NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review)
This article profiles five newly drugs containing fluorine along with fragments of amino acids or their derivatives approved by the FDA in 2024. These pharmaceuticals include Voydeya® (danicopan), Ojemda® (tovorafenib), Itovebi® (inavolisib), Scemblix® (asciminib), and Revuforj® (revumenib). For ea...
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V.I.Vernadsky Institute of General and Inorganic Chemistry
2024
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Ukrainian Chemistry Journal| _version_ | 1871466075494809600 |
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| author | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_facet | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Jianlin Han",
"institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China"
},
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Gagan Dhawan",
"institution": "School of Allied Medical Sciences, Delhi Skill and Entrepreneurship University, Dwarka, 110077 New Delhi, India;"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, 02125 Boston MA, Unites States;"
},
{
"author": "Alexander Sorochinsky",
"institution": "Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences of Ukraine, 1 Murmanska str., Kyiv 02094, Ukraine"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195Berlin, Germany"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Han, Jianlin |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:55Z |
| description | This article profiles five newly drugs containing fluorine along with fragments of amino acids or their derivatives approved by the FDA in 2024. These pharmaceuticals include Voydeya® (danicopan), Ojemda® (tovorafenib), Itovebi® (inavolisib), Scemblix® (asciminib), and Revuforj® (revumenib). For each drug, we discuss the discovery, therapeutic areas of application, and detailed chemical synthesis. |
| doi_str_mv | 10.33609/2708-129X.90.9.2024.31-56 |
| first_indexed | 2025-09-24T17:43:58Z |
| format | Article |
| fulltext |
31
UDC 546.26-162 doi: 10.33609/2708-129X.90.9.2024.31-56
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING
FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.
Jianlin Han1*, Alicja Wzorek2, Gagan Dhawan3,4*, Wei Zhang5*, Alexander E. Sorochinsky6*,
Daniel Baecker7*, Taizo Ono8, Karel D. Klika9, Vadim A. Soloshonok10,11*
1Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,
College of Chemical Engineering, Nanjing Forestry University,
210037 Nanjing, China;
2Institute of Chemistry, Jan Kochanowski University in Kielce,
7 Uniwersytecka, 25–406 Kielce, Poland;
3School of Allied Medical Sciences, Delhi Skill and Entrepreneurship University,
Dwarka, 110077 New Delhi, India;
4 Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi,
Kalkaji, 110019 New Delhi, India;
5 Department of Chemistry, University of Massachusetts Boston,
02125 Boston MA, Unites States;
6V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, the National Academy of Sciences
of Ukraine,
02094 Kyiv, Ukraine
7 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin,
2+4 Königin-Luise-Straße, 14195 Berlin, Germany;
8National Institute of Advanced Industrial Science and Technology (AIST),
2266–98, Anagahora, Shimoshidami, Moriyama-ku, 463–8560 Nagoya, Japan;
9Molecular Structure Analysis, German Cancer Research Center (DKFZ),
280 Im Neuenheimer Feld, 69120 Heidelberg, Germany;
10 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU,
3 Paseo Manuel Lardizábal, 20018 San Sebastián, Spain;
11IKERBASQUE, Basque Foundation for Science,
3 María Díaz de Haro, Plaza Bizkaia, 48013 Bilbao, Spain
*email: vadimsoloshonok@gmail.com
This article profiles five newly drugs containing fluorine along with fragments of amino
acids or their derivatives approved by the FDA in 2024. These pharmaceuticals include Voy
deya® (danicopan), Ojemda® (tovorafenib), Itovebi® (inavolisib), Scemblix® (asciminib), and
Revuforj® (revumenib). For each drug, we discuss the discovery, therapeutic areas of applica
tion, and detailed chemical synthesis.
Key words: Fluorine, Tailor-made amino acids, Pharmaceutical drugs, Drug design, Syn
thesis, Bioactivity.
32 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
INTRODUCTION. Amino acids are funda
mental to the development of life as they are
the building blocks of proteins, which perform
a vast array of functions within living orga
nisms [1]. Proteins are involved in virtually
every cellular process, including enzymatic ca
talysis, structural support, transport, commu
nication, and immune response. Without ami
no acids, the complex molecules necessary for
life as we know it would notexist [2–18]. They
play a crucial role in maintaining the structure
and function of cells, tissues, and organs, mak
ing them essential for growth, repair, and ove
rall health [19–32].
In the modern pharmaceutical industry,
amino acids are invaluable due to their versa
tility and their influence on drug design and
development. Tailor-made amino acids (AAs)
[33] can be incorporated into drugs to enhance
their efficacy, stability, and specificity. By ma
nipulating the structure of amino acids, phar
maceutical researchers can design drugs that
precisely target specific biological pathways,
reduce side effects, and improve patient out
comes [34–41]. Additionally, amino acids are
used in the synthesis of peptide-based drugs,
which are increasingly important in treating a
range of conditions from cancer to metabolic
disorders [42–48]. Their role in the pharma
ceutical industry underscores the profound
impact of amino acids not only on life itself but
also on the advancement of medical science
and therapeutics [49–51].
Another trend in the design of modern
pharmaceuticals is a selective incorporation
of fluorine atoms or/and fluorine-containing
groups [52–63]. Thus, fluorine plays a crucial
role in modern drug design due to its unique
chemical properties, such as high electrone
gativity, small atomic size, and ability to form
stable bonds. These properties allow fluorine
to enhance the potency, selectivity, metabolic
stability, and pharmacokinetics of drugs. In
corporating fluorine into drug molecules can
improve their efficacy and reduce side effects,
making them more effective therapeutic agents
[64–69].
Fluorine-containing amino acids are parti
cularly valuable in drug design because they
combine the benefits of fluorine with the
structural versatility of amino acids [70–74].
These tailor-made amino acids can be used to
fine-tune the activity and pharmacokinetics
of drug candidates, leading to more targeted
and efficient treatments. The synthesis of tai
lor-made fluorinated α- [75–100] and β-amino
acids [101–121] has been one of the areas of
intense research activity in the last 20+ years
[122–143]. The selective introduction of fluo
rine into bioactive compounds has become a
mature strategy in drug development, result
ing in numerous FDA-approved fluorinated
drugs [64, 66–69].
Overall, the incorporation of fluorine and
amino acids into pharmaceuticals represents
a significant advancement in the field of me
dicinal chemistry, offering new opportunities
for the development of more effective and saf
er drugs. In the present article, we profile five
newly FDA-approved (2024) small-molecule
pharmaceuticals (Figure 1) that contain fluo
rine and a residue of an amino acid or its de
rivative. These include: Voydeya® (danicopan)
1, Ojemda® (tovorafenib) 2, Itovebi®(inavolis
ib) 3, Scemblix® (asciminib) 4, and Revuforj®
(revumenib) 5. For each drug, we discuss the
discovery, therapeutic areas of application, and
detailed chemical synthesis.
33https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 9 / Vol. 90
Fig. 1. Chemical structures of new pharmaceutical drugs 1-5 containing fluorine (marked in red)
and a residue of an amino acid or its derivative (marked in blue).
discovery, therapeutic areas of application, and detailed chemical synthesis.
N
F
H
N
O
O
N
N
Me
ON
N
N Br
Me
1
Voydeya® (danicopan) Ojemda® (tovorafenib)
N
N
NH2
Cl
O NH
S
N
Me
HN
O
N
Cl
CF3
2
Itovebi® (inavolisib)
H
N
NH2
O
N O
NN
O
Me
F F
O
3
Scemblix® (asciminib)
NN
O
H
N
O Cl
F
F
N NH
HO
4
Revuforj® (revumenib)
F
O
N
O
N
N
O
ON
N
S
H
N
5
Fig. 1. Chemical structures of new pharmaceutical drugs 1-5 containing fluorine (marked in red)
and a residue of an amino acid or its derivative (marked in blue).
