbaldehydes HMF-CoA reductase inhibitors [146], COX-2 selective inhibitors
75 was also accessed in the presence of AgOTf (Scheme 24). [147], phosphodiesterase 4 (PDE4) inhibitors [148], 5-HT6 receptor
In 2012, Rostamizadeh et al. reported a magnetically recoverable antagonists [149,150], CRF1 antagonists [151,152], translocator
nanocatalyst, (a-Fe2O3)-MCM-41 for the synthesis of pyrazolo[4,3- protein (TSPO) ligands [153,154], dipeptidyl peptidase IV (DPP-IV)
c]pyridines from pyridine a,b-unsaturated ketones with hydrazine inhibitors [155], neuropeptide Y1 receptor antagonists [156],
hydrates at room temperature [140]. No significant decrease in Aurora-A kinase inhibitors [157], Checkpoint kinase 1 (CHK1) in-
activity was observed even after 5 runs. hibitors [158,159], Matrix metalloproteinase 13 (MMP-13) in-
Other important pyrazolopyridines come to pyrazolo[4,3-e] hibitors [160], B-RafV600E kinase inhibitors [161], mitogen-activated
pyridines which have been identified as anti-inflammatory protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors
[141,142], antibacterial agents [143]. Limited literatures reported [162], and Janus kinase 2 (Jak2) inhibitors [163]. Several methods
the preparation of these kind of compounds. In 2012, Mohammad have been established for the synthesis of pyrazolo[1,5-a]pyrimi-
et al. reported the regioselective synthesis of fused azo-linked dines and most of them involve the [3 þ 2] cyclization between 5-
pyrazolo[4,3-e]pyridines 84 or 85 via 3-component reactions (3- amino-1H-pyrazoles and 1,3-bis-electrophilic reagents, such as b-
CR) of 3-amino-5-methylpyrazole 83, indan-1,3-dione 82 and dicarbonyl, a,b-unsaturated carbonyl, alkoxymethylene-b-dicar-
azo-linked aldehydes 81 under the catalyzation of reusable nano- bonyl, b-enaminone compounds and benzylidenemalononitriles
Fe3O4 in high yields (Scheme 25) [144]. The structures of the [164e169]. For example, Portilla et al. reported the regioselective
products were influenced by the nature of substrates, when azo- synthesis pyrazolo[1,5-a]pyrimidines by the reaction of 5-amino-
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 45. Synthesis of H-pyrazolo[5,1-a]isoquinolines via AgOTf with co-catalyst,

dioxygen-copper system catalyzed reaction.
Scheme 43. Synthesis of pyrazolo[4,3-f]quinolines.

Scheme 44. Synthesis of H-pyrazolo[5,1-a]isoquinolines via AgOTf 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 321

Scheme 47. Synthesis of H-pyrazolo[5,1-a]isoquinolines from bromo-substituted

substrates. Scheme 50. Synthesis of pyrano[2,3-c]pyrazoles through DKHDA reaction.

Scheme 48. Synthesis of H-pyrazolo[5,1-a]isoquinolines via tandem 1,3-dipolar

cycloaddition/oxidative aromatization. Scheme 51. Synthesis of pyrano[2,3-c]pyrazoles via 3-CR.

1H-pyrazoles 90 and b-dicarbonyl compounds under fusion or Traditional methods for the synthesis of pyrazolo[3,4-d]pyrim-
microwave irradiation conditions (Scheme 27) [170]. And Mokhtar idines involve two steps from 5-amino-N-substituted-1H-pyrazole-
et al. reported an efficient catalysts, MgeAl hydrotalcites for aza- 4-carbonitrile with esters or acyl chlorides, which need vigorous
Micheal addition of aminopyrazoles to enaminone derivatives conditions and have low yields [197]. Zhong et al. developed a
without solvent under microwave irradiation for the preparation of POCl3-catalyzed reactions of 5-amino-N-substituted-1H-pyrazole-
pyrazolo[1,5-a]pyrimidines [171]. 4-carbonitrile 105 with various lower aliphatic acids to give pyr-
Multi-component reactions have also been applied for the azolo[3,4-d]pyrimidines 106 in good yields (Scheme 30) [198]. And
synthesis of pyrazolo[1,5-a]pyrimidines. Rahmati et al. reported the Capretta et al. reported a microwave-assisted synthesis of N1- and
synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6- C3-substituted pyrazolo[3,4-d]pyrimidines from 5-amino-1H-pyr-
carbonitrile 100 via 3-CR of aldehydes 98, aminomethylpyrazoles azole-4-carbonitrile and formamide within 30 min [199].
97 and malononitrile 99 under refluxing conditions without any Vilsmeier-type reagents have also been employed for the syn-
catalyst (Scheme 28) for the first time [172]. And then, Pal et al. thesis of pyrazolo[3,4-d]pyrimidines. Wong et al. developed a
reported a 3-CR of aromatic aldehydes 102, terminal alkynes 103 synthetic route from 5-amino-pyrazoles 107 or pyr-
and 5-amino-1H-pyrazolo-4-carboxylate 101 catalyzed by azolylimidoformamides 109 with various halomethylenimium
CF3COOH in acetic acid in the presence of aerial oxygen (Scheme salts, as Vilsmeier agents synthesized from formamide with POCl3
29) affording pyrazolo[1,5-a]pyrimidines 104 as potential PDE4 or PBr3, via amidination reaction followed by heterocyclization to
inhibitors [173]. form the pyrazolo[3,4-d]pyrimidines 108 or 110 (Scheme 31)
Pyrazolo[3,4-d]pyrimidines, as another structural analogs of [200,201].
pyrazolopyrimidines have been identified with good biological Other methods have also been applied for the preparation of
activities, such as cyclooxygenase-2 (COX-2) inhibitors [174], ATP- pyrazolo[3,4-d]pyrimidines. Ryabukhin et al. reported the
competitive inhibitors [175], phosphatidylinositol-3-kinases condensation of 5-heterylaminnopyrazoles 113 with carbonyl
(PI3K) inhibitors [176,177], insulin-like growth factor-1 receptor compounds facilitated by AcOH or Me3SiCl furnished pyrazolo[3,4-
(IGF1R) inhibitors [178], p38a kinase inhibitors [179], tyrosine ki- d]dihydropyrimidines 114 in good yields (Scheme 32) [202]. The
nase c-Src inhibitors [180], dual Src/Abl inhibitors [181], dual in- reaction was proposed to undergo two steps: 5-aminopyrazoles 111
hibitors of Aurora kinases and CDK1 [182], anti-inflammatory react with 2-halogenazines or azoles 112 under NaH/THF condi-
activity [183], RET protein kinase inhibitors [184], PDE9A inhibitor tions followed by cyclization with carbonyl compounds mediated
[185,186], anti-tubercular activities [187], casein kinase 1 (CK1) by Me3SiCl or AcOH.
inhibitors [188], antiamoebic activity [189], antimicrobial activity Multi-component reactions have also been developed. Baltork
[190e192], and anti-tumor activities [193e196]. et al. reported a regioselective multi-component synthesis of 1H-

