FDA-Approved Fluorinated Heterocyclic Drugs from 2016 to 2022

The inclusion of fluorine atoms or heterocyclic moiety into drug structures represents a recurrent motif in medicinal chemistry. The combination of these two features is constantly appearing in new molecular entities with various biological activities. This is demonstrated by the increasing number of newly synthesized fluorinated heterocyclic compounds among the Food and Drug Administration FDA-approved drugs. In this review, the biological activity, as well as the synthetic aspects, of 33 recently FDA-approved fluorinated heterocyclic drugs from 2016 to 2022 are highlighted.


Introduction
The presence of many different heterocyclic rings in natural products, such as alkaloids, vitamins, antibiotics, peptides, etc., prompted the introduction of structural motifs into synthetic drugs [1,2]. Therefore, heterocycles are considered to be prominent scaffolds for the synthesis of biologically active compounds and prospective drugs [3,4]. In fact, it is estimated that heterocyclic moieties are present in around 85% of bioactive compounds [5]. On the other hand, in the second half of 20th century, another fundamental tool for drug design was introduced with the incorporation of fluorine atoms into drugs [6][7][8]. Since the introduction of the first fluorocorticosteroid, fludrocortisone, in 1954 [9], the fluorinated drugs market has exponentially evolved, with 20% of those on the market being fluorinated drugs and around 30% of fluorinated drugs being blockbuster pharmaceuticals, such as Lipitor, Fluoxetine, Linezolid or Fluticasone [8]. To date, more than 300 fluorinated pharmaceuticals have been approved for use as drugs [6]. The success of the introduction of fluorine atoms is linked to the peculiar physicochemical properties of the C-F bond [10], which are the high bond strength, polarity and minimal steric hindrance of fluorine [11], combined with a general metabolic stability that, nevertheless, is an issue that is currently under exploration [12].
The introduction of fluorine, for example, allows researchers to easily modulate the pK a of neighboring functionalities, improving the bioavailability and affinity to specific receptors [13,14].
In addition, the monofluorination or trifluoromethylation of alkyl groups decreases the drug lipophilicity due to the strong electron-withdrawing capabilities of fluorine. On the other hand, fluoro-arenes are more lipophilic due to the low polarizability of the C-F bond [15]. In addition, the presence of a fluorine atom can also enhance the membrane's permeability [16].
The importance of fluorinated compounds is also linked to their use as diagnostic tools within imaging techniques such as 19 F-MRI and 18 F-PET [17,18].
The direct link between fluorinated moieties and heterocycles led to the formation of the sub-class of fluorinated heterocycles, which combine the strength of these two fundamental scaffolds in modern medicinal chemistry. This important class of fluorinated pharmaceuticals includes some of the selected examples of FDA-approved drugs reported in Figure 1. Among these compounds, there have been several game changers over the last decades, such as fluorouracil, the class of fluoroquinolones, sitagliptin and fluorodeoxyglucose, just to mention a few [19].
bond [15]. In addition, the presence of a fluorine atom can also enhance the membrane's permeability [16].
The importance of fluorinated compounds is also linked to their use as diagnostic tools within imaging techniques such as 19 F-MRI and 18 F-PET [17,18].
The direct link between fluorinated moieties and heterocycles led to the formation of the sub-class of fluorinated heterocycles, which combine the strength of these two fundamental scaffolds in modern medicinal chemistry. This important class of fluorinated pharmaceuticals includes some of the selected examples of FDA-approved drugs reported in Figure 1. Among these compounds, there have been several game changers over the last decades, such as fluorouracil, the class of fluoroquinolones, sitagliptin and fluorodeoxyglucose, just to mention a few [19].
In this review, recent advances in the field of fluorinated heterocyclic drugs are presented, discussing FDA-approved molecules from 2016 to 2022. The molecules considered in this article are limited to those with a fluorinated group directly linked to the heterocyclic ring. The biological targets and the therapeutic indications are presented together with synthetic details. The fluorination strategy and influence of the fluorinated moiety on bioactivity are also discussed. The sections are reported in chronological order, starting with the most recently approved drugs; for each section, the compounds are presented in alphabetical order.

Introduction of Fluorine Atoms in Organic Molecules
Fluorinated starting materials used as precursors to obtain fluorinated, approved drugs can present mono-, di-and trifluoro alkyl groups; the last ones can be generally introduced via building blocks such as trifluoroacetate, trifluoroethylamine, trifluoro and ethyl triflate. Furthermore, several starting materials used for this purpose are formed by aromatic or heterocyclic rings bearing F atoms, such as (poly)fluorobenzoic acid, fluoroor trifluoromethylpyridines, just to cite a few of them (see below). In this review, recent advances in the field of fluorinated heterocyclic drugs are presented, discussing FDA-approved molecules from 2016 to 2022. The molecules considered in this article are limited to those with a fluorinated group directly linked to the heterocyclic ring. The biological targets and the therapeutic indications are presented together with synthetic details. The fluorination strategy and influence of the fluorinated moiety on bioactivity are also discussed. The sections are reported in chronological order, starting with the most recently approved drugs; for each section, the compounds are presented in alphabetical order.

Introduction of Fluorine Atoms in Organic Molecules
Fluorinated starting materials used as precursors to obtain fluorinated, approved drugs can present mono-, di-and trifluoro alkyl groups; the last ones can be generally introduced via building blocks such as trifluoroacetate, trifluoroethylamine, trifluoro and ethyl triflate. Furthermore, several starting materials used for this purpose are formed by aromatic or heterocyclic rings bearing F atoms, such as (poly)fluorobenzoic acid, fluoro-or trifluoromethylpyridines, just to cite a few of them (see below).

Figure 2.
Representative reaction schemes for introduction of F atoms into organic molecules. Introduction of (a) two, (b) one or (c) three fluorine atoms into alkyl chains. Introduction of (d) one fluorine or (e) trifluoromethyl into aromatics. Trifluoromethylated starting materials such as trifluoroacetic acid are industrially prepared in excellent yields by the electrochemical fluorination of acetyl chloride or acetic anhydride in anhydrous hydrogen fluoride, followed by the hydrolysis of the resulting trifluoroacetyl fluoride (Figure 2c) [22]. Fluorination methods of arenes include traditional nucleophilic substitution ( Figure 2d) and transition-metal-catalyzed nucleophilic fluorination or deoxofluorination [21]. For the introduction of trifluoromethyl groups, substrates can be trifluoromethylated by employing electrophilic trifluoromethylating reagents [23], such as Togni reagents [24], and S-(trifluoromethyl)dibenzothiophenium salts [25], or lower cost reagents such as CF 3 I or CF 3 H, which are favored for industrial processes, while the use of the solid and bench-top-stable reagents such as NaSO 2 CF 3 in radical trifluoromethylations for the trifluoromethylation of electron-rich arenes avoids perfluoroalkylations (Figure 2e) [21].