Voydeya® (Danicopan) (1)
Danicopan, marketed under the name Voydeya®, is a drug derived from
γ-fluorine-substituted proline. The FDA approved this compound on March 29, 2024.
Developed by Alexion Pharmaceuticals, a subsidiary of AstraZeneca, this drug targets
rare diseases, with Alexion being renowned for their expertise in orphan drugs [144].
Cyclic amino acids, such as those used in this compound, are particularly important in
drug design because they are more sterically constrained than their linear counterparts
[145,146]. Adding fluorine [147] or CF3 groups [148–150] on five-membered rings
further restricts the range of accessible conformations, enabling the fine-tuning of
biological properties. The introduction of a fluorine atom into the
pyrrolidine-2-carboxamide framework, as compared to non-fluorinated analogs like
compounds 6 and 7 (Figure 2), significantly boosts activity, achieving an IC50 of 0.027
μM. This modification demonstrates exceptional potency and underscores the
compound's potential to surpass other molecules in its class [151,152].
Voydeya® (Danicopan) (1)
Danicopan, marketed under the name Voy
deya®, is a drug derived from γ-fluorine-sub
stituted proline. The FDA approved this com
pound on March 29, 2024. Developed by Alexi
on Pharmaceuticals, a subsidiary of AstraZene
ca, this drug targets rare diseases, with Alexion
being renowned for their expertise in orphan
drugs [144]. Cyclic amino acids, such as those
used in this compound, are particularly impor
tant in drug design because they are more steri
cally constrained than their linear counterparts
[145, 146]. Adding fluorine [147] or CF3 groups
[148–150] on five-membered rings further re
stricts the range of accessible conformations,
enabling the fine-tuning of biological proper
ties. The introduction of a fluorine atom into
the pyrrolidine-2-carboxamide framework, as
compared to non-fluorinated analogs like com
pounds 6 and 7 (Figure 2), significantly boosts
activity, achieving an IC50 of 0.027 μM. This
modification demonstrates exceptional potency
and underscores the compound’s potential to
surpass other molecules in its class [151, 152].
N
HO
H
N
O
O
N
N
Me
ON
N
N Br
Me 6
N
H
H
N
O
O
N
N
Me
ON
N
N Br
Me
N
F
H
N
O
O
N
N
Me
ON
N
N Br
MeIC50 < 1 M IC50 < 1 M IC50 = 0.027 M7 1
Fig. 2. Structures of Voydeya® (Danicopan) 1 and its fluorine-free analogs 6 and 7.
Voydeya, an oral complement factor D inhibitor, serves as an add-on therapy to
the complement C5 inhibitors Ravulizumab and Eculizumab for treating extravascular
hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH)
[153,154]. PNH is a rare condition where the immune system's complement attacks red
and white blood cells and platelets, leading to intravascular hemolysis and a heightened
risk of thrombosis and organ damage. Although C5 inhibitors are the primary treatment,
some patients still experience residual extravascular hemolysis and anemia [155].
Danicopan received its initial approval in Japan on January 18, 2024, for treating adults
with PNH in combination with C5 inhibitors [156]. On February 23, 2024, the
European Medicines Agency also recommended its market authorization for patients
with residual hemolytic anemia despite C5 inhibition therapy [157].
The synthesis of Voydeya® (Danicopan) was developed by Alexion
Pharmaceuticals [158–160]. This process starts with the creation of several key
intermediates. As outlined in Scheme 1, 5-bromo-1H-indazole-3-carbonitrile 8 reacts
with methyl magnesium bromide forming an imine magnesium salt intermediate. This
intermediate is then hydrolyzed with acid treatment at pH 5 to produce ketone 9.
Following this, a Michael addition is carried out, yielding the ester 10 with an 81%
yield.
t-Bu-O
O
N
N
Me O
Br
10
Br
NC
N
N
H
Br
N
N
H
O
THF/(CH3CH2)2O,
0 C to RT, 3 h, 93%
(pH 5) using HCl
3 equiv MeMgBr
2.5 equiv K2CO3,
1.2 equiv tert-Butyl
bromoacetate
DMF, 50 C, 3 h, 81%
8 9
Scheme 1. Synthesis of key intermediate 10.
The synthesis of another important compound 13, is detailed in Scheme 2.
Boc-protected fluoropyrrolidine 11 undergoes amide alkylation using Ghosez reagent
and diisopropylethylamine (DIPEA) [161]. This is followed by deprotection of the
amino group, resulting in the precursor 13.
Fig. 2. Structures of Voydeya® (Danicopan) 1 and its fluorine-free analogs 6 and 7.
34 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Voydeya, an oral complement factor D in
hibitor, serves as an add-on therapy to the
complement C5 inhibitors Ravulizumab and
Eculizumab for treating extravascular hemoly
sis (EVH) in adults with paroxysmal noctur
nal hemoglobinuria (PNH) [153,154]. PNH is
a rare condition where the immune system’s
complement attacks red and white blood cells
and platelets, leading to intravascular hemo
lysis and a heightened risk of thrombosis and
organ damage. Although C5 inhibitors are the
primary treatment, some patients still expe
rience residual extravascular hemolysis and
anemia [155]. Danicopan received its initial
approval in Japan on January 18, 2024, for
treating adults with PNH in combination with
C5 inhibitors [156]. On February 23, 2024, the
European Medicines Agency also recommend
ed its market authorization for patients with
residual hemolytic anemia despite C5 inhibi
tion therapy [157].
The synthesis of Voydeya® (Danicopan) was
developed by Alexion Pharmaceuticals [158–
160]. This process starts with the creation
of several key intermediates. As outlined in
Scheme 1, 5-bromo-1H-indazole-3-carboni
trile 8 reacts with methyl magnesium bromide
forming an imine magnesium salt intermedi
ate. This intermediate is then hydrolyzed with
acid treatment at pH 5 to produce ketone 9.
Following this, a Michael addition is carried
out, yielding the ester 10 with an 81% yield.
N
HO
H
N
O
O
N
N
Me
ON
N
N Br
Me 6
N
H
H
N
O
O
N
N
Me
ON
N
N Br
Me
N
F
H
N
O
O
N
N
Me
ON
N
N Br
MeIC50 < 1 M IC50 < 1 M IC50 = 0.027 M7 1
Fig. 2. Structures of Voydeya® (Danicopan) 1 and its fluorine-free analogs 6 and 7.
Voydeya, an oral complement factor D inhibitor, serves as an add-on therapy to
the complement C5 inhibitors Ravulizumab and Eculizumab for treating extravascular
hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH)
[153,154]. PNH is a rare condition where the immune system's complement attacks red
and white blood cells and platelets, leading to intravascular hemolysis and a heightened
risk of thrombosis and organ damage. Although C5 inhibitors are the primary treatment,
some patients still experience residual extravascular hemolysis and anemia [155].
Danicopan received its initial approval in Japan on January 18, 2024, for treating adults
with PNH in combination with C5 inhibitors [156]. On February 23, 2024, the
European Medicines Agency also recommended its market authorization for patients
with residual hemolytic anemia despite C5 inhibition therapy [157].
The synthesis of Voydeya® (Danicopan) was developed by Alexion
Pharmaceuticals [158–160]. This process starts with the creation of several key
intermediates. As outlined in Scheme 1, 5-bromo-1H-indazole-3-carbonitrile 8 reacts
with methyl magnesium bromide forming an imine magnesium salt intermediate. This
intermediate is then hydrolyzed with acid treatment at pH 5 to produce ketone 9.