Scheme 49. Synthesis of 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles. Scheme 52. Asymmetric synthesis of tetrahydropyrano[2,3-c]pyrazoles.

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

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
Scheme 53. Four-component syntheses of pyranopyrazoles catalyzed by base
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].
Scheme 54. Synthesis of pyrano[2,3-c]pyrazoles via catalyst-free atom-economical 4- To date, diverse classes of polyheterocyclic compounds have
CRs. 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
pyrazolo[3,4-d]pyrimidine-6(7H)-thiones 118 via 3-component
[217,218]. Among these derivatives, pyrazolo-triazolo-pyrimidines
reaction of 5-methyl-1H-pyrazol-3-amine 116, arylisothiocyanates
(PTPs), especially pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines
115 and aldehydes 117 in the presence of p-TSA in ionic liquid
have been identified as highly potent and selective human A2A and
[Bmim]Br at 100  C with excellent yields (Scheme 33) [203].
A3 adenosine receptor antagonists [219e227] and the most potent
Another kind of important pyrazolopyrimidines comes to pyr-
hA3 antagonist known to date is MRE-3005-F20 [222]. In 2012,
azolo[4,3-d]pyrimidines which have been identified with recog-
Moro et al. reported the synthesis of a series of 5-
nized pharmacological activities for the treatment of
alkylaminopyrazolo-[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines 135
thromboembolic disorders [204] and bronchoconstriction and
from the well-known triazolylpyrazolamino derivative 132 and the
cardiac insufficiency [205]. Some have also been reported as Hsp90
construction of the tricircle system was realized in two steps with a
inhibitors [206], potential anti-cancer agents [207], phosphodies-
general method (Scheme 37) [219].
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 3.3. Pyrazoloquinolines
widely applicable route is the cyclization of 4-substituted-amido-
1H-pyrazole-3-carboxamide under base conditions [212]. Wu et al. Quinoline ring is a prominent moiety in numerous naturally
developed an iminophosphorane-mediated annulation, followed occurring compounds possessing excellent biological activities,
by an intermolecular nucleophilic addition with amines or phenols/ such as quinine, a well known antiptritic, antimalarial, analgesic

Scheme 55. Synthesis of 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines.

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-


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
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.

Scheme 64. Synthesis of indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-ones.

mediated heterogeneous reactions would be that the unbound

inhibitor [242] and anti-HIV activity [243], and synthetic com-
hydroxyl groups in water interact with organic reactants and the
pounds possessing a broad spectrum of pharmacological activities,
transition states, which would lower the activation energies, enable
such as antifungal, antimalarial, antihypertensive, antitumor and
reaction rates and enhance yields.
antihistaminic activities [244,245]. Furthermore, H-pyrazolo[5,1-a]
Tu et al. established a three-component domino reaction from
isoquinoline core which combined both isoquinoline and pyrazolo
aldehydes 152, 2-hydroxynaphthalene-1,4-dione 151 and 5-amino-
[1,5-a]pyridine skeletons exhibit notable biological activities for the
3-methylpyrazole 153 with HOAc as catalyst under microwave
inhibition of CDC25B, TC-PTP and PTP1B leading to the great de-
irradiation to afford benzopyrazolo[3,4-b]quinolines 154 with high
mand for more diverse H-pyrazolo[5,1-a]isoquinolines [246].
regioselectivity and a broad substrates scope (Scheme 42) [236].
The general synthetic methodology of H-pyrazolo[5,1-a]iso-
The generated o-diketone unit would serve as important building
quinolines has been developed by Wu et al. starting from 2-
blocks for further reactions with nucleophilic agents, such as o-
alkynylbenzaldehyde or N0 -(2-alkynylbenzylidene)hydrazide with
various catalysts. Silver triflate (AgOTf) is the most common cata-
Pyrazolo[4,3-f]quinolines are another important pyr-
lyst employed in these reactions which promotes the 6-endo
azoloquinolines possessing significant biological activities, such as
cyclization to form the isoquinolinium-2-yl amide intermediates. If
antibacterial [237] and antiviral activities [238]. Tu et al. reported a
substrates permitted, inter/intramolecular nucleophilic addition or
general synthetic route for pyrazolo[4,3-f]quinolines 159 from ar-
[3 þ 2] cycloaddition would take place and followed by aromati-
omatic aldehydes 157, 5-aminoindazole 156, and various cyclic 1,3-
zation to complete the reaction for H-pyrazolo[5,1-a]isoquinolines
dicarbonyl compounds 158 under microwave irradiation in high
164 (Scheme 44) [246e250]. Yet, if conditions were not satisfied for
yields (Scheme 43) [239,240].
the subsequent reactions, co-catalysts would be needed. CuI and
Another important type of pyrazoloquinolines is the pyrazolo
CuBr were employed via CeH activation mechanism by oxidative
[4,3-c]quinoline ring system. As a review by Ramadan A.
addition and reductive elimination to realize the reaction
Mekheimer published in 2012 [241] is describing this system in
[251,252]; dioxygen-copper systems were also employed to active
detail, so we did not undertook this in the present review.
the CeH bond via oxidation to accomplish the reactions (Scheme
45) [253,254]; PPh3 as Lewis base to facilitate allenoates [255],
3.4. Pyrazolo[5,1-a]isoquinolines
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
Isoquinoline nucleus is identified to be one of the most abun-
employed to promote the reaction. Further investigation revealed
dant structural motifs in numerous naturally occurring alkaloids,
that the 6-endo cyclization could also be promoted by Br2 or I2 to
which exhibit strong biological activities such as topoisomerase I
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)
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