FDA-Approved Drugs in 2022
In 2022, the FDA approved 37 new therapeutic and diagnostic products [26]. Monoclonal antibodies (mAbs) continue to be one of the most widely licensed groups of biological therapies. Nevertheless, 22 of them are novel chemical entities (NCEs), 14 of which contain fluorine atoms and nitrogen heterocycles [27]. Lenacapavir (Schemes 1 and 2) and Oteseconazole (Scheme 3), two new approved drugs released in the past year, combine these two key characteristics.

FDA-Approved Drugs in 2022
In 2022, the FDA approved 37 new therapeutic and diagnostic products [26]. Monoclonal antibodies (mAbs) continue to be one of the most widely licensed groups of biological therapies. Nevertheless, 22 of them are novel chemical entities (NCEs), 14 of which contain fluorine atoms and nitrogen heterocycles [27]. Lenacapavir (Schemes 1 and 2) and Oteseconazole (Scheme 3), two new approved drugs released in the past year, combine these two key characteristics. Lenacapavir (SUNLENCA ® ) is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor developed by Gilead Science Inc., and it is administered in cases when conventional antiretroviral therapies are ineffective. The mechanism of action is totally different from that of other antivirals used for the treatment of HIV-1. Indeed, Lenacapavir establishes several hydrophobic and electrostatic interactions with capsid subunits (CA1 and CA2). For example, the difluorobenzyl group can be stabilized inside a hydrophobic pocket of the CA1 N-terminal domain. This entails interference with virus life cycle processes where CA is involved, such as reverse transcription, nuclear import and integration [28,29].
The synthetic method to obtain Lenacapavir is divided into three steps and is reported in Schemes 1 and 2 [30].
The Claisen condensation of 1 using a strong base, such as lithium bis(trimethylsilyl)amide and ethyl 2,2,2-trifluoroacetate, leads to enolate 2, presenting a CF 3 group. At this point, pyrazole ring 3 formation occurs due to the addition of an ethyl hydrazinoacetate salt.
Intermediate 4 is obtained through N-hydroxyphtalimide-catalyzed selective oxidation, followed by saponification with NaOH. To obtain building block 6, the desulfurative fluorination of dithiolane 5 takes place, followed by supercritical fluid chromatography (SFC).
The synthesis proceeds with the construction of building block 9. To acquire substituted indazole core 8, hydrazine is combined with fluorobenzonitrile 7, and then a trifluoroethyl group is introduced via a substitution at position one.
A cross-coupling reaction between bis(pinacolato)diboron and 8 in the presence of a palladium/triphenylphosphine catalyst and potassium propionate creates 9. In order to produce Lenacapavir, deprotection preceded by the formation of an amide bond between carboxylic acid 6 and ammine 14 must occur.
Intermediate 14 is obtained via two palladium-catalyzed coupling reactions between fluorinated compound 10 and amine 13, followed by a protection with methanesulfonyl chloride on the amino group linked to the indazole ring.

Sotorasib
The brand name for the new drug marketed by Amgen is LUMAKRASTM TM . The pharmacologically active agent, Sotorasib, it is an RAS small GTPase inhibitor used to treat colorectal cancer and non-small-cell lung cancer brought on by the KRAS G12C oncogene [42]. To improve the pharmacokinetic properties such as oral bioavailability, azaquinazolinone is designed with a fluorine atom on C6 carbon, a fluorophenol residue on C7 and a nitrogen atom instead of C8 carbon [43]. The Sotorasib synthetic process is described in Scheme 6 [44].
Starting with 2,6-dichloro-5-fluoronicotinic acid 29, acyl chloride is obtained through the use of oxalyl chloride; this is then converted to the corresponding amide, 30. The formation of compound 31 is carried out through the reaction between nicotinamide 30 and 2-isopropyl-4-methylpyridin-3-amine. Compound 31 is then treated with potassium hexamethyldisilazane to drive cyclization and produce the duly substituted 2,4-dihydroxypyrido [2,3-d]pyrimidine ring 32. At this point, the chlorination reaction produces intermediate 33, which, in turn, can be combined with a Boc-protected methylpiperazine to produce a selective amination. The resulting compound 34 is reacted with organotrifluoroborate salt via a Suzuki−Miyaura cross-coupling reaction to attach fluorophenol moiety 35. Deprotection and amidation of nitrogen of the piperazine ring eventually produces Sotorasib. In 2022, the same Amgen group developed a commercial manufacturing process, in which they improved several synthetical steps, starting with compound 32 [45].

Sotorasib
The brand name for the new drug marketed by Amgen is LUMAKRASTM TM . The pharmacologically active agent, Sotorasib, it is an RAS small GTPase inhibitor used to treat colorectal cancer and non-small-cell lung cancer brought on by the KRAS G12C oncogene [42]. To improve the pharmacokinetic properties such as oral bioavailability, azaquinazolinone is designed with a fluorine atom on C6 carbon, a fluorophenol residue on C7 and a nitrogen atom instead of C8 carbon [43]. The Sotorasib synthetic process is described in Scheme 6 [44].
Starting with 2,6-dichloro-5-fluoronicotinic acid 29, acyl chloride is obtained through the use of oxalyl chloride; this is then converted to the corresponding amide, 30. The formation of compound 31 is carried out through the reaction between nicotinamide 30 and 2-isopropyl-4-methylpyridin-3-amine. Compound 31 is then treated with potassium hexamethyldisilazane to drive cyclization and produce the duly substituted 2,4-dihydroxypyrido [2,3-d]pyrimidine ring 32. At this point, the chlorination reaction produces intermediate 33, which, in turn, can be combined with a Boc-protected methylpiperazine to produce a selective amination. The resulting compound 34 is reacted with organotrifluoroborate salt via a Suzuki−Miyaura cross-coupling reaction to attach fluorophenol moiety 35. Deprotection and amidation of nitrogen of the piperazine ring eventually produces Sotorasib. In 2022, the same Amgen group developed a commercial manufacturing process, in which they improved several synthetical steps, starting with compound 32 [45].

Umbralisib
Umbralisib is sold under the brand name Ukuoniq and was developed by TG Therapeutics. It was approved in February 2021 for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL) [46]. The mode of action of Umbralisib is related to the inhibition of kinase PI3K-delta and casein kinase CK1-epsilon. Umbralisib contains a 6-fluoro-chromen-4-one central heterocyclic core and two other fluorophenyl groups. The synthesis was disclosed in a patent in 2014 and is presented in Scheme 7 [47].