Following this, a Michael addition is carried out, yielding the ester 10 with an 81%
yield.
t-Bu-O
O
N
N
Me O
Br
10
Br
NC
N
N
H
Br
N
N
H
O
THF/(CH3CH2)2O,
0 C to RT, 3 h, 93%
(pH 5) using HCl
3 equiv MeMgBr
2.5 equiv K2CO3,
1.2 equiv tert-Butyl
bromoacetate
DMF, 50 C, 3 h, 81%
8 9
Scheme 1. Synthesis of key intermediate 10.
The synthesis of another important compound 13, is detailed in Scheme 2.
Boc-protected fluoropyrrolidine 11 undergoes amide alkylation using Ghosez reagent
and diisopropylethylamine (DIPEA) [161]. This is followed by deprotection of the
amino group, resulting in the precursor 13.
Scheme 1. Synthesis of key intermediate 10.
The synthesis of another important com
pound 13, is detailed in Scheme 2. Boc-pro
tected fluoropyrrolidine 11 undergoes amide
alkylation using Ghosez reagent and diisopro
pylethylamine (DIPEA) [161]. This is followed
by deprotection of the amino group, resulting
in the precursor 13.
Scheme 2. Synthesis of key intermediate 13.
Scheme 2. Synthesis of key intermediate 13.
The assembly of Danicopan's structure using key compounds 10 and 13 is
detailed in Scheme 3. Initially, bromide 10 reacts with 14, forming intermediate 15.
This is followed by a Suzuki – Miyaura coupling reaction with compound 16 in the
presence of a palladium catalyst and a base, resulting in ester 17. Ester hydrolysis with
trifluoroacetic acid (TFA) then produces carboxylic acid 18 in quantitative yield.
Finally, a coupling reaction with fluoro-proline derivative 13 leads to the synthesis of
Voydeya® (Danicopan) (1).
N
H
F
H
N
O
N Br
2.5 equiv DIPEA, 1.0 equiv HATU
DMF, RT, 18 h
N N
N
N
O
N
N+
PF6
-
N
F
NH
OO
N
N
MeO
N
N
N
Br
Me
HATU
HCl
t-Bu-O
O
N
N
Me
O
N N
Me
HO
O
N
N
Me
O
N N
Me
TFA (1 mL)
DMF, 12 h,
100%
Voydeya® (Danicopan)
BB
O
O O
O N
N
Me Br
t-Bu-O
O N
N
Me O
B
O
O
2.0 equiv K2CO3,
0.1 equiv Pd(PPh3)4
DMF/H2O (9/1), 5 h,
90 C, 74.9%
CH3CO2K, Pd(dppf)Cl2
1,4-dioxane, 20 to 120 C,
2 h, 89%
Argon atmosphere
16 1.0 equiv
13
14
17 18
1
t-Bu-O
O
N
N
Me O
Br10 15
Scheme 3. Synthesis of Danicopan1.
Ojemda® (Tovorafenib) (2)
Tovorafenib, branded as Ojemda® (2), is an aromatic trifluoromethyl-containing
complex structure developed by Day One Biopharmaceuticals Inc (California, USA)
under a license agreement with Takeda Oncology (Massachusetts, USA). This drug,
35https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 9 / Vol. 90
The assembly of Danicopan’s structure us
ing key compounds 10 and 13 is detailed in
Scheme 3. Initially, bromide 10 reacts with
14, forming intermediate 15. This is followed
by a Suzuki – Miyaura coupling reaction with
compound 16 in the presence of a palladium
catalyst and a base, resulting in ester 17. Es
ter hydrolysis with trifluoroacetic acid (TFA)
then produces carboxylic acid 18 in quanti
tative yield. Finally, a coupling reaction with
fluoro-proline derivative 13 leads to the syn
thesis of Voydeya® (Danicopan) (1).
Scheme 2. Synthesis of key intermediate 13.
The assembly of Danicopan's structure using key compounds 10 and 13 is
detailed in Scheme 3. Initially, bromide 10 reacts with 14, forming intermediate 15.
This is followed by a Suzuki – Miyaura coupling reaction with compound 16 in the
presence of a palladium catalyst and a base, resulting in ester 17. Ester hydrolysis with
trifluoroacetic acid (TFA) then produces carboxylic acid 18 in quantitative yield.
Finally, a coupling reaction with fluoro-proline derivative 13 leads to the synthesis of
Voydeya® (Danicopan) (1).
N
H
F
H
N
O
N Br
2.5 equiv DIPEA, 1.0 equiv HATU
DMF, RT, 18 h
N N
N
N
O
N
N+
PF6
-
N
F
NH
OO
N
N
MeO
N
N
N
Br
Me
HATU
HCl
t-Bu-O
O
N
N
Me
O
N N
Me
HO
O
N
N
Me
O
N N
Me
TFA (1 mL)
DMF, 12 h,
100%
Voydeya® (Danicopan)
BB
O
O O
O N
N
Me Br
t-Bu-O
O N
N
Me O
B
O
O
2.0 equiv K2CO3,
0.1 equiv Pd(PPh3)4
DMF/H2O (9/1), 5 h,
90 C, 74.9%
CH3CO2K, Pd(dppf)Cl2
1,4-dioxane, 20 to 120 C,
2 h, 89%
Argon atmosphere
16 1.0 equiv
13
14
17 18
1
t-Bu-O
O
N
N
Me O
Br10 15
Scheme 3. Synthesis of Danicopan1.
Ojemda® (Tovorafenib) (2)
Tovorafenib, branded as Ojemda® (2), is an aromatic trifluoromethyl-containing
complex structure developed by Day One Biopharmaceuticals Inc (California, USA)
under a license agreement with Takeda Oncology (Massachusetts, USA). This drug,
Scheme 3. Synthesis of Danicopan1.
Ojemda® (Tovorafenib) (2)
Tovorafenib, branded as Ojemda® (2), is an
aromatic trifluoromethyl-containing complex
structure developed by Day One Biopharma
ceuticals Inc (California, USA) under a license
agreement with Takeda Oncology (Massachu
setts, USA). This drug, also known as DAY101,
is a targeted therapy for cancers with RAF al
terations, including pediatric low-grade gli
oma [162–164]. Tovorafenib2 has shown the
most effective inhibitory activity against RAF
kinases like BRAF and CRAF when compared
36 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
to non-fluorinated analogs, such as 19 (Fi
gure 3) [165, 166]. It received FDA approval
on April 23, 2024. Ojemda is an oral kinase in
hibitor that targets mutant BRAF V600E, wild-
type BRAF, and wild-type CRAF kinases. It is
intended for patients aged 6 months and older
with relapsed or refractory pediatric low-grade
glioma (pLGG) harboring BRAF fusions, re
arrangements, or V600 mutations [167, 168].
This accelerated approval was granted based
on clinical responses and the duration of re
sponse observed in the phase 2 FIREFLY-1
trial (NCT04775485; PNOC026) [169]. The
recommended dose is 380 mg/m² taken orally
once weekly (maximum 600 mg) until disease
progression or unacceptable toxicity [170].
Fig. 3. Structures of Tovorafenib2 and its non-fluorinated analog 19.
also known as DAY101, is a targeted therapy for cancers with RAF alterations,
including pediatric low-grade glioma [162–164]. Tovorafenib2 has shown the most
effective inhibitory activity against RAF kinases like BRAF and CRAF when
compared to non-fluorinated analogs, such as 19 (Figure 3) [165, 166]. It received FDA
approval on April 23, 2024. Ojemda is an oral kinase inhibitor that targets mutant
BRAF V600E, wild-type BRAF, and wild-type CRAF kinases. It is intended for
patients aged 6 months and older with relapsed or refractory pediatric low-grade glioma
(pLGG) harboring BRAF fusions, rearrangements, or V600 mutations [167, 168]. This
accelerated approval was granted based on clinical responses and the duration of
response observed in the phase 2 FIREFLY-1 trial (NCT04775485; PNOC026) [169].
The recommended dose is 380 mg/m² taken orally once weekly (maximum 600 mg)
until disease progression or unacceptable toxicity [170].