Scheme 63. Synthesis of several series of 2-hydroxypyrazolo[5,1-b][1,3]oxazine-7- with rich bioactivity profile, such as antibacterial [261], anti-
ones. inflammatory [262], and molluscicidal activities [263], and have
M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 325

Scheme 65. Synthesis of pyrazolo[3,4-b]pyrazines through MW-assisted


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 Scheme 67. Synthesis of several series of pyrazolo[1,5-a]pyrazin-4(5H)-ones.
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 malononitrile by the tertiary moiety, as well as activating the
substrates, three-component synthetic reactions and four- carbonyl group of 4-aryliden-5-pyrazolnes, the reaction products of
component synthetic reactions. 184 and 185, by hydrogen bonds with the N-Hs.
Appropriate catalysts and substrates are crucial for the simple In 2012, Ender et al. reported an efficient organocatalytic one-
reactions with two substrates. Zhao et al. reported an enantiose- pot asymmetric synthesis of 4H,5H-pyrano[2,3-c]pyrazoles 190
lective tandem Michael additionecyclization reaction from 3- from crotonaldehyde 187, 3-trifluoro-N-substituted-pyrazolone
methyl-2-pyrazolin-5-one 177 and benzylidenemalononitriles 178 188 and Wittig reagent 189 via Michael/Wittig/oxa-Michael reac-
with modularly designed organocatalysts (MDOs) as catalyst to tion sequence in very good yields and enantioselectivities (Scheme
yield 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles 179 in high 52) [271]. This is the first asymmetric synthesis of a tetrahy-
yields and moderate to good enantioselectivities (Scheme 49) dropyrano[2,3-c]pyrazoles.
[266]. The MDO performed as a Lewis base catalyst and the struc- Four-component syntheses pyranopyrazoles using ethyl ace-
ture is shown. toacetate, hydrazine hydrate, aldehydes or ketones and malononi-
Parmar et al. reported a tetrabutylammonium hydrogen sulfate trile have been reported in the presence of base catalysts such as b-
(TBA-HS) mediated procedure to afford benzopyran-annulated cyclodextrin [272], triethylamine [273], cinchona alkaloid de-
pyrano[2,3-c]pyrazoles 183 through domino/Knoevenagel-hetero- rivatives [274], and imidazole (Scheme 53) [275]. Recently, various
Diels-Alder (DKHDA) reaction from substituted salicylaldehydes catalysts and conditions have also been employed to realize this
180 and 5-pyrazolones 181 (Scheme 50) [267]. transformation, such as catalyzed by piperidine under ultrasound
As for three-component reactions, Rani et al. [268] and Azarifar irradiation condition [276], catalyzed by biocatalyst, lipase from
et al. [269] reported the synthesis of pyrano[2,3-c]pyrazoles 186 Aspergillus niger (ANL) in ethanol at 30  C [277].
from substituted pyrazolone 184, malononitrile and aryl/alkyl al- In 2012, Zonouz et al. reported a catalyst-free atom-economical
dehydes 185 catalyzed with 1,8-diazabicyclo[5.4.0]undec-7-ene 4-CRs of aldehyde, malononitrile, hydrazine hydrate and dimethyl
(DBU) and recyclable magnetic La0.7Sr0.3MnO3 nanoparticles, acetylenedicarboxylate 195 in water for the synthesis of pyrano
respectively (Scheme 51). The former reaction was carried out [2,3-c]pyrazoles 196 in good yields (Scheme 54) [278].
under solvent-free conditions within 5 min in good yields and the
latter was confirmed with better generality. Based on this reaction,
3.6. Pyrazolotriazines
Zhao et al. developed an enantioselective synthesis of chiral fluo-
rinated dihydropyrano[2,3-c]pyrazoles with diaminocyclohexane-
The biological activities of pyrazolotriazines have been carefully
thiourea as catalyst in high yields (up to 98%) [270]. The bifunc-
studied since these moieties are bioisosteric with purine, a mo-
tional thiourea catalyst performs as a base to deprotonate the
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 66. Synthesis of pyrazolo[1,5-a]pyrazines. 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 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
Scheme 69. Synthesis of pyrazolo[3,4-d]pyridazines from hydrazonoyl halides.
kind of reactions and obtained lower yields of desired products.
Pyrazolo[5,1-c][1,2,4]triazines have also been prepared for their