Umbralisib
Umbralisib is sold under the brand name Ukuoniq and was developed by TG Therapeutics. It was approved in February 2021 for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL) [46]. The mode of action of Umbralisib is related to the inhibition of kinase PI3K-delta and casein kinase CK1-epsilon. Umbralisib contains a 6-fluoro-chromen-4-one central heterocyclic core and two other fluorophenyl groups. The synthesis was disclosed in a patent in 2014 and is presented in Scheme 7 [47].

Vericiguat
Vericiguat is sold under the brand name Verquvo and was developed by Bayer AG and Merck & Co. It was approved in January 2021 to reduce the risks of cardiovascular death and heart failure [48].
Vericiguat is a guanylate cyclase (sGC) stimulator with a 1H-pyrazolo [3,4-b]pyridine core bearing a fluorine atom at C-5. The presence of the fluorine atom increases the metabolic stability and induces lower clearance. The method for the synthesis of Vericiguat is reported in Scheme 8 [48].
Tetrafluoropropanol 50, the starting fluorinated building block, is converted in two steps into morpholino derivative 51, and then into morpholinium cation 52 after methylation with methyl methanesulfonate. Compound 53 is obtained after a treatment with NaOH, which induces the elimination of the first fluorine atom as HF.
Other two fluorine atoms from the difluoromethyl group are lost during hydrolysis into 2-fluoroacrolein derivative 54. α,β-unsaturated aldehyde 54 reacts with aminopyrazole 55 under acidic cyclization conditions, allowing the introduction of the 5-fluorine atom into the 1H-pyrazolo [3,4-b]pyridine core of derivative 56. Ester 56 is then converted in three steps into amidine 59, via amide 57 and nitrile 58. The C-3 pyrimidine ring is then constructed with a condensation between 59 and hydrazonomalonitrile 60. Using compound 61, the synthesis of Vericiguat is completed in two steps via the catalytic hydrogenation of the diazo moiety of 61 to triaminopyrimidine 62, and finally, via the formation of the carbamate group of the target compound after a treatment with methyl chloroformate.

Vericiguat
Vericiguat is sold under the brand name Verquvo and was developed by Bayer AG and Merck & Co. It was approved in January 2021 to reduce the risks of cardiovascular death and heart failure [48].
Vericiguat is a guanylate cyclase (sGC) stimulator with a 1H-pyrazolo [3,4-b]pyridine core bearing a fluorine atom at C-5. The presence of the fluorine atom increases the metabolic stability and induces lower clearance. The method for the synthesis of Vericiguat is reported in Scheme 8 [48].
Tetrafluoropropanol 50, the starting fluorinated building block, is converted in two steps into morpholino derivative 51, and then into morpholinium cation 52 after methylation with methyl methanesulfonate. Compound 53 is obtained after a treatment with NaOH, which induces the elimination of the first fluorine atom as HF.
Other two fluorine atoms from the difluoromethyl group are lost during hydrolysis into 2-fluoroacrolein derivative 54. α,β-unsaturated aldehyde 54 reacts with aminopyrazole 55 under acidic cyclization conditions, allowing the introduction of the 5-fluorine atom into the 1H-pyrazolo [3,4-b]pyridine core of derivative 56. Ester 56 is then converted in three steps into amidine 59, via amide 57 and nitrile 58. The C-3 pyrimidine ring is then constructed with a condensation between 59 and hydrazonomalonitrile 60. Using compound 61, the synthesis of Vericiguat is completed in two steps via the catalytic hydrogenation of the diazo moiety of 61 to triaminopyrimidine 62, and finally, via the formation of the carbamate group of the target compound after a treatment with methyl chloroformate.

FDA-Approved Drugs in 2020
In 2020, the FDA approved 53 new molecular entities, including 34 small molecules and 4 diagnostic agents [49]. Thirty-one out of thirty-four molecules contain at least one

FDA-Approved Drugs in 2020
In 2020, the FDA approved 53 new molecular entities, including 34 small molecules and 4 diagnostic agents [49]. Thirty-one out of thirty-four molecules contain at least one heterocyclic ring, and eleven out of thirty-four molecules contain at least one fluorine atom. In the following paragraph, four heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 9-12). Additionally, the approved 18 F-containing diagnostic agent, Tauvid, is presented (Scheme 13).

Berotralstat
Berotralstat is sold under the brand name Orladeyo and was developed by BioCryst Pharmaceuticals. It was approved in December 2020 to treat Hereditary Angioedema (HAE) attacks [50]. Berotralstat is a selective inhibitor of plasma kallikrein, bearing a trifluoromethylpyrazole moiety. Another fluorine is present on the central phenyl ring. The patented synthetic approach to acquiring this drug is reported below (Scheme 9) [51].
The trifluoromethylpyrazole portion of compound 65 is constructed through the condensation of trifluoro β-diketone 63 and arylhydrazine 64 in acetic acid. Cyanopyrazole 65 is then reduced into amine 66, using LiAlH 4 , which is in turn protected as N-Boc derivative 67 during the successive oxidation of the furan ring to yield acid 68. Coupling between amine 69 and amide 70 is performed using bromotris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) as an activating agent. The formation of amine 71 occurs after the treatment of 70 with thionyl chloride, and then cyclopropanemethylamine. Berotralstat was finally obtained as a single enantiomer after acidic Boc-deprotection and chiral SFC resolution. heterocyclic ring, and eleven out of thirty-four molecules contain at least one fluorine atom. In the following paragraph, four heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 9-12). Additionally, the approved 18 Fcontaining diagnostic agent, Tauvid, is presented (Scheme 13).

Berotralstat
Berotralstat is sold under the brand name Orladeyo and was developed by BioCryst Pharmaceuticals. It was approved in December 2020 to treat Hereditary Angioedema (HAE) attacks [50]. Berotralstat is a selective inhibitor of plasma kallikrein, bearing a trifluoromethylpyrazole moiety. Another fluorine is present on the central phenyl ring. The patented synthetic approach to acquiring this drug is reported below (Scheme 9) [51].
The trifluoromethylpyrazole portion of compound 65 is constructed through the condensation of trifluoro β-diketone 63 and arylhydrazine 64 in acetic acid. Cyanopyrazole 65 is then reduced into amine 66, using LiAlH4, which is in turn protected as N-Boc derivative 67 during the successive oxidation of the furan ring to yield acid 68. Coupling between amine 69 and amide 70 is performed using bromotris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) as an activating agent. The formation of amine 71 occurs after the treatment of 70 with thionyl chloride, and then cyclopropanemethylamine. Berotralstat was finally obtained as a single enantiomer after acidic Boc-deprotection and chiral SFC resolution.