Fig. 3. Structures of Tovorafenib2 and its non-fluorinated analog 19.
Scheme 4 outlines the synthesis of Ojemda® (Tovorafenib) [171]. The process
begins with the reaction of thiazole 20 with compound 21 using oxalyl chloride as the
activating reagent, yielding target amide 22 with a 96% yield. Compound 22 is then
mixed with ethanol, 1.1 equivalents of diphenylmethanamine23, and acetic acid in a
flask equipped with a Dean–Stark trap, and the mixture is refluxed for 6.5 hours. After
cooling and stirring for 1 hour, Schiff base 24 is obtained with an 87% yield. Next,
compound 24 is dissolved in dichloromethane and combined with [Ir (cod)2] BArF and
(S)-Monophos, then placed in an autoclave. Hydrogen is introduced, and the mixture is
heated to 50°C and stirred for 24 hours, resulting in compound 25. Acetonitrile and
water are added, followed by 1.1 equivalents of N-bromosuccinimide, and the reaction
proceeds at room temperature for 18 hours to generate the corresponding free amino
compound in situ. Optical resolution [172] is performed using (S)-mandelic acid,
yielding crystallized product 26 with a 75% yield. Subsequent purification involving
2.0 equivalents of sodium bicarbonate and activated carbon in a water–acetonitrile
mixture produces compound 27. Finally, intermediate 27 is coupled with
6-amino-5-chloropyrimidine-4-carboxylic acid 28 under EDC/t-BuOH conditions,
resulting in Ojemda® (Tovorafenib) 2 with an 88% yield [171].
Scheme 4 outlines the synthesis of Ojemda®
(Tovorafenib) [171]. The process begins with
the reaction of thiazole 20 with compound
21 using oxalyl chloride as the activating re
agent, yielding target amide 22 with a 96%
yield. Compound 22 is then mixed with eth
anol, 1.1 equivalents of diphenylmethanami
ne 23, and acetic acid in a flask equipped with
a Dean–Stark trap, and the mixture is refluxed
for 6.5 hours. After cooling and stirring for 1
hour, Schiff base 24 is obtained with an 87%
yield. Next, compound 24 is dissolved in di
chloromethane and combined with [Ir (cod)2]
BArF and (S)-Monophos, then placed in an
autoclave. Hydrogen is introduced, and the
mixture is heated to 50°C and stirred for 24
hours, resulting in compound 25. Acetonitrile
and water are added, followed by 1.1 equiva
lents of N-bromosuccinimide, and the reaction
proceeds at room temperature for 18 hours
to generate the corresponding free amino
compound in situ. Optical resolution [172] is
performed using (S)-mandelic acid, yielding
crystallized product 26 with a 75% yield. Sub
sequent purification involving 2.0 equivalents
of sodium bicarbonate and activated carbon
in a water–acetonitrile mixture produces com
pound 27. Finally, intermediate 27 is coupled
with 6-amino-5-chloropyrimidine-4-carbo
xylic acid 28 under EDC/t-BuOH conditions,
resulting in Ojemda® (Tovorafenib) 2 with an
88% yield [171].
Itovebi® (inavolisib)(3)
Inavolisib, marketed under the brand name
Itovebi®, has been approved by the FDA for
treating locally advanced or metastatic breast
cancer [173]. It functions as an inhibitor of the
phosphatidylinositol-4,5-bisphosphate 3-kina
se (PI3K) pathway, representing a new gene
ration of inhibitors with an improved toxicity
profile compared to the previously approved
inhibitor alpelisib [174, 175].
37https://ucj.org.ua
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Scheme 4. Synthesis of Ojemda® (Tovorafenib) 2.
Scheme 4. Synthesis of Ojemda® (Tovorafenib) 2.
Itovebi® (inavolisib)(3)
Inavolisib, marketed under the brand name Itovebi®, has been approved by the
FDA for treating locally advanced or metastatic breast cancer [173]. It functions as an
inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway,
representing a new generation of inhibitors with an improved toxicity profile compared
to the previously approved inhibitor alpelisib [174,175].
PI3K enzymes play a crucial role in cell growth and differentiation, consisting of
regulatory and catalytic subunits [176]. There are four isoforms: PI3Kα, PI3Kβ, PI3Kγ,
and PI3Kδ. PI3Kα is most closely linked to tumorigenesis due to mutations and
amplifications in the PIK3CA gene encoding the p110α unit [177,178]. Approximately
one-third of breast cancer cases exhibit such pathway disorders [179], which are
considered poor prognostic factors [173].Therefore, selective inhibitors of PI3Kα,
which do not induce side effects by blocking other PI3K isoforms, are highly desirable
[180]. Inavolisib demonstrates an enzyme inhibitory concentration (IC50) of 0.034 nM
for PI3Kα, 100 nM for PI3Kβ, 18 nM for PI3Kγ, and 12 nM for PI3Kδ, indicating a
more than 350-fold selectivity for PI3Kα [181]. Additionally, inavolisib promotes the
degradation of the mutated p110α subunit [182].
It is note worthy that the introduction of a trifluoromethyl group in compound 29
(Figure 4), which has a PI3Kα IC50 of 0.095 nM and a PI3Kδ/PI3Kα ratio of 171,
resulted in less selectivity towards the α isoform compared to the difluoromethyl group
in compound 3 (PI3Kα IC50 of 0.034 nM and a PI3Kδ/PI3Kα ratio of 361) [183].
PI3K enzymes play a crucial role in cell
growth and differentiation, consisting of reg
ulatory and catalytic subunits [176]. There
are four isoforms: PI3Kα, PI3Kβ, PI3Kγ, and
PI3Kδ. PI3Kα is most closely linked to tum
origenesis due to mutations and amplifications
in the PIK3CA gene encoding the p110α unit
[177, 178]. Approximately one-third of breast
cancer cases exhibit such pathway disorders
[179], which are considered poor prognostic
factors [173].Therefore, selective inhibitors
of PI3Kα, which do not induce side effects by
blocking other PI3K isoforms, are highly desi
rable [180]. Inavolisib demonstrates an enzyme
inhibitory concentration (IC50) of 0.034 nM for
PI3Kα, 100 nM for PI3Kβ, 18 nM for PI3Kγ,
and 12 nM for PI3Kδ, indicating a more than
350-fold selectivity for PI3Kα [181]. Additio
nally, inavolisib promotes the degradation of
the mutated p110α subunit [182].
38 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
It is note worthy that the introduction of
a trifluoromethyl group in compound 29 (Fi
gure 4), which has a PI3Kα IC50 of 0.095 nM
and a PI3Kδ/PI3Kα ratio of 171, resulted in
less selectivity towards the α isoform compared
to the difluoromethyl group in compound 3
(PI3Kα IC50 of 0.034 nM and a PI3Kδ/PI3Kα
ratio of 361) [183].
Fig. 4. Structures of Itovebi® (inavolisib)3 and its CF3-containing analog 29.
Chemically, inavolisib features a benzoxazepine oxazolidinone core, an alanine
amide moiety, and an amino alcohol derived from difluoroalanine. This difluoroalanine
derivative is particularly favored by PI3Kα, enhancing the selectivity for this isoform.
The precise interactions of inavolisib with its target are facilitated by hydrogen bonds
from the amide and amino groups of the alanine fragment. Additionally, the
difluoromethyl group of inavolisib interacts with the hydroxyl group of Ser774 within
the p110α pocket [181]. Thus, fluorination plays a crucial role in the unique
effectiveness of this next-generation PI3Kα inhibitor.