which are potential therapeutic agents for inflammatory disease potential biological activity investigation and some displayed
[280]. Furthermore, a well-known CRF1 receptor antagonist, Pex- antimicrobial activities [290]. In addition, Guerrini et al. reported a
acerfont has been tested as potential agent for the control and pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide system as a GABAA re-
treatment of some disease related to stress such as anxiety and ceptor ligand with selective anxiolytic-like effects and might be
depression [281]. In 2012, Insuaaty et al. reported three practical novel subtype as new agents for pain relief [291e293]. In 2011,
methods for the synthesis of 4,7-dihetarylpyrazolo[1,5-a][1,3,5] Cankar et al. established an efficient approach for the synthesis of
triazines 200/205 starting from isothiocyanates 201 with 5-amino- pyrazolo[5,1-c][1,2,4]triazines 216 through thermal cyclization of
3-furyl-1H-pyrazoles 202 under conventional heating conditions in 1H-pyrazol-5-yl hydrazones 215 in boiling ethanol (Scheme 58)
DMF giving moderate to good yields (59e71%); starting from S,S- [294]. Further investigation of the reaction revealed that the reac-
diethyl hetaroylimidodithiocarbonates 197 with 5-amino-3-furyl- tion was directed by both the substitution of the pyrazole ring and
1H-pyrazoles 198 in the absence of solvent employing microwave the cyclization medium. Nader et al. reported a two-step ionic-
irradiation gave an overall yields in 75e84%; reactions performed mechanism involving initial nucleophilic addition followed by
in two steps, first under microwave irradiation and second under cyclization reaction from 3-diazo-5-methyl-4-phenyl-1H-pyrazole
conventional heating conditions in DMF gave overall yields in 217 with [11C]lithium trimethylsilylynolate 218 for the synthesis of
68e78% (Scheme 55) [282]. The microwave-assisted reactions 7-methyl-8-phenyl-3-trimethylsilylpyrazolo[5,1-c][1,2,4]triazine-
seem to be more efficient. (1H)-4-one 220 (Scheme 59) [295].
Pyrazolo[4,3-e][1,2,4]triazines have been less studied in com-
parison with other pyrazolotriazines, yet some of naturally pro- 3.7. Pyrazoleoxazines
duced pyrazolo[4,3-e][1,2,4]triazines exhibit anticancer and
antibacterial activities [283] and some synthesized compounds Compounds containing oxazines have been widely studied due
have been described as moderate purine nucleoside phosphorylase to their remarkable biological activities against different diseases.
inhibitors [284], and CDKs inhibitors which may be considered as An imidazo[2,1-b][1,3]oxazine derivative, PA-824 (Fig. 5) has been
new scaffold for the development of antiproliferative agents [285]. demonstrated to have a novel mechanism against Mycobacterium
Al-Matar et al. developed an efficient route for the synthesis of tuberculosis and Helicobacter pylori, comparable with isoniazid
pyrazolo[3,4-e][1,2,4]triazines 209 from arylhydrazonomalononi- [296,297] and analogs have also been synthesized with excellent
triles 206 as starting materials (Scheme 56) [286]. The starting activities against M. tuberculosis [298]. Since the discovery of tri-
material is also versatile for the synthesis of a new ring system, fluoromethyl-1,3-oxazin-2-one (Fig. 5) [299], known as Efavirenz, a
[1,2,4]triazino[5,6-d][1,2,3]triazines. non-nucleoside reverse-transcriptase inhibitor and selective anti-
Pyrazolo[3,4-d][1,2,3]triazines have also been identified as HIV drug, much attention has been paid on the synthesis of ben-
important heterocyclic compounds because of their various bio- zooxazines and anologues. Though only a few literature reported
logical activities, such as anticonvulsant [287], antifungal, antiviral the biological activities of pyrazolecondensed 1,3-oxazines, many
and anticancer activities [288]. In 2011, Moyano et al. established an synthetic methods have been established. For example, an anti-
efficient one-pot diazotization of 5-amino-1H-pyrazole-4- microbial agent 5-amino-2-methyl-pyrazolo[5,1-b][1,3]oxazine-7-
carbonitriles 210 for the synthesis of pyrazolo[3,4-d][1,2,3]triazin- one was prepared with ethyl acetate and cyanoacetohydrazide as
4-ones 211 in good to very good yields (Scheme 57) [289]. The starting materials [300].