Cedazuridine
Cedazuridine, in combination with decitabine, is sold under the brand name Inqovi and was developed by Otsuka Pharma. It was approved in July 2020 for the treatment of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), reducing the risk of progression of secondary acute myeloid leukemia (sAML) [52].
Cedazuridine is a cytidine deaminase inhibitor that is able to improve the oral bioavailability of decitabine, avoiding its degradation in the gastrointestinal tract. The presence of two fluorine atoms at the ribose ring increase the level of metabolic stability under acidic conditions, improving the pharmacokinetic profile via unfluorinated analogs, Scheme 9. Synthesis of Berotralstat.

Cedazuridine
Cedazuridine, in combination with decitabine, is sold under the brand name Inqovi and was developed by Otsuka Pharma. It was approved in July 2020 for the treatment of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), reducing the risk of progression of secondary acute myeloid leukemia (sAML) [52].
Cedazuridine is a cytidine deaminase inhibitor that is able to improve the oral bioavailability of decitabine, avoiding its degradation in the gastrointestinal tract. The presence of two fluorine atoms at the ribose ring increase the level of metabolic stability under acidic conditions, improving the pharmacokinetic profile via unfluorinated analogs, retaining the same binding mode of unfluorinated tetrahydrouridines [53]. The synthesis of Cedazuridine is performed in two steps, starting with the analogue, Gemcitabine (Scheme 10). The Rh/C catalytic hydrogenation of Gemcitabine produces compound 76, which is reduced into a mixture of isomers containing Cedazurine and its epimer as major products using NaBH 4 . The difluorotetrahydrofuran ring of Gemcitabine is synthesized via a Reformatzky reaction of fluorinated bromoacetate 72 with D-glyceraldehyde acetonide 73 to furnish 74 as a mixture of anti/syn diasteroisomers at a 3:1 ratio. The hydrolysis/lactonization of 74 into 75 is performed with Dowex 50 resin. Lactone 75 is then converted into Gemcitabine in four steps [54].
retaining the same binding mode of unfluorinated tetrahydrouridines [53]. The synthesis of Cedazuridine is performed in two steps, starting with the analogue, Gemcitabine (Scheme 10). The Rh/C catalytic hydrogenation of Gemcitabine produces compound 76, which is reduced into a mixture of isomers containing Cedazurine and its epimer as major products using NaBH4. The difluorotetrahydrofuran ring of Gemcitabine is synthesized via a Reformatzky reaction of fluorinated bromoacetate 72 with D-glyceraldehyde acetonide 73 to furnish 74 as a mixture of anti/syn diasteroisomers at a 3:1 ratio. The hydrolysis/lactonization of 74 into 75 is performed with Dowex 50 resin. Lactone 75 is then converted into Gemcitabine in four steps [54].

Pralsetinib
Pralsetinib is sold under the brand name Gavreto and was developed by Blueprint Medicines [55]. It was approved in September 2020 for the treatment of metastatic fusionpositive non-small-cell lung cancer [56]. Pralsetinib is REarranged during transfection (RET) inhibitor and it is the first-in-class specific RET inhibitor with more selectivity than other kinases have. The presence of the 4-fluoropyrazolo group allows a different binding mode on the BP-II pocket, which is crucial for high-affinity binding and to avoid resistance from gatekeeper mutations [56].
4-Fluoropyrazole 77 gives nucleophilic displacement of bromopyridine 78 under basic conditions, yielding pyrazolylpyridine 79. The stereoselective reductive amination to hydrochloride 82 is accomplished by means of the condensation of the acyl group of 79 with chiral sulfinamide 80, followed by the reduction with L-Selectride and acidic hydrolysis of sulfinamide 81. The latter fluorinated building block is coupled with acid 83 (as mixture of diastereoisomers) using PyBop as activating agents. A final chiral SFC resolution produces Pralsetinib as a single enantiomer. The method for the patented synthesis of Pralsetinib is described in Scheme 11 [57].

Pralsetinib
Pralsetinib is sold under the brand name Gavreto and was developed by Blueprint Medicines [55]. It was approved in September 2020 for the treatment of metastatic fusionpositive non-small-cell lung cancer [56]. Pralsetinib is REarranged during transfection (RET) inhibitor and it is the first-in-class specific RET inhibitor with more selectivity than other kinases have. The presence of the 4-fluoropyrazolo group allows a different binding mode on the BP-II pocket, which is crucial for high-affinity binding and to avoid resistance from gatekeeper mutations [56].
4-Fluoropyrazole 77 gives nucleophilic displacement of bromopyridine 78 under basic conditions, yielding pyrazolylpyridine 79. The stereoselective reductive amination to hydrochloride 82 is accomplished by means of the condensation of the acyl group of 79 with chiral sulfinamide 80, followed by the reduction with L-Selectride and acidic hydrolysis of sulfinamide 81. The latter fluorinated building block is coupled with acid 83 (as mixture of diastereoisomers) using PyBop as activating agents. A final chiral SFC resolution produces Pralsetinib as a single enantiomer. The method for the patented synthesis of Pralsetinib is described in Scheme 11 [57].

Selumetinib
Selumetinib is sold under the brand name Koselugo and was developed by Astra-Zeneca. It was approved in April 2020 for the treatment of neurofibromatosis type 1 (NF1) [58]. Selumetinib, characterized by the presence of a 4-fluorobenzimidazole core, is a mi-Scheme 11. Synthesis of Pralsetinib.

Selumetinib
Selumetinib is sold under the brand name Koselugo and was developed by As-traZeneca. It was approved in April 2020 for the treatment of neurofibromatosis type 1 (NF1) [58]. Selumetinib, characterized by the presence of a 4-fluorobenzimidazole core, is a mitogen-activated protein kinase (MEK) inhibitor that is able to target the Raf-MEK-ERK signaling pathway. The synthesis of Selumetinib is described in Scheme 12 [59]. Trifluorobenzoic

Tauvid
Tauvid, also named Flortaucipir F18, was developed by Eli Lilly and was approved in May 2020 as a positron emission tomography (PET) imaging probe for Alzheimer's disease (AD) [60].
Tauvid is the first approved tracer able to bind tau protein [61]. The [ 18 F]fluoropyridine lateral ring is the radioactive portion of this probe. Two developed synthetic pro-Scheme 12. Synthesis of Selumetinib.