The synthetic route to prepare inavolisib (Scheme 5) starts with
1,2:5,6-bis-O-(1-methylethylidene)-D-mannitol 30, which serves as a source for the
desired stereochemical configuration [183]. Sodium periodate (NaIO4) in hot water is
added to silica, forming a powder. This mixture is then combined with compound 30
dissolved indichloromethane (DCM) and stirred at room temperature for 1 hour,
producing carbaldehyde 31. To the cooled carbaldehyde 31 solution in DCM,
diethylaminosulfur trifluoride (DAST) is added dropwise and stirred at room
temperature for 3 hours, yielding (R)-4-difluoromethyl-2,2-dimethyl [1,3] dioxolane 32.
This intermediate is dissolved in methanol (MeOH), and hydrochloric acid (HCl) in
dioxane is added, stirring at room temperature for 30 minutes. The acetal is cleaved to
form the respective diol. After work-up, the residue is dissolved in DCM, followed by
the addition of tert-butyldimethylsilyl chloride(TBDMS), Et3N, and catalytic amounts
of 4-Dimethylaminopyridine(DMAP). Compound 33 was obtained after stirring for 1
hour at room temperature. Following this, trifluoromethanesulfonic anhydride (Tf2O)
was added dropwise to a solution of 33 and pyridine in DCM. The temperature was
maintained at -20°C for 20 minutes, then brought to 0°C for 1 hour while stirring. After
extraction and work-up, the residue was dissolved in DMF, and sodium azide (NaN3)
was added, stirring for 2 hours at room temperature to produce intermediate 34. The
azide was then reduced using palladium hydroxide on carbon (Pd-OH/C) under
hydrogen (H2) by stirring for 16 hours in ethyl acetate (EtOAc) and MeOH, yielding
primary amine 35. This product was dissolved in MeOH and stirred in a solution of HCl
(in dioxane) for 2 hours at room temperature to remove the protective group. After
work-up, the crude product was dissolved in toluene and aqueous potassium hydroxide
(KOH) at 0°C. Phosgene (COCl2) was added gradually, followed by stirring for 1 hour
to obtain (S)-4-difluoromethyloxazolidin-2-one 36. This was combined with
9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]-oxazepane 37, copper acetate
monohydrate (Cu(OAc)2·H2O), 3,4,7,8-tetramethyl-1,10-phenanthroline (TMPhen),
Fig. 4. Structures of Itovebi® (inavolisib)3 and its CF3-containing analog 29.
Chemically, inavolisib features a benzox
azepine oxazolidinone core, an alanine amide
moiety, and an amino alcohol derived from di
fluoroalanine. This difluoroalanine derivative
is particularly favored by PI3Kα, enhancing
the selectivity for this isoform. The precise in
teractions of inavolisib with its target are facil
itated by hydrogen bonds from the amide and
amino groups of the alanine fragment. Addi
tionally, the difluoromethyl group of inavolisib
interacts with the hydroxyl group of Ser774 wi
thin the p110α pocket [181]. Thus, fluorination
plays a crucial role in the unique effectiveness
of this next-generation PI3Kα inhibitor.
The synthetic route to prepare inavolisib
(Scheme 5) starts with 1,2:5,6-bis-O-(1-methy
lethylidene)-D-mannitol 30, which serves as a
source for the desired stereochemical configu
ration [183]. Sodium periodate (NaIO4) in hot
water is added to silica, forming a powder. This
mixture is then combined with compound
30 dissolved indichloromethane (DCM) and
stirred at room temperature for 1 hour, pro
ducing carbaldehyde 31. To the cooled car
baldehyde 31 solution in DCM, diethylamin
osulfur trifluoride (DAST) is added dropwise
and stirred at room temperature for 3 hours,
yielding (R)-4-difluoromethyl-2,2-dimethyl
[1,3] dioxolane 32. This intermediate is dis
solved in methanol (MeOH), and hydrochlo
ric acid (HCl) in dioxane is added, stirring at
room temperature for 30 minutes. The acetal
is cleaved to form the respective diol. After
work-up, the residue is dissolved in DCM, fol
lowed by the addition of tert-butyldimethyl
silyl chloride(TBDMS), Et3N, and catalytic
amounts of 4-Dimethylaminopyridine(DM
AP). Compound 33 was obtained after stirring
for 1 hour at room temperature. Following this,
trifluoromethanesulfonic anhydride (Tf2O) was
added dropwise to a solution of 33 and pyri
dine in DCM. The temperature was maintained
at -20 °C for 20 minutes, then brought to 0 °C
for 1 hour while stirring. After extraction and
work-up, the residue was dissolved in DMF, and
sodium azide (NaN3) was added, stirring for 2
hours at room temperature to produce inter
mediate 34. The azide was then reduced using
39https://ucj.org.ua
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palladium hydroxide on carbon (Pd-OH/C)
under hydrogen (H2) by stirring for 16 hours in
ethyl acetate (EtOAc) and MeOH, yielding pri
mary amine 35. This product was dissolved in
MeOH and stirred in a solution of HCl (in diox
ane) for 2 hours at room temperature to remove
the protective group. After work-up, the crude
product was dissolved in toluene and aqueous
potassium hydroxide (KOH) at 0°C. Phosgene
(COCl2) was added gradually, followed by stir
ring for 1 hour to obtain (S)-4-difluoromethy
loxazolidin-2-one 36. This was combined with
9-bromo-2-iodo-5,6-dihydrobenzo[f]imida
zo[1,2-d][1,4]-oxazepane 37, copper acetate
monohydrate (Cu(OAc)2·H2O), 3,4,7,8-tetram
ethyl-1,10-phenanthroline (TMPhen), and ce
sium carbonate (Cs2CO3) in dioxane. The mix
ture was heated to 100 °C for 18 hours under
an argon (Ar) atmosphere, resulting in com
pound 38. The reagent 37 can be obtained as
described in the literature [184]. Compound
38 was then suspended in dimethyl sulfoxide
(DMSO) with L-alanine, cuprous iodide (CuI),
and potassium phosphate tribasic (K3PO4), and
heated at 100 °C for 2 hours. After cooling to
room temperature, DMSO, ammonium chlo
ride (NH4Cl), and Et3N were added. To this
suspension, 1-[bis(dimethylamino)methylene]-
1H-1,2,3-triazolo[4,5-b]-pyridinium 3-oxide
hexafluorophosphate (HATU) was added drop
wise and stirred at room temperature for 1 hour.
Finally, inavolisib3 was obtained [183].
Scheme 5. Synthesis of Itovebi® (inavolisib) 3.
and cesium carbonate (Cs2CO3) in dioxane. The mixture was heated to 100°C for 18
hours under an argon (Ar) atmosphere, resulting in compound 38. The reagent 37 can
be obtained as described in the literature [184]. Compound 38 was then suspended in
dimethyl sulfoxide (DMSO) with L-alanine, cuprous iodide (CuI), and potassium
phosphate tribasic (K3PO4), and heated at 100°C for 2 hours. After cooling to room
temperature, DMSO, ammonium chloride (NH4Cl), and Et3N were added. To this
suspension, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-pyridinium
3-oxide hexafluorophosphate (HATU) was added dropwise and stirred at room
temperature for 1 hour. Finally, inavolisib3 was obtained [183].
O
O OH
HO
O
O O
O
O
H
F
O
O
F
F
O
OH
F TBMS
F
O
N3
F TBMS
F
O
NH2
F TBMS
F
F O
H
N O
N
O
Br N I N
OBr
N
N
O
O
F
F
N
OH
N
N
N
O
O
F
F
H2N O
30
NaIO4,
H2O
DCM,
rt, 1 h 31, 75% yield
DCM,
DAST
0 °C - rt,
3 h 32, 79% yield
1) MeOH, HCl/dioxane
rt, 30 min
2) DCM, TBDMSCl
DMAP, Et3N
-10 °C - rt, 1 h
33, 31% yield
1) DCM, Tf2O,
pyridine
-20 °C, 20 min;
0 °C, 1 h
2) DMF, NaN3
rt, 2 h 34
EtOAc/MeOH
H2, Pd-OH/C
16 h
35, 90% yield
1) MeOH, HCl/dioxane
rt, 2 h
2) toluene, KOHaq, COCl2
0 - 10 °C, 1 h
36, 68% yield
37
dioxane, Cu(OAc)2·H2O,
TMPhen, Cs2CO3, Ar
100 °C, 18 h
38, 63% yield
1) DMSO, CuI, K3PO4
100 °C, 2 h,
2) L-alanine
DMSO, NH4Cl, HATU
rt, 1 h
3, 46% yield
Scheme 5. Synthesis of Itovebi® (inavolisib) 3.