Scheme 70. Synthesis of pyrazolo[1,2-a]pyridazines via 3-CR. 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.
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
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-
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.

Scheme 78. Synthesis of pyrazolo[3,4-g]quinoxalines.

3.9. Pyrazolopyridazines
3.10. Pyrazolo[3,4-c][1,2]benzothiazines
Pyrazolopyridazines are reported as important organic com-
pounds because of their wide application in pharmaceuticals and Benzothiazines are known as potential biological agents, for
agrochemicals. For example, several pyrazolo[3,4-d]pyridazines example, 1,2-benzothiazine-3-carboxamide 1,1-dioxide derivatives
exhibit antifungal [323] and antibacterial activities [324], and some (Meloxicam and Piroxicam) are famous as analgesic and anti-
pyrazolo[1,2-a]pyridazine-5,8-diones were reported as anti- inflammatory agents (Fig. 6). Furthermore, benzothiazines are re-
inflammatory, analgesic, anti-hypoxic and anti-pyretic agents ported as potent calpain I inhibitors [334] and antifungal agents
[325]. Due to their potential biological activities, various pyr- against Bacillus subtilis [335]. They have also been reported as po-
azolopyridazines have been designed and synthesized. tential antibacterial and anti-oxidants agents [336]. In recent years,
Pyrazolo[3,4-d]pyridazines were usually constructed from pyrazolo[3,4-c][1,2]benzothiazines have also been synthesized
cyclization of 4-aroyl/acyl-1H-pyrazole-3-carboxylic acid or -acid with important biological activities, such as anti-oxidants, anti-
chloride 260 with 2-hydroxyethyl hydrazine (Scheme 68) [326]. bacterial and antitumor [337e339].
Giovannoni et al. reported the synthesis of pyrazolo[3,4-d]pyr- Siddiiqui et al. reported the synthesis of a series of potential
idazinones as potential phosphodiesterase 4 (PDE4) inhibitors, anti-oxidant and anti-bacterial N0 -arylmethylidene-2-(3,4-
which are widely applied in therapeutic treatment of inflammatory dimethyl-5,5-dioxidopyrazolo[3,4-c][1,2]benzothiazin-2(4H)-yl)
and immune disorders with the aforesaid method [327]. Shawali acetohydrazides 276 starting from saccharine 273 and ultrasonic
et al. established a convenient synthetic procedure with the utility irradiation was employed for the construction of the pyrazolo[3,4-
of hydrazonoyl halides as precursors for the synthesis of pyrazolo c][1,2]benzothiazine core in high yields (Scheme 72) [337]. Another
[3,4-d]pyridazines (Scheme 69) [328e330]. Based on this method, a series of chalcone-based pyrazolobenzothiazines were also syn-
series of 3-arylazo-8H-imidazo[1,2-b]pyrazolo[3,4-d]pyridazines thesized with potent anti-bacterial activity by them [340].
264 were synthesized and realized the site-selectivity in the reac- In 2012, Sabatini et al. synthesized a new class of pyrazolo[3,4-c]
tion of hydrazine hydrate with 3,40 -bis-(functionalized carbonyl)- [1,2]benzothiazine 5,5-dioxide analogs 281 performed as Staphy-
4,30 -bis(pyrazol)ketones 265 and cyanoacetic hydrazides with lococcus aureus NorA multidrug efflux pump inhibitors [338].
hydrazonoyl chlorides. Saccharin sodium salt 273 was also employed as starting materials
Multicomponent reactions (MCRs) are attractive to organic and and the construction of pyrazolo[3,4-c][1,2]benzothiazine core was
pharmaceutical chemists since these reactions effectuate the con- realized from the condensation of key intermediate 279 with
struction of basic and important compounds possessing unique phenylhydrazines hydrochloride in refluxing EtOH with conc H2SO4
biological activities in a single step [331]. Teimouri et al. reported a as dehydrating agent (Scheme 73).
one-pot three-component condensation reaction of isocyanides In 2013, Tomita et al. reported a series of 1,5-dimethyl-1,5-
267 with dialkyl acetylenedicarboxylates 268 and 3,6- dihydropyrazolo[4,3-c][1,2]benzothiazine derivatives 284 which
dihydroxypyridazine 269 for the synthesis of dialkyl 3-(alkyl/ary- could selectively inhibit kinase activity of focal adhesion kinase
lamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2- (FAK) without affecting other kinases and could be developed as
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. 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 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
Scheme 79. Synthesis of PHA-848125. 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
antitumor agents [339]. The pyrazolo[4,3-c][1,2]benzothiazine in vivo antitumor activities [344]. And they were firstly obtained as
scaffold was synthesized from methyl anthranilates 283 and N,N- byproducts from the photodecomposition of azides [345,346]. In
dimethylformamide dimethylacetal (DMFDMA) and hydrazines 2009, Linker et al. synthesized a series of pyrazolo[1,5-a]quinoxa-
were employed for the construction of pyrazole ring (Scheme 74). lines 293 from aryloxymethylquinoxaline oximes 291 in the pres-
The structure was fully modified with different groups leading to an ence of acetic anhydride through a proposed formal [3,5]-
optimized compound N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5- sigmatropic rearrangement process (Scheme 76) [347]. In 2010,
dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide Reeves et al. established a CuI-catalyzed annulation of o-amino-
which possessed FAK inhibitory activities both in cell-free iodoarene with formylpyrazole in high yields [348]. And in 2013,
(IC50 ¼ 0.64 mM) and in cellular assays (IC50 ¼ 7.1 mM). Wu et al. developed a two-step procedure from 2-
methylthiosubstituted 1,4-enediones 294 and substituted o-phe-
3.11. Pyrazoloquinoxalines nylenediamines 295 forming the key intermediate dihy-
droquinoxalines 296 for the synthesis of pyrazolo[1,5-a]
Quinoxaline derivatives are widely used in pharmaceutical in- quinoxalines oxides 297 in excellent yields (Scheme 77) [349].
dustry because of their broad spectrum biological activities, such as Also, another pyrazoloquinoxaline derivatives, pyrazolo[3,4-g]
antiviral, antidiabetic and anti-inflammatory [341]. Additionally, quinoxalines have been synthesized as particular kinases in-
nitrogen-containing tricyclic compounds have been demonstrated hibitors, such as Akt inhibitors [350], tyrosine kinase or PKC in-
with various applications in pesticide and are potential enzyme hibitors [351]. In 2010, Moreau et al. reported the synthesis of
inhibitors. Most common structures of the pyrazoloquinoxalines pyrazolo[3,4-g]quinoxaline derivatives 301 as in vivo Pim-3 kinase
are 1H-pyrazolo[3,4-b]quinoxalines, known as flavazoles, which inhibitors and some have demonstrated favorable antiproliferative
can be readily synthesized by oxidative cyclization of the corre- potencies [352]. The synthesis of these compounds was carried out
sponding quinoxalines hydrazones [342]. In 2011, Guirado et al. starting from 1H-indazole-5,6-diamine 300 which was obtained
developed a general method for the synthesis of 3-amino-5,8- from 6-nitroindazole 298 through nitration with H2SO4 and KNO3
dichloroflavazoles from the key intermediate, 5,8-dichloro-2,3- 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 80. Synthesis of pyrazolo[1,5-c]quinazolines as PDE10A inhibitors. 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 85. Synthesis of pyrazolo[1,2-b]phthalazines through 4-CRs in ionic liquid.

Scheme 83. Synthesis of pyrazolo[1,2-b]phthalazines through 3-CRs.