Tauvid
Tauvid, also named Flortaucipir F18, was developed by Eli Lilly and was approved in May 2020 as a positron emission tomography (PET) imaging probe for Alzheimer's disease (AD) [60].
Tauvid is the first approved tracer able to bind tau protein [61]. The [ 18 F]fluoropyridine lateral ring is the radioactive portion of this probe. Two developed synthetic procedures are described in Scheme 13. Scheme 12. Synthesis of Selumetinib.

Tauvid
Tauvid, also named Flortaucipir F18, was developed by Eli Lilly and was approved in May 2020 as a positron emission tomography (PET) imaging probe for Alzheimer's disease (AD) [60].
Tauvid is the first approved tracer able to bind tau protein [61]. The [ 18 F]fluoropyridine lateral ring is the radioactive portion of this probe. Two developed synthetic procedures are described in Scheme 13. Scheme 13. Synthesis of Tauvid.
The first synthetic approach is based on the nucleophilic displacement of the nitro group of precursor 96 with [ 18 F]fluoride and using Kryptofix 222 (K222) as a phase transfer catalyst (PTC) [61]. This approach suffers from some drawbacks related to trace purity; therefore, a different synthetic approach was developed starting with N-Boc protected cation 97, which undergoes nucleophilic displacement to produce radioactive fluorine, followed by acidic Boc removal [62]. This synthetic sequence allows the obtainment of Tauvid in higher yields and purity. Interestingly, this synthesis represents the only Scheme 13. Synthesis of Tauvid.
The first synthetic approach is based on the nucleophilic displacement of the nitro group of precursor 96 with [ 18 F]fluoride and using Kryptofix 222 (K 222 ) as a phase transfer catalyst (PTC) [61]. This approach suffers from some drawbacks related to trace purity; therefore, a different synthetic approach was developed starting with N-Boc protected cation 97, which undergoes nucleophilic displacement to produce radioactive fluorine, followed by acidic Boc removal [62]. This synthetic sequence allows the obtainment of Tauvid in higher yields and purity. Interestingly, this synthesis represents the only example of late-stage fluorination among all the molecules considered in this review. Obviously, the short half-life of 18 F forces researchers to follow this peculiar synthetic approach.

FDA-Approved Drugs in 2019
In 2019, the FDA approved 48 new molecular entities, including 33 small molecules and 3 diagnostic agents [63]. Among the small molecules, 28 out of 33 contain at least one heterocyclic ring, and 11 out of 33 contain at least one fluorine atom [64,65]. In the following paragraph, four heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 14-17).

Alpelisib
Alpelisib is sold under the brand name Rinvoq and was developed by Novartis. It was approved in May 2019 for the treatment of advanced or metastatic breast cancer [66]. Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor possessing a trifluoro-t-butyl group at position two of the pyridine ring [67]. The presence of the fluorinated moiety induces a higher metabolic stability and excellent oral bioavailability.
Furthermore, the fluorinated group is responsible for high affinity toward the PI3K binding site due to the hydrogen bond with K802, as revealed by X-ray data [68]. Alpelisib synthesis is performed using different approaches [69,70]. One method is shown in Scheme 14 [68]. ran-4-one 101 after a treatment with trifluoroacetic acid (TFA). The reaction of 101 with ammonium hydroxide produces fluorinated pyridin-4-one 102 via an ANRORC-like reaction. The treatment with POBr3 yields bromopyridine 103, which is, in turn, coupled with acetylaminothiazole 104 using Pd(OAc)2 in a CH activation process. The resulting coupled product, 105, is hydrolyzed using HCl into corresponding amine 106. The treatment with carbonyldiimidazole (CDI) leads to intermediate 107, which is then converted into Alpelisib after a treatment with S-prolinamide. Scheme 14. Synthesis of Apelisib.

Lemborexant
Lemborexant is sold under the brand name Dayvigo and was developed by Purdue Pharma L. Lemborexant is a dual orexin receptor antagonist, with fluorine in the position Scheme 14. Synthesis of Apelisib.

Lemborexant
Lemborexant is sold under the brand name Dayvigo and was developed by Purdue Pharma L. Lemborexant is a dual orexin receptor antagonist, with fluorine in the position five of the pyridine moiety [71]. Another fluorine is also present at position three of the central phenyl ring. It was approved in December 2019 for the treatment of insomnia [72].
The presence of each fluorine is crucial to achieve high in vitro binding affinity, good solubility and a good pharmacological profile, as evidenced during the discovery process with the screening of different fluorination patterns [73].
The synthesis of Lemborexant starts with 3-fluorobenzyl cyanide 108, which is con- five of the pyridine moiety [71]. Another fluorine is also present at position three of the central phenyl ring. It was approved in December 2019 for the treatment of insomnia [72]. The presence of each fluorine is crucial to achieve high in vitro binding affinity, good solubility and a good pharmacological profile, as evidenced during the discovery process with the screening of different fluorination patterns [73].
The synthesis of Lemborexant starts with 3-fluorobenzyl cyanide 108, which is con-

Pexidartinib
Pexidartinib is sold under the brand name Turalio and was developed by Daiichi Sankyo Inc. It was approved in August 2019 for the treatment of symptomatic tenosyno-Scheme 15. Synthesis of Lemborexant.

Pexidartinib
Pexidartinib is sold under the brand name Turalio and was developed by Daiichi Sankyo Inc. It was approved in August 2019 for the treatment of symptomatic tenosynovial giant cell tumor (TGCT) [74]. Pexidartinib is a tyrosine kinase inhibitor with selective efficacy for colony-stimulating factor (CSF) receptor; thus, it hampers the binding of CSF1 to CSF-receptor 1 (CSF1R).
Three steps in the synthesis of Pexidartinib at the kilogram scale are shown in Scheme 16 [75].

Ubrogepant
Ubrogepant is sold under the brand name Ubrelvy and was developed by Allergan. It was approved in December 2019 for the treatment of migraines with or without an aura in adults [76]. Ubrogepant is an effective calcitonin gene-related peptide (CGRP) receptor antagonist, bearing a chiral N-trifluoroethylpiperidinone ring, but its mechanism of action is still unknown. The synthesis of Ubrogepant was patented in 2012 and is reported in Scheme 17 [77]. The synthesis of fluorinated chiral amine 123, starting with phenylacetone 120, which alkylates with iodide 119 in the presence of Cs2CO3 as a base, produces derivative 121 in three steps. The reductive amination of the latter substance using trifluoroethylamine in the presence of sodium triacetoxyborohydride, leads to pyridinone 122 as a single enantiomer, after chiral resolution via normal-phase liquid chromatography (NPLC).
The treatment with HCl deprotects the N-Boc group, yielding 123. The coupling of amine 123 with acidic spyro-subunit 128 (prepared as outlined in Scheme 17) using BOP as an activating agent yields Ubrogepant as a single enantiomer via SFC.