Scemblix® (asciminib)(4)
Asciminib is an efficacious, small-molecule, orally bioavailable, and a selective
allosteric inhibitor discovered and developed by Novartis for the treatment of
hematologic malignancies, including Philadelphia chromosome-positive (Ph+) chronic
myeloid leukemia (CML) [185,186]. In October 2021, the U.S. FDA approved
Scemblix® for two distinct indications in CML [185]. In vitro anticancer activity tests
against MV411 (ATCC) and K562 (ATCC) leukemia cells demonstrated that asciminib
exhibited potent inhibitory activity, with cellular IC50 values of 8.65 μmol/L for K562
and 0.32 μmol/L for MY411. However, its structurally similar analog, compound 39
40 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Scemblix® (asciminib)(4)
Asciminib is an efficacious, small-molecule,
orally bioavailable, and a selective allosteric in
hibitor discovered and developed by Novartis
for the treatment of hematologic malignancies,
including Philadelphia chromosome-posi
tive (Ph+) chronic myeloid leukemia (CML)
[185,186]. In October 2021, the U.S. FDA ap
proved Scemblix® for two distinct indications
in CML [185]. In vitro anticancer activity tests
against MV411 (ATCC) and K562 (ATCC)
leukemia cells demonstrated that asciminib
exhibited potent inhibitory activity, with cel
lular IC50 values of 8.65 μmol/L for K562 and
0.32 μmol/L for MY411. However, its structur
ally similar analog, compound 39 (Figure 5),
showed moderate activity against the leukemia
cell lines (K562 IC50 > 30 μmol/L and MY411
IC50 > 30 μmol/L).
Fig. 5. Structures of Scemblix® (asciminib) 4 and its fluorine-free analog 39.
(Figure 5), showed moderate activity against the leukemia cell lines (K562 IC50> 30
μmol/L and MY411 IC50> 30 μmol/L).
Fig. 5. Structures of Scemblix® (asciminib) 4 and its fluorine-free analog 39.
This study indicated that the CF2Cl group in the asciminib structure is crucial for
inducing inactive conformations. Additionally, the pyrazole ring in its structure reduces
hERG toxicity [186,187]. As an allosteric inhibitor targeting ABL1, asciminib binds to
the myristoyl pocket of ABL1 to inhibit BCR-ABL1 activity, differing from
competitive inhibitors that target the ATP-binding site, such as imatinib, dasatinib, and
nilotinib, which are associated with risks of resistance and site mutations [188–191].
Due to its unique allosteric regulatory mechanism, asciminib not only inhibits
wild-type ABL1 kinase but also exhibits high activity against the T315I-mutated ABL1,
significantly reducing the potential off-target effects of ATP-binding site inhibitors. In
October 2024, the U.S. FDA granted accelerated approval to asciminib for the
treatment of newly diagnosed adult patients with Philadelphia chromosome-positive
chronic myeloid leukemia in chronic phase (Ph+ CML-CP) [192].
The synthesis of asciminib 4 has been documented by several groups [186, 193,
194]. One efficient method, illustrated in Scheme 6, begins with
5-bromo-6-chloronicotinic acid 40 as the starting material [186]. Chlorination of
5-bromo-6-chloronicotinic acid 40 using thionyl chloride in the presence of DMF in
toluene at 80 °C produces acid chloride 41. This intermediate then undergoes insitu
condensation with 4-(chlorodifluoromethoxy)aniline 42 in the presence of DIPEA in
THF at room temperature, forming amide 43 with a 77% yield. Next, compound 43 is
reacted with (R)-pyrrolidin-3-ol 44 in the presence of DIPEA and isopropanol at 140 °C
for 1 hour, producing derivative 45 with a 92% yield. Compound 45 is then subjected to
a standard Suzuki – Miyaura coupling reaction with the protected
(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid pinacol ester 46, resulting
in compound 47. Finally, the protecting group is removed at 10 °C in the presence of
trifluoroacetic acid in DCM, yielding the target product, asciminib 4, with a 77% yield.
This study indicated that the CF2Cl group in
the asciminib structure is crucial for inducing
inactive conformations. Additionally, the pyra
zole ring in its structure reduces hERG toxicity
[186, 187]. As an allosteric inhibitor targeting
ABL1, asciminib binds to the myristoyl pocket
of ABL1 to inhibit BCR-ABL1 activity, differ
ing from competitive inhibitors that target the
ATP-binding site, such as imatinib, dasatinib,
and nilotinib, which are associated with risks of
resistance and site mutations [188–191]. Due
to its unique allosteric regulatory mechanism,
asciminib not only inhibits wild-type ABL1 ki
nase but also exhibits high activity against the
T315I-mutated ABL1, significantly reducing
the potential off-target effects of ATP-binding
site inhibitors. In October 2024, the U.S. FDA
granted accelerated approval to asciminib for
the treatment of newly diagnosed adult pa
tients with Philadelphia chromosome-positive
chronic myeloid leukemia in chronic phase
(Ph+ CML-CP) [192].
The synthesis of asciminib 4 has been docu
mented by several groups [186, 193, 194]. One
efficient method, illustrated in Scheme 6, be
gins with 5-bromo-6-chloronicotinic acid 40
as the starting material [186]. Chlorination of
5-bromo-6-chloronicotinic acid 40 using thio
nyl chloride in the presence of DMF in toluene
at 80 °C produces acid chloride 41. This inter
mediate then undergoes insitu condensation
with 4-(chlorodifluoromethoxy)aniline 42 in
the presence of DIPEA in THF at room tem
perature, forming amide 43 with a 77% yield.
Next, compound 43 is reacted with (R)-pyrro
lidin-3-ol 44 in the presence of DIPEA and iso
propanol at 140 °C for 1 hour, producing deriv
ative 45 with a 92% yield. Compound 45 is then
41https://ucj.org.ua
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subjected to a standard Suzuki – Miyaura cou
pling reaction with the protected (1-(tetrahyd
ro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic
acid pinacol ester 46, resulting in compound
47. Finally, the protecting group is removed at
10 °C in the presence of trifluoroacetic acid in
DCM, yielding the target product, asciminib 4,
with a 77% yield.
Scheme 6. Synthesis of Scemblix® (asciminib) 4.
NN
O
H
N
O Cl
F
F
N NH
HO
Asciminib 4, 77% yield
NN
O
H
N
O Cl
F
F
N N
HO
O
NN
O
H
N
O Cl
F
F
HO
O
O
B
N N O
Pd(PPh3)4, K3PO4
toluene, 110 oC
NCl
O
H
N
O Cl
F
F
BrBr
HO NH
DIPEA, i-PrOH,
140 oC
Br
Cl
O
Cl N
H2N
O Cl
F
F
DIPEA, THF, rt
Br
OH
O
Cl N
SOCl2, DMF
toluene, 80 oC
40 41
42
43, 77% yield
44
45, 92% yield
46
47
DCM, 10 oC
TFA
Scheme 6. Synthesis of Scemblix® (asciminib) 4.