under microwave irradiation [369]. The pyrazolo[4,3-f]quinazolin-
9-ones 319, which were demonstrated as DYRK1A inhibitors at
[354], antiviral [355], anticancer [356], and antitubercular agents submicromolar concentrations, were synthesized under the same
[357]. Recently, the synthesis of pyrazoloquinazolines has drawn condition (Scheme 82).
considerable attention due to their good biological activities. Pyr-
azolo[4,3-h]quinazoline derivatives have been demonstrated as 3.13. Pyrazolo[1,2-b]phthalazines
inhibitors of several cell cycle kinases which might be developed as
potential antineoplastic agents. Traquandi et al. reported the Phthalazine derivatives have attracted increasing attention in
identification of pyrazolo[4,3-h]quinazoline-3-carboxamides as recent years due to their excellent pharmacological and biological
cyclin-dependent kinases (CDKs) inhibitors, and one of the deriv- activities [370,371], such as anticonvulsant [372], cardiotonic [373],
ative PHA-848125 (Fig. 7), mainly targeting CDK2 and TRKA, is and vasorelaxant activities [374]. Pyrazolo[1,2-b]phthalazine-dione
advanced in phase II clinical trials [358,359]. Beria et al. identified a is identified as anti-inflammatory, analgesic, anti-hypoxic and anti-
series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as pyretic agent [375]. In 1937, Drew and Hart initially reported the
Polo-like-kinase 1 (PLK1) inhibitors and one of the derivative, NMS- synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione skeleton
P937 (Fig. 7) is presently in phase I clinical trials evaluation from phthalhydrazide and cinnamaldehyde [376]. Until now, most
[360e362]. Caldarelli et al. developed a series of 4,5-dihydro-pyr- of pyrazolo[1,2-b]phthalazines were synthesized by one-pot multi-
azolo[4,3-h]quinazoline-3-carboxamide derivatives 308 as potent component reactions in various different conditions as summarized
and selective Monopolar Spindle-1 kinase (MPS1) inhibitors and below.
identified NMS-P715 (Fig. 7) with favorable pharmacokinetic pa- As for the three-component reactions (3-CRs) of phthalhy-
rameters, good potency and selectivity profile [363]. The con- drazide 320, malononitrile or ethyl cyanoacetate or 1,3-diketones
struction of the pyrazolo[4,3-h]quinazoline core was commonly 322/323, and aromatic aldehydes 321(Scheme 83), various
realized through condensation of enaminone with dinucleophile, methods were developed: 1) in the presence of p-TSA at 100  C in
as illustrated by the synthesis of PHA-848125 (Scheme 79) [359]. ionic liquid [bmim]Br [377]; 2) with Et3N (20 mol%) as catalyst in
N-Fused heterocycles of pyrazoles and quinazolines, pyrazolo ethanol at 50  C under ultrasonic irradiation [378]; 3) without
[1,5-c]quinazolines have been demonstrated as potent IkB kinase catalyst in ionic liquid [bmim]OH under microwave irradiation at
inhibitors [364], AMPA and kainate receptor [365] and NMDA re- 45  C [379]; 4) with mesoporous aluminosilicates (Al-KIT-6) as
ceptor antagonists [366]. In 2011, Asproni et al. identified a series of heterogeneous catalyst in ethanol under refluxing conditions, Al-
potent phosphodiesterases 10A (PDE10A inhibitors) by combining KIT-6 was found to be a good recyclable solid catalyst [380]; 5)
the pyrazolo[1,5-c]quinazoline system with a phenylimidazole with (S)-camphorsulfonic acid as catalyst under solvent-free con-
fragment and the most potential derivative was demonstrated with ditions at 80  C as well as under solvent-free conditions at room
an IC50 value of 16 nM [367]. The synthetic procedure is shown temperature, and this method was quite tolerated to aldehydes and
(Scheme 80). cyclic or acyclic 1,3-diketones, yet when cyclic 1,3-diketones were
In 2011, Fu et al. established an efficient one-pot synthesis of treated with phthalhydrazide and aldehyde failed to give the tar-
pyrazolo[1,5-c]quinazoline derivatives 316 under mild CuI- geted product [381]. These reactions are proposed to be realized
catalyzed condition from substituted 1-(2-halophenyl)-3- through domino Knoevenagel condensation/Michael addition/
alkylprop-2-yn-1-ones 314, hydrazine hydrochloride and amidine intramolecular cyclodehydration sequence.
hydrochlorides in good to excellent yields (Scheme 81) [368]. This By reacting isatin or acenaphthylene-1,2-dione with either
method provides diverse and useful pyrazolo[1,5-c]quinazoline phthalhydrazide, malononitrile or ethyl cyanoacetate, spiro com-
derivatives for medicinal chemistry. pounds were obtained. Shi et al. reported the synthesis of spiro
In 2012, Demeunynck et al. established a catalyst-free synthesis [indoline-pyrazolo[1,2-b]phthalazine] derivatives 327 catalyzed by
of quinazolin-4-ones in two steps, guanidine formation and cycli- piperidine (10 mol%) in CH3CN under refluxing conditions or ul-
zation, from (hetero)aryl-guanidines and the intramolecular cycli- trasound irradiation conditions (Scheme 84) [382,383]; the
zation was realized by catalyst-free thermolysis at 130  C in water

Scheme 86. Synthesis of functionalized 1H-pyrazolo[1,2-b]phthalazine-1,2-

Scheme 84. Synthesis of spiro[indoline-pyrazolo[1,2-b]phthalazine] derivatives. dicarboxylates.
M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340 331

Scheme 87. Synthesis of pyrazolo[1,2-b]phthalazines through NiCl2-catalyzed 4-CR. Scheme 88. Synthesis of pyrazolo[4,3-c]cinnolines.