Ubrogepant
Ubrogepant is sold under the brand name Ubrelvy and was developed by Allergan. It was approved in December 2019 for the treatment of migraines with or without an aura in adults [76]. Ubrogepant is an effective calcitonin gene-related peptide (CGRP) receptor antagonist, bearing a chiral N-trifluoroethylpiperidinone ring, but its mechanism of action is still unknown. The synthesis of Ubrogepant was patented in 2012 and is reported in Scheme 17 [77]. The synthesis of fluorinated chiral amine 123, starting with phenylacetone 120, which alkylates with iodide 119 in the presence of Cs 2 CO 3 as a base, produces derivative 121 in three steps. The reductive amination of the latter substance using trifluoroethylamine in the presence of sodium triacetoxyborohydride, leads to pyridinone 122 as a single enantiomer, after chiral resolution via normal-phase liquid chromatography (NPLC).
The treatment with HCl deprotects the N-Boc group, yielding 123. The coupling of amine 123 with acidic spyro-subunit 128 (prepared as outlined in Scheme 17) using BOP as an activating agent yields Ubrogepant as a single enantiomer via SFC. ative 121 in three steps. The reductive amination of the latter substance using trifluoroethylamine in the presence of sodium triacetoxyborohydride, leads to pyridinone 122 as a single enantiomer, after chiral resolution via normal-phase liquid chromatography (NPLC).
The treatment with HCl deprotects the N-Boc group, yielding 123. The coupling of amine 123 with acidic spyro-subunit 128 (prepared as outlined in Scheme 17) using BOP as an activating agent yields Ubrogepant as a single enantiomer via SFC.

FDA-Approved Drugs in 2018
In 2018, the FDA approved a collection of 59 new molecular entities, including 39 small molecules [78]. Thirty-two out of thirty-eight molecules contain at least one heterocyclic ring, and seventeen out of thirty-eight molecules contain at least one fluorine atom [16]. In the following paragraphs, eight heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 18-25).

Apalutamide
Apalutamide is sold under the brand name Erleada and was discovered by employees of the University of California and developed by Janssen [79]. It was approved in February 2018 for the treatment of prostate cancer (PC) [80]. Apalutamide is a non-steroidal oral androgen receptor inhibitor, presenting a trifluoromethylpyridine moiety linked to the central thiohydantoin core [81]. One of the initial patented Apalutamide synthesis procedures is reported below (Scheme 18) [82].
Chloro-trifluoromethylpyridine 129 is treated with water to induce the nucleophilic displacement of chlorine to obtain pyrimidone 130. This compound can be easily nitrated into 131, and again, converted into corresponding chloropyridine 132 via a treatment with PCl 5 /POCl 3 . The hydrogenation on Raney Ni into amine 133 is then followed by N-Boc protection with Boc-anhydride, yielding 134. A Sandmeyer reaction causes cyanation to produce derivative 135, which is subsequently deprotected into aminopyrimidine 136 using TFA. Isothiocyanate 137 is then obtained via the treatment the 136 using thiophosgene. Apalutamide is finally obtained from the construction of the thiohydantoin ring via the reaction of 137 with isocyanide 138 under microwave irradiation. The synthesis of crystalline forms of Apalutamide has recently been reviewed [83].
PCl5/POCl3. The hydrogenation on Raney Ni into amine 133 is then followed by N-Boc protection with Boc-anhydride, yielding 134. A Sandmeyer reaction causes cyanation to produce derivative 135, which is subsequently deprotected into aminopyrimidine 136 using TFA. Isothiocyanate 137 is then obtained via the treatment the 136 using thiophosgene. Apalutamide is finally obtained from the construction of the thiohydantoin ring via the reaction of 137 with isocyanide 138 under microwave irradiation. The synthesis of crystalline forms of Apalutamide has recently been reviewed [83].

Baloxavir Marboxil
Baloxavir marboxil is sold under the brand name Xofluza and was developed by Shionogi [84]. It was approved in October 2018 for the treatment of acute uncomplicated influenza types A and B [85].

Baloxavir Marboxil
Baloxavir marboxil is sold under the brand name Xofluza and was developed by Shionogi [84]. It was approved in October 2018 for the treatment of acute uncomplicated influenza types A and B [85].
Baloxavir marboxil is a cap-dependent endonuclease inhibitor characterized by the presence of two fluorine atoms on the 6,11-dihydrodibenzo[b,e]thiepine ring [86]. The patented synthesis of Baloxavir marboxil is depicted in Scheme 19 [87]. Difluorobenzoic acid 139 is initially formylated via LDA/DMF at low temperature, yielding cyclization product 140. A reaction with thiophenol under acidic conditions pro-duces phenylthiolphthalide 141. The reductive breaking of the C-O bond mediated by the action 1,1,3,3-Tetramethyldisiloxane yields thioether 142, which undergoes intramolecular cyclization by heating at 120 • C. The obtained ketone 143 is reduced into alcohol 144 using NaBH 4 , and then coupled with chiral compound 145 under acidic conditions to produce compound 146. The deprotection of hexyl ether into 147, and a final reaction with chloromethyl methyl carbonate allows the obtainment of Baloxavir marboxil.

Binimetinib
Binimetinib is sold under the brand name Mektovi and was developed by Array Biopharma. It was approved in June 2018 for the treatment of metastatic BRAF V600E/Kpositive advanced melanoma in association with Encorafenib [88].
As for the analogue, Selumetinib, the synthetic route of Binimetinib is based on ester 87 (Scheme 20) [90]. The nucleophilic displacement of 2-fluoroaniline 148 to obtain derivative 149 is followed by hydrogenation in the presence of formic acid to directly yield benzimidazole 150. NBS-mediated bromination and methylation at N-1 give compounds 151 and 152, respectively. Ester 117 is, therefore, hydrolyzed using NaOH, and the resulting acid, 153, after activation using EDC/HOBt is converted into hydroxamic acid 155 upon a reaction with O-alkyl hydroxylamine 154. Binimetinib is finally obtained by the acidic hydrolysis of the vinyl ether group of 155.