Revuforj® (revumenib)(5)
Revumenib, an orally administered and first-in-class menin inhibitor developed
by Syndax Pharmaceuticals, received FDA approval in November 2024 for the
treatment of patients with relapsed or refractory (R/R) acute leukemia harboring lysine
methyltransferase 2A (KMT2A) gene translocations [195, 196]. Before this approval,
revumenib was granted orphan drug designation by the FDA for the treatment of acute
myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and acute
undifferentiated leukemia (ALAL), as well as by the European Commission for the
treatment of AML [197].
This novel drug disrupts the interaction between menin and KMT2A fusion
proteins, which are key drivers of leukemogenesis [195,198]. By inhibiting this
interaction, revumenib helps restore normal gene expression, effectively halting cancer
cell proliferation and promoting cell differentiation.
In cellular experiments, revumenib demonstrated an IC50 of 10–20 nmol/L for
inhibiting Menin-MLL, whereas its structurally similar compounds 48 and 49 (Figure 6)
showed poorer inhibitory activity with IC50 values for Menin-MLL exceeding 20
nmol/L. The superior inhibitory activity of revumenib5against Menin-MLL may be
attributed to the fluorine atom in its structure [199].
Revuforj® (revumenib)(5)
Revumenib, an orally administered and first-
in-class menin inhibitor developed by Syndax
Pharmaceuticals, received FDA approval in No
vember 2024 for the treatment of patients with
relapsed or refractory (R/R) acute leukemia
harboring lysine methyltransferase 2A (KM
T2A) gene translocations [195, 196]. Before this
approval, revumenib was granted orphan drug
designation by the FDA for the treatment of
acute myeloid leukemia (AML), acute lympho
blastic leukemia (ALL), and acute undifferenti
ated leukemia (ALAL), as well as by the Europe
an Commission for the treatment of AML [197].
This novel drug disrupts the interaction
between menin and KMT2A fusion proteins,
which are key drivers of leukemogenesis
[195,198]. By inhibiting this interaction, revu
menib helps restore normal gene expression,
effectively halting cancer cell proliferation and
promoting cell differentiation.
In cellular experiments, revumenib demon
strated an IC50 of 10–20 nmol/L for inhibiting
Menin-MLL, whereas its structurally simi
lar compounds 48 and 49 (Figure 6) showed
poorer inhibitory activity with IC50 values for
Menin-MLL exceeding 20 nmol/L. The supe
rior inhibitory activity of revumenib 5 against
Menin-MLL may be attributed to the fluorine
atom in its structure [199].
42 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
F
O
N
O
N
N
O
ON
N
S
H
N
Revumenib 5
H
N
S
N
N O
O
N
N
O
N
O
Cl
OH
H
N
S
N
N O
O
N
N
O
N
O
OH
Menin-MLL IC50 10-20 nmol/L
Menin-MLL IC50 20 nmol/L Menin-MLL IC50 20 nmol/L48 49
Fig. 6. Structures of Revuforj® (revumenib) 5 and its fluorine-free analogs 48 and 49.
Clinical trials have shown promising results. When used as monotherapy for
relapsed or refractory AML, revumenib 5 demonstrated significant efficacy,
particularly in cases with nucleophosmin 1 (NPM1) mutations. This approval marks a
significant advancement in the field of leukemia treatment, offering new hope for
patients with limited therapeutic options [200, 201].
The synthetic route for the preparation of revumenib (5) is outlined in Scheme 7,
starting with 2-bromo-4-fluorophenol 50 as the initial material [202]. Compound 50
underwent a substitution reaction with ethyl 2-bromoacetate in the presence of K2CO3,
yielding compound 51 with an 86% yield. Compound 51 was first reacted in anhydrous
THF, using ethyl formate and NaH as reagents. It then underwent a cyclization
condensation reaction with thiourea at 90°C, resulting in the pyrimidinone compound
52 with a 54% yield.
Fig. 6. Structures of Revuforj® (revumenib) 5 and its fluorine-free analogs 48 and 49.
Clinical trials have shown promising re
sults. When used as monotherapy for relapsed
or refractory AML, revumenib 5 demonstrated
significant efficacy, particularly in cases with
nucleophosmin 1 (NPM1) mutations. This ap
proval marks a significant advancement in the
field of leukemia treatment, offering new hope
for patients with limited therapeutic options
[200, 201].
The synthetic route for the preparation of
revumenib (5) is outlined in Scheme 7, start
ing with 2-bromo-4-fluorophenol 50 as the in
itial material [202]. Compound 50 underwent
a substitution reaction with ethyl 2-bromoace
tate in the presence of K2CO3, yielding com
pound 51 with an 86% yield. Compound 51
was first reacted in anhydrous THF, using ethyl
formate and NaH as reagents. It then under
went a cyclization condensation reaction with
thiourea at 90°C, resulting in the pyrimidinone
compound 52 with a 54% yield.
Subsequently, compound 52 was subject
ed to a desulfurization reduction reaction in
the presence of Raney Ni, yielding compound
53 with a 99% yield. Compound 53 was then
reacted with CO and methanol under the ca
talysis of Pd(dppf)Cl2, affording compound
54 with a 45% yield. In the presence of SOCl2,
compound 54 underwent a substitution reac
tion, resulting in derivative55 with a 57% yield.
Ester 55 was then reacted with bicyclic pro
perly protected diamine 56 in the presence of
TEA, using isopropanol as the solvent, to yield
compound 57 with a 77% yield. Precursor 57
first underwent a hydrolysis reaction in the
presence of LiOH, followed by an amidation
reaction with amine 58 in the presence of BOP,
yielding product 59 with a 70% yield. Deriva
tive 59 was first deprotected of its Boc-protect
ing group in the presence of TEA and DCM as
solvents. It subsequently reacted with activa
ted cyclic amino alcohol 60 in the presence of
K2CO3, KI, and NMP, giving rise torevumenib
5 with a 37% yield [202].
43https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 9 / Vol. 90
Scheme 7. Synthesis of Revuforj® (revumenib) 5.
F
O
N
O
N
N
O
ON
N
S
H
NO
O
S
NH
OS
O
O
F
O
N
O
N
N N
N
O
O
F
O
OMe
O
N
N N
N
O
O
H
N
F
O
OMe
O
N
N Cl
O
O
N NH HCl
F
O
OMe
O
N
N OH
N
N
O
Br
F
F Br
O
N
H
NH
O
SF Br
O
OEt
O
F Br
OH
OEt
O
Br
K2CO3, MeCN
90 oC, 1.5 h 51, 86% yield
1) ethyl formate, THF
NaH, 35-45 oC, 18 h
2) thiourea, EtOH
90 oC, 16 h 52, 54% yield
EtOH, Raney Ni
reflux, 6 h
53, 99% yield
TEA, Pd(dppf)Cl2, CO
DMF, MeOH
80 oC, 24 h
54, 45% yiled
SOCl2, DMF
70 oC, 2 h
55, 57% yield
TEA, 2-PrOH, 80 oC, 3 h
57, 77% yield
1) LiOH, MeOH
20 oC, 4 h
59, 70% yield
2)
TEA, DMF, BOP
rt, 4 h
1) TFA, DCM, 20 oC, 0.5 h
Revumenib 5, 37% yield
2) K2CO3, KI, NMP, 70 oC, 18 h
50
56
60
OH
58
Scheme 7. Synthesis of Revuforj® (revumenib) 5.
Subsequently, compound 52 was subjected to a desulfurization reduction reaction
in the presence of Raney Ni, yielding compound 53 with a 99% yield. Compound 53
was then reacted with CO and methanol under the catalysis of Pd(dppf)Cl2, affording
compound 54 with a 45% yield. In the presence of SOCl2, compound 54 underwent a
substitution reaction, resulting in derivative55 with a 57% yield. Ester 55 was then
reacted with bicyclic properly protected diamine 56 in the presence of TEA, using
isopropanol as the solvent, to yield compound 57 with a 77% yield. Precursor 57 first
underwent a hydrolysis reaction in the presence of LiOH, followed by an amidation
reaction with amine 58 in the presence of BOP, yielding product 59 with a 70% yield.