synthesis of spirowiacenaphthylene derivatives with Et3N as cata- series of pyrazolo[4,3-c]cinnoline derivatives 340 and a useful
lyst under ultrasound irradiation conditions [384] and the syn- model of a new class of dual non-acidic anti-inflammatory-anti-
thesis of pyrazolophthalazinyl spirooxindoles catalyzed by NiCl2 bacterial agents was developed [393]. The construction of the
(20 mol%) in polyethylene glycol 600 at 100  C were also reported pyrazolo[4,3-c]cinnoline framework was realized through
[385]. condensation of 3-acetyl-7-chloro-6-fluorocinnolin-4(1H)-one 338
Pyrazolo[1,2-b]phthalazines were also prepared through four- with acid hydrazides 339 in 1,4-dioxane containing a catalytic
component reactions (4-CRs) which could improve the diversity amount of conc. HCl (Scheme 88).
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- 3.14.2. Pyrazolo[1,5-f]phenanthridines
argyloxy)benzaldehyde 328, malononitrile or ethyl cyanoacetate, Apart from the attractive applications of phenanthridine-fused
and an azide in the presence of Cu(OAc)2/sodium L-ascorbate as heterocycles in organic diodes and discotic liquid crystals owing
catalyst in ionic liquid [Hmim](CF3COO) for the synthesis of pyr- to the electroluminescent properties of the compounds, phenan-
azolo[1,2-b]phthalazine derivatives 330. Knoevenagel condensa- thridine moiety has been suggested as an effective pharmacophore
tion and click reaction, and subsequent Michael-type addition were as DNA-intercalating antitumor agents [394,395]. In 2010, Martin
proposed to effectuate this reaction (Scheme 85) [386]. Shaabani et al. reported the synthesis of a series of pyrazolo[1,5-f]phenan-
et al. reported an isocyanide-based 4-CRs of various cyclic anhy- thridine derivatives 344 by a straightforward sequence. First, a
drides 331, hydrazine hydrate, isocyanides 332 and dialkyl acety- tandem amine-exchange/heterocyclization of enaminones was
lenedicarboxylates 333 in EtOH/acetone (1:1) at room temperature carried out for the preparation of 1,5-diarylpyrazole intermediates
for the synthesis of highly functionalized 1H-pyrazolo[1,2-b] 343; second, cyclization by intramolecular biaryl bond formation
phthalazine-1,2-dicarboxylates 334 in good to moderate yields was accomplished by two alternative methods: free-radical SRN1
(Scheme 86) [387]. He et al. reported a NiCl2-catalyzed 4-CR of coupling employing tris(trimethysilyl)silane (TTMSS) and AIBN or
phthalimide 335, hydrazine, malononitrile or ethyl cyanoacetate catalytic direct arylation via CeH activation (Scheme 89) [396].
322, and aromatic aldehydes 336 in ethanol under refluxing con-
ditions (Scheme 87) [388]. The Lewis acid NiCl2$6H2O showed an
3.14.3. Pyrazolo[1,5-a][1,4]benzoxazines
excellent catalytic activity leading to high yields of target products.
As a key structural component in many biological and thera-
Shaterian et al. reported a 4-CRs of hydrazine monohydrate,
peutic compounds, such as the anticancer agent actinomycin D
phthalic anhydride, malononitrile or ethyl cyanoacetate, and aro-
[397], benzoxazinorifamycin KRM-1648 known as antitubercular
matic aldehydes employing three weak basic ionic liquids, DBU
agent [398], flumioxazin and thidiazimin used as herbicides [399],
[CH3COO], [Pyrr][HCOO] and [Pyrr][CH3COO] as efficient catalysts
1,4-benzoxazines have attracted considerable interest of organic
under ambient and solvent-free conditions in excellent yields
and pharmaceutical chemists and Zhao et al. have explored the
[389]. These reusable ionic liquids played crucial roles in these
important biological activity of 2,3-dihydro-3-hydroxymethyl-1,4-
reactions and proposed to be the most efficient catalyst respect to
benzoxazines as HUVEC (human umbilical vein endothelial cell)
the less reaction time and the higher yields.
apoptosis inhibitors [400e405]. Also, pyrazolobenzoxazines have
been demonstrated as inhibitor of the mitotic kinesin spindle
3.14. Other [5, 6]-condensed pyrazole derivatives protein [406] and viral replications in recent years. In spite of the
good biological activities of pyrazolobenzoxazines, only a few
3.14.1. Pyrazolo[4,3-c]cinnolines synthetic methods are available for them. Garati et al. reported the
Cinnoline has been developed as potent anti-inflammatory synthesis of pyrazolo[5,1-c][1,4]benzoxazines through the intra-
agents [390], such as cinnopentazone, cinoxacin (Fig. 8) and anti- molecular cycloaddition of nitrilimines with terminal alkynes,
bacterial agents [391]. Furthermore, some cinnoline derivatives substituted ethylenes and acetylenes [407,408]. Shimizu et al. re-
have been reported as dual anti-inflammatory-antibacterial agents ported the synthesis of pyrazolo[5,1-c][1,4]benzoxazines through
possessing improved safety profile for improved therapeutic ben- 1,3-dipolar cycloaddition reaction from 2-(allyloxy)phenyl-
efits and better patient compliance [392]. Bawa et al. synthesized a hydrazine with arylaldehydes in the presence of HCl [409].

Fig. 8. Structures of compounds containing cinnoline core. 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.

Scheme 92. Synthesis of 3H-benzolo[3,4-h][1,6]naphthyridines as potent anti-HSV-1

In 2011, Chowdhury et al. established an efficient strategy for the agents.
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 1-phenyl-1H-pyrazole through condensation with diethyl ethox-
90) [410]. Furthermore, the results revealed that the reaction pro- ymethylenemalonate followed by cyclization [417,418].
tocol could also be applied in bis-heteroannulation and the syn-
thesis of uracil derivatives. 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
3.14.4. Pyrazolo[3,4-h][1,6]naphthyridines SPS allows convenient handling and distribution of the synthetic
1,6-Naphthyridine derivatives have been developed as lumi- intermediates and offers an alternative pathway for organic
nescence materials in molecular recognition [411] and anticancer synthesis.
agents, such as HIN-1 integrase inhibitors [412,413], FGF receptor-1
tyrosine kinase inhibitors [414] and acetylcholinesterase inhibitors 4. [5, 7]-Condensed pyrazole derivatives
Jachak et al. established a general method for the synthesis of 4.1. Pyrazolo-1,4-benzodiazepines
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] 1,4-Benzodiazepine moieties are important skeletons in natu-
pyridine-5-carbaldehyde 349, which was easily obtained through rally occurring as well as synthetic products with a wide range of
diazotization, reduction, and oxidation from ethyl 4-chloro-1- biological activities. For example, Deoxyharringtonine displays the
phenyl-3-aryl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 348, lowest IC50 against leukemic cells [420,421]. They are also reported
with active methylenes or cyclic ketones in high yields (Scheme 91) as potential antitumor agents [422], anti-inflammatory [423], anti-
[416]. Furthermore, more angular tricyclic and tetracyclic hetero- HIV agents [424], anxiolytics [425], antibiotics [426] and potent
annulated compounds could be synthesized by the condensation of arginine vasopressin antagonists [427].
4-aminopyrazolo[3,4-b]pyridine-5-carbaldehyde (Scheme 91). All Due to their remarkable biological activities, various synthetic
the synthesized compounds have potential applications in opto- methods have been developed. In 2010, Khodairy reported the
electronic devices because of their efficient blue light emission synthesis of 1,4-diphenyl-1,10-dihydrobenzopyrazolo[3,4-e][1,4]
and thermostability. diazepine 362 from 3-dimethylaminomethyleno-4-phenyl-1H-1,5-
Bernardino et al. reported the synthesis of two series of 3H- benzodiazepin-2-one 361 with hydrazines (Scheme 94) [428].
benzolo[3,4-h][1,6]naphthyridines as potent anti-HSV-1 agents. A Abonia et al. developed a radical mediated intramolecular
general approach was employed for preparing the targeted prod- alkylation from ethyl pyrazolylbenzylaminoxanthates 365 for the
ucts from 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5- synthesis of 4H-benzopyrazolo[1,5-a][1,3]diazepin-5(6H)-ones 366
carboxylate 354 (Scheme 92), which was prepared from 5-qmino- in moderate yields (Scheme 95) [429]. Dilauroyl peroxide (DLP) was
employed for the generation of a-alkylcarbonyl radicals.