Doravirine
Doravirine is sold under the brand name Pifeltro and was developed by Merck. It was approved in August 2018 for the treatment of human immunodeficiency virus 1 (HIV-1) infections [91]. Doravirine is a non-nucleoside reverse transcriptase inhibitor, presenting improved ADME properties due the presence of a CF3-substituted pyridone central ring. In fact, the presence of this strong electron-withdrawing group is correlated with a longer elimination half-life in rats and dogs compared to that of unfluorinated analogs [92]. The patented method of the synthesis of Doravirine is shown in Scheme 21 [93].

Doravirine
Doravirine is sold under the brand name Pifeltro and was developed by Merck. It was approved in August 2018 for the treatment of human immunodeficiency virus 1 (HIV-1) infections [91]. Doravirine is a non-nucleoside reverse transcriptase inhibitor, presenting improved ADME properties due the presence of a CF 3 -substituted pyridone central ring. In fact, the presence of this strong electron-withdrawing group is correlated with a longer elimination half-life in rats and dogs compared to that of unfluorinated analogs [92]. The patented method of the synthesis of Doravirine is shown in Scheme 21 [93].
Fluorinated building block 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine 156 is first used in a reaction with phenol 157 using K 2 CO 3 as a base to induce fluoride displacement and obtain ether 158. The hydrolysis of chloropyridine 158 into pyridinone 159 is then performed via a treatment with KOH. The cyanation of the C-Br bond of the phenyl portion with CuCN yields substrate 160, which reacts under basic condition with chloromethyltriazole 161 to produce pyridone N-alkylation product 162. Doravirine is finally obtained by the regio-selective methylation of the 1,2,4-triazole ring at N-4 with methyliodide in DMF in the presence of K 2 CO 3 as a base. Other synthetic approaches have recently been reviewed [16].
ring. In fact, the presence of this strong electron-withdrawing group is correlated with a longer elimination half-life in rats and dogs compared to that of unfluorinated analogs [92]. The patented method of the synthesis of Doravirine is shown in Scheme 21 [93].
Fluorinated building block 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine 156 is first used in a reaction with phenol 157 using K2CO3 as a base to induce fluoride displacement and obtain ether 158. The hydrolysis of chloropyridine 158 into pyridinone 159 is then performed via a treatment with KOH. The cyanation of the C-Br bond of the phenyl portion with CuCN yields substrate 160, which reacts under basic condition with chloromethyltriazole 161 to produce pyridone N-alkylation product 162. Doravirine is finally obtained by the regio-selective methylation of the 1,2,4-triazole ring at N-4 with methyliodide in DMF in the presence of K2CO3 as a base. Other synthetic approaches have recently been reviewed [16].

Fostamatinib
Fostamatinib is sold under the brand name Tavalisse and was developed by Rigel Pharmaceuticals. It was approved in April 2018 for the treatment of thrombocytopenia in adults with persistent or chronic immune thrombocytopenia (ITP) [94].
Fostamatinib is a potent spleen tyrosine kinase (Syk) inhibitor, bearing a 5-fluoropyrimidine ring, and it is used to improve membranes' permeability [95]. Actually, Fostamatinib is a pro-drug of compound 168, and its synthesis is described in Scheme 22 [96].
Two subsequent chloride displacements with different amines then occur. The first one at C-4 with amino-pyridoxazinone 165 yields 166; the second one at C-2 with 3,4,5-trimethoxyaniline 167 produces compound 168. As mentioned above, this compound is converted into the prodrug Fostamatinib via a treatment with di-tert-butyl(chloromethyl)phosphate to produce ester 169, which is then hydrolyzed and converted into target phosphate disodium salt.

Ivosidenib
Ivosidenib is sold under the brand name Tibsovo and was developed by Servier. It was approved in July 2018 for the treatment of relapsed or refractory acute myeloid leukemia [97]. Ivosidenib is an inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1); thus, it lowers the level of oncometabolite D-2-hydroxyglutarate (2-HG) [98]. Fluorine at the position five of the pyridine ring is crucial in order to ensure a high level of potency and metabolic stability [98]. The synthesis of Ivosidenib at the multi-gram scale is outlined in Scheme 23 [99]. The synthetic process is based on a multi-component Ugi reaction of 3-amino-5-fluoropyridine 170 with 2-chlorobenzaldehyde 171, followed by L-pyroglutamic acid and isocyanide 172, to produce peptide derivative 173. N-H coupling with bromopyridine 174 under Buchwald conditions produces Ivosidenib as a single enantiomer after crystallization. treatment with POCl3.
Two subsequent chloride displacements with different amines then occur. The first one at C-4 with amino-pyridoxazinone 165 yields 166; the second one at C-2 with 3,4,5trimethoxyaniline 167 produces compound 168. As mentioned above, this compound is converted into the pro-drug Fostamatinib via a treatment with di-tert-butyl(chloromethyl)phosphate to produce ester 169, which is then hydrolyzed and converted into target phosphate disodium salt. Scheme 22. Synthesis of Fostamatinib.

Ivosidenib
Ivosidenib is sold under the brand name Tibsovo and was developed by Servier. It was approved in July 2018 for the treatment of relapsed or refractory acute myeloid leukemia [97]. Ivosidenib is an inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1); thus, it lowers the level of oncometabolite D-2-hydroxyglutarate (2-HG) [98]. Fluorine at the position five of the pyridine ring is crucial in order to ensure a high level of potency and metabolic stability [98]. The synthesis of Ivosidenib at the multi-gram scale is outlined in Scheme 23 [99]. The synthetic process is based on a multi-component Ugi

Talazoparib
Talazoparib is sold under the brand name Talzenna and was developed by Pfizer [100]. It was approved in October 2018 for the treatment of locally advanced or metastatic breast cancer patients with a germline BRCA mutation [101]. Talazoparib, a fluorine-containing tetrahydropyridophthlazinones is active as a poly(ADP-ribose) polymerase (PARP) inhibitor [101]. To achieve inhibitory activity and metabolic stability, as well as to increase the number of interactions at the binding site via H-bonding, 5-fluoro substitution and the 4-fluorophenyl groups are crucial [101]. The synthetic method for the preparation of Talazoparib at the 30 g scale is described in Scheme 24 [102].
Fluorinated dihydroquinolinone 177 is constructed with a two steps acylation/reductive amination of fluoroaniline 175 with β-ketoacid 176. The following chiral resolution with (-)-tartaric acid is crucial to obtain the desired enantiomer, 178. The base-induced reaction between 178 and 5-chloro-1-methyl-1,2,4-triazole 179 leads to the desired trans stereoisomer, 180, which is finally converted into Talazoparib via a reaction with hydrazine in EtOH under reflux.