Derivative 59 was first deprotected of its Boc-protecting group in the presence of TEA
and DCM as solvents. It subsequently reacted with activated cyclic amino alcohol 60 in
the presence of K2CO3, KI, and NMP, giving rise torevumenib 5 with a 37% yield
[202].
CONCLUSIONS. This year’s crop of FDA-approved small-molecule drugs
containing fluorine and amino acid residues consists of five pharmaceuticals: Voydeya®
(danicopan) 1, Ojemda® (tovorafenib) 2, Itovebi® (inavolisib) 3, Scemblix® (asciminib)
4, and Revuforj® (revumenib) 5. Four of these drugs (2-5) were developed to fight
various types of cancer, while danicopan (1) was approved for the treatment of a rare
CONCLUSIONS. This year’s crop of FDA-
approved small-molecule drugs containing
fluorine and amino acid residues consists of
five pharmaceuticals: Voydeya® (danicopan) 1,
Ojemda® (tovorafenib) 2, Itovebi® (inavolisib) 3,
Scemblix® (asciminib) 4, and Revuforj® (revu
menib) 5. Four of these drugs (2-5) were de
veloped to fight various types of cancer, while
danicopan (1) was approved for the treatment
of a rare form of blood disease.
The tailor-made amino acidsinclude 3-sub
stituted proline (1), alanine (2, 3), and amino
acid-derived cyclic amino alcohols (3, 4) and
diamines (5). The types of fluorination are rep
resented by cyclic CHF (1), hetero-aromatic
CF3 (2), aliphatic CHF2 group (3), aromatic
CClF2-O group (4), and aromatic fluorine (5).
An important trend observed in new small-
molecule pharmaceuticals, and this group of
drugs in particular, is that all five compounds
44 ISSN 2708-129X. Укр. хім. журн., 2024
NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
under discussion are chiral, possessing one
(2, 3) or two (1, 3, 4) stereogenic carbons.
Considering the FDA requirements for chiral
drugs, continuous advances in the asymmetric
synthesis and characterization of chiral fluo
rine-containing compounds are of great im
portance. In this regard, particular attention
should be given to the phenomenon of the
self-disproportionation of enantiomers (SDE),
a non-linear behavior of enantiomerically en
riched compounds [203–205]. The SDE pro
perties of chiral drugs, especially those con
taining fluorine [206–208] and/or AA residues
[209–211], are a critical public safety issue, re
quiring additional scrutiny in evaluating their
enantiomeric purity [212–215].
We gratefully acknowledge the finan
cial support from the National Na
tural Science Foundation of China
(No. 21761132021), the Qing-Lan Pro
ject of Jiangsu Province (for Han) and
IKERBASQUE, Basque Foundation
for Science (for Soloshonok).
НОВІ ПРЕПАРАТИ НА ФАРМАЦЕВТИЧНОМУ
РИНКУ, ЩО МІСТЯТЬ ФТОР І ЗАЛИШКИ
СПЕЦІАЛЬНО СТВОРЕНИХ АМІНОКИСЛОТ
Ц. Хань1*, А. Взорек2, Г. Дхаван3,4*, В. Зханг5*,
О. Є. Сорочинський6*, Д. Бекер7*, Т. Оно8,
К. Д. Клика9, В. A. Солошонок10,11*
1Спільний інноваційний центр Цзянсу з ефек-
тивного оброблення та використання лісових
ресурсів, Коледж хімічної інженерії,
Нанкінський лісотехнічний університет,
210037 Нанкін, Китай;
2Інститут хімії, Університет імені Яна Коха-
новського в Кельцях, Кельці, Польща;
3 Школа медичних наук, Університет підприєм-
ництва,
Делі, 110077 Нью-Делі, Індія
4Коледж Ачаріа Нарендра Дев, Університет Делі,
110019 Нью-Делі, Індія;
5Департамент хімії, Массачусетський універ-
ситет,
Бостон, 02125 Массачусетс, США;
6Інститут біоорганічної хімії та нафтохімії
ім. В. П. Кухаря НАН України,
Київ, Україна;
7Департамент фармацевтичної та медичної
хімії, Інститут фармації,
Вільний університет Берліна,
14195 Berlin, Germany;
8Національний інститут передових промисло-
вих наук і технологій,
463–8560 Нагоя, Японія
9Німецький центр дослідження раку (DKFZ),
69120 Гейдельберг, Німеччина;
10Хімічний факультет, Університет Країни
Басків,
20018 Сан-Себастьян, Іспанія;
11ІКЕРБАСК, Баскський фонд науки,
48013 Більбао, Іспанія
*email: vadimsoloshonok@gmail.com
У статті розглянуто п’ять нових пре
паратів, схвалених FDA, що містять фтор
і фрагменти амінокислот або їхніх похід
них. До цих лікарських засобів належать:
Voydeya® (danicopan), Ojemda® (tovorafenib),
Itovebi® (inavolisib), Scemblix® (asciminib) та
Revuforj® (revumenib). Описано відкриття
кожного препарату, терапевтичне застосу
вання та детальний хімічний синтез.
Ключові слова: фтор, спеціально ство
рені амінокислоти, фармацевтичні препа
рати, дизайн ліків, синтез, біоактивність.
45https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 9 / Vol. 90
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Cтаття надійшла 10.07.2024.
НАЦІОНАЛЬНА АКАДЕМІЯ НАУК УКРАЇНИ
ІНСТИТУТ ЗАГАЛЬНОЇ ТА НЕОРГАНІЧНОЇ ХІМІЇ імені В. І. ВЕРНАДСЬКОГО
КИЇВСЬКИЙ НАЦІОНАЛЬНИЙ УНІВЕРСИТЕТ імені ТАРАСА ШЕВЧЕНКА
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| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-689 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:12:10Z |
| publishDate | 2024 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/84/7ce7e498c8dc3015cb1c14c595365084.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-6892026-07-22T08:23:55Z NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim Fluorine, Tailor-made amino acids, Pharmaceutical drugs, Drug design, Synthesis, Bioactivity. This article profiles five newly drugs containing fluorine along with fragments of amino acids or their derivatives approved by the FDA in 2024. These pharmaceuticals include Voydeya® (danicopan), Ojemda® (tovorafenib), Itovebi® (inavolisib), Scemblix® (asciminib), and Revuforj® (revumenib). For each drug, we discuss the discovery, therapeutic areas of application, and detailed chemical synthesis. V.I.Vernadsky Institute of General and Inorganic Chemistry 2024-10-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/689 10.33609/2708-129X.90.9.2024.31-56 Ukrainian Chemistry Journal; Vol. 90 No. 9 (2024): Ukrainian Chemistry Journal; 31-56 Украинский химический журнал; ##issue.vol## 90 ##issue.no## 9 (2024): Ukrainian Chemistry Journal; 31-56 Український хімічний журнал; Том 90 № 9 (2024): Ukrainian Chemistry Journal; 31-56 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/689/343 Copyright (c) 2024 Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander Sorochinsky, Daniel Baecker, Taizo Ono, Karel Klika, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title | NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title_full | NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title_fullStr | NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title_full_unstemmed | NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title_short | NEW DRUGS ON THE PHARMACEUTICAL MARKET CONTAINING FLUORINE AND RESIDUES OF TAILOR-MADE AMINO ACIDS(Review) |
| title_sort | new drugs on the pharmaceutical market containing fluorine and residues of tailor-made amino acids(review) |
| topic_facet | Fluorine Tailor-made amino acids Pharmaceutical drugs Drug design Synthesis Bioactivity. |
| url | https://ucj.org.ua/index.php/journal/article/view/689 |
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