Scheme 91. Synthesis of pyrazolo[3,4-h][1,6]naphthyridines 350, 351. 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 333

Scheme 94. Synthesis of 1,4-diphenyl-1,10-dihydrobenzopyrazolo[3,4-e][1,4]


Scheme 97. Synthesis of tetracyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazepine-


FibreCat™ catalyst was also examined without notable progress in

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 95. Synthesis of 4H-benzopyrazolo[1,5-a][1,3]diazepin-5(6H)-ones.
(Scheme 99) [433]. The anti-tumor activities of these compounds
were related to the nature of substituents in benzene moiety. Three
In spite of the conventional methods, metal-catalysts were also conditions were tested and the microwave irradiation seemed to be
employed in these reactions. Batra et al. established a CuI-catalyzed the most efficient method.
cascade reactions via intermolecular condensation followed by a
copper-mediated intramolecular CeN or CeO coupling reaction 4.2. Pyrazolo-1,4-thiazepines
from substituted 4-iodopyrazolecarbaldehydes 367 with 1,2-
phenylenediamines 368 or 2-aminophenols 370 to obtain dihy- 1,4-Thiazepines are important heterocyclic compounds existing
drobenzopyrazolo [4,3-e] [1,4]diazepines 369 or benzopyrazolo both in natural products and synthetic compounds with various
[3,4-f][1,4]-oxazepines 371, respectively (Scheme 96) [430]. biological activities [434,435], such as anticonvulsant, analgesic,
Beccalli et al. reported Pd-catalyzed amination/1,3-dipolar antifeedant activities. Among them, heteroaryl-fused derivatives
cycloaddition as the key reaction steps for the synthesis of tetra- are proved to be an important class of compounds exhibiting
cyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazepine-5,8- interesting pharmaceutical properties, such as HIV-1 enzyme
diones 375 (Scheme 97) [431]. The construction of pyrazolo ring integrase [436] and reverse transcriptase inhibitors [437] and cal-
was realized via 1,3-dipolar cycloaddition. cium channel antagonists [438].
In 2011, Martin et al. developed a straightforward entry for In recent years, many approaches have been developed for the
pyrazolodibenzo[1,4]diazepines 377 prepared by a tandem synthesis of pyrazolothiazepines. In 2011, Mohamed reported a
sequence amine-exchange/heterocyclization with Pd-catalyzed simple condensation of benzo[1,5]thiazepines with phenyl-
intramolecular N-arylation as key step, from enaminones and hydrazine for the synthesis of phenyl-2H-pyrazolo[3,4-b][1,5]ben-
arylhydrazines (Scheme 98) [432]. Heterogeneous catalyst, 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 96. Synthesis of dihydrobenzopyrazolo [4,3-e] [1,4]diazepines through CuI- Scheme 98. Synthesis of pyrazolodibenzo[1,4]diazepines through Pd-catalyzed
catalyzed reactions. reaction.
334 M. Li, B.-X. Zhao / European Journal of Medicinal Chemistry 85 (2014) 311e340

Scheme 103. Synthesis of 5-chloro-8H-dibenzo[c,f]pyrazolo[1,5-a]azepin-8-ones.

Scheme 99. Synthesis of chiral ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-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]
Scheme 100. Synthesis of phenyl-2H-pyrazolo[3,4-b][1,5]benzothiazepines. [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
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.

Scheme 101. Synthesis of spiro[indoline-3,4-pyrazolo[3,4-e][1,4]thiazepine] dione

derivatives. 5. Conclusion

In conclusion, we have summarized the reported synthetic

4.3. Pyrazolo-1,4-oxazepines methods of various condensed pyrazole derivatives including [5, 5],
[5, 6], and [5, 7]-condensed pyrazole derivatives and introduced
1,4-Oxazepine unit is an important moiety for psychoactive their multiplicate biological activities and applications in pharma-
pharmaceuticals, for example Oxazepam, a drug which is a short- ceutical fields briefly. People have paid much attention to the
to-intermediate-acting 3-hydroxy benzodiazepine derivative. In synthesis of [5, 5] or [5, 6]-condensed pyrazole derivatives, yet little
addition, aryl-fused 1,4-oxazepines have been described as potent attention has been paid to [5, 7]-condensed pyrazole derivatives or
non-peptidergic GPCR inhibitors, squalene synthase inhibitors, other macrocyclic condensed pyrazole derivatives and polycyclic
reverse transcriptase inhibitors, and integrin antagonists [441]. In condensed pyrazole derivatives which might be due to their poor
2013, Liu et al. reported the synthesis of a series of pyrazolo[1,5-d] stability. With the development of organic synthesis chemistry,
[1,4]oxazepin-8(7H)-one derivatives 391 as telomerase inhibitors various atom economy and eco-friendly methods have been
[442]. The products were prepared in general way (Scheme 102). 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
4.4. Other [5, 7]-condensed pyrazole derivatives
remarkably improves the reaction yields and shortens the reaction
time which may provide abundant compounds for high throughput
Other kinds of [5, 7]-condensed pyrazole derivatives have also
screening of drugs with satisfactory biological activities. The ap-
been reported. In 2011, Sackus et al. reported the construction of a
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 102. Synthesis of pyrazolo[1,5-d][1,4]oxazepin-8(7H)-ones. 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 335

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