Talazoparib
Talazoparib is sold under the brand name Talzenna and was developed by Pfizer [100]. It was approved in October 2018 for the treatment of locally advanced or metastatic breast cancer patients with a germline BRCA mutation [101]. Talazoparib, a fluorinecontaining tetrahydropyridophthlazinones is active as a poly(ADP-ribose) polymerase (PARP) inhibitor [101]. To achieve inhibitory activity and metabolic stability, as well as to increase the number of interactions at the binding site via H-bonding, 5-fluoro substitution and the 4-fluorophenyl groups are crucial [101]. The synthetic method for the preparation of Talazoparib at the 30 g scale is described in Scheme 24 [102].
Fluorinated dihydroquinolinone 177 is constructed with a two steps acylation/reductive amination of fluoroaniline 175 with β-ketoacid 176. The following chiral resolution with (-)-tartaric acid is crucial to obtain the desired enantiomer, 178. The base-induced reaction between 178 and 5-chloro-1-methyl-1,2,4-triazole 179 leads to the desired trans stereoisomer, 180, which is finally converted into Talazoparib via a reaction with hydrazine in EtOH under reflux.
increase the number of interactions at the binding site via H-bonding, 5-fluoro substitution and the 4-fluorophenyl groups are crucial [101]. The synthetic method for the preparation of Talazoparib at the 30 g scale is described in Scheme 24 [102].

Tezacaftor
Tezacaftor is sold under the brand name Symdeko, as a co-formulation with ivacaftor and was developed by Vertex Pharms Inc. It was approved in February 2018 for the treatment of cystic fibrosis [103]. Tezacaftor improves the processing and trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) in vitro and improves CFTR's function alone and in combination with other drugs [104].
The synthesis of Tezacaftor has been recently reviewed [105], the second generation process is described in Scheme 25 [106].
The scheme is based on the initial formation of 6-fluoroindole's nucleus using 3-fluoro-4-nitroaniline 181. Bromination with elemental bromine in acetic acid yields compound 182, and the nucleophilic ring opening by the anilino moiety on chiral epoxide 183 produces compound 184. Nitro-group reduction with Zinc and salt formation with PTSA from amine 185,produce tosylate 186. The latter one is coupled with terminal alkyne 187 under Sonogashira conditions to produce compound 188. Indole ring formation is achieved via a Pd-catalyzed reaction using Pd(CH 3 CN) 2 Cl 2 . 6-Fluoroindole 189, obtained as a single enantiomer, is then used in a reaction with chloride 190 to yield Bn-protected derivative 191, which is finally converted into Tezacaftor by means of hydrogenation over Pd/C. produces compound 184. Nitro-group reduction with Zinc and salt formation with PTSA from amine 185,produce tosylate 186. The latter one is coupled with terminal alkyne 187 under Sonogashira conditions to produce compound 188. Indole ring formation is achieved via a Pd-catalyzed reaction using Pd(CH3CN)2Cl2. 6-Fluoroindole 189, obtained as a single enantiomer, is then used in a reaction with chloride 190 to yield Bn-protected derivative 191, which is finally converted into Tezacaftor by means of hydrogenation over Pd/C. Scheme 25. Synthesis of Tezacaftor.

FDA-Approved Drugs in 2017
In 2017, the FDA approved 46 new drugs, including 34 small molecules [107,108]. Thirty-one out of thirty-four molecules contain at least one heterocyclic ring, and ten out of thirty-four molecules contain at least one fluorine atom. In the following paragraphs, seven heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 26-32).

FDA-Approved Drugs in 2017
In 2017, the FDA approved 46 new drugs, including 34 small molecules [107,108]. Thirty-one out of thirty-four molecules contain at least one heterocyclic ring, and ten out of thirty-four molecules contain at least one fluorine atom. In the following paragraphs, seven heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 26-32).

Abemaciclib
Abemaciclib is sold under the brand name Verzenio and was developed by Eli Lilly. It was approved in September 2017 for the treatment of advanced or metastatic breast cancers. Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor that is selective for isoforms CDK4 and CDK6 [109]. Abemaciclib contains two fluorinated heterocycles, namely 4-fluorobenzimidazole and 5-fluoropyrimidine, which are directly linked to form a 6-(pyrimidin-4-yl)-benzimidazole core (Scheme 26). The synthesis described by Frederick et al. starts with the formation of this bond via a Suzuki reaction between fluorobenzimidazolyl pinacol boronate 192 and 2,4-dichloro-5-fluoropyrimidine 193 [110]. The reaction occurs selectively with the displacement of chlorine at position 4, producing 194, while less-reactive chlorine at position 2 is then used in a reaction with aminopyridine 195 under Buchwald-Hartwig conditions to yield intermediate 196. The latter substance is converted into Abemaciclib through reductive amination with ethylpyperazine 197 via a Leuckart-Wallach reaction, with trimethyl orthoformate as a dehydrating agent. A further improvement has introduced a more convergent scheme, which involves the performance of flow synthesis [111].
zimidazolyl pinacol boronate 192 and 2,4-dichloro-5-fluoropyrimidine 193 [110]. The reaction occurs selectively with the displacement of chlorine at position 4, producing 194, while less-reactive chlorine at position 2 is then used in a reaction with aminopyridine 195 under Buchwald-Hartwig conditions to yield intermediate 196. The latter substance is converted into Abemaciclib through reductive amination with ethylpyperazine 197 via a Leuckart-Wallach reaction, with trimethyl orthoformate as a dehydrating agent. A further improvement has introduced a more convergent scheme, which involves the performance of flow synthesis [111]. Scheme 26. Synthesis of Abemaciclib.

Delafloxacin
Delafloxacin is sold under the brand name Baxdela and was developed by Melinta. It was approved in June 2017 for the treatment of acute bacterial skin and skin structure infections [112]. Such as other members of the fluoroquinolone family, it is a DNA gyrase topoisomerase IV inhibitor that is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus Aureus (MRSA), and Gram-negative organisms, such as Escherichia Coli and Pseudomonas Aeruginosa [113].
Additionally, some quinolone-resistant strains are susceptible to Delafloxacin. The synthetic process is in line with the classical fluoroquinolone method (Scheme 27) [114].

Delafloxacin
Delafloxacin is sold under the brand name Baxdela and was developed by Melinta. It was approved in June 2017 for the treatment of acute bacterial skin and skin structure infections [112]. Such as other members of the fluoroquinolone family, it is a DNA gyrase topoisomerase IV inhibitor that is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus Aureus (MRSA), and Gram-negative organisms, such as Escherichia Coli and Pseudomonas Aeruginosa [113].
Additionally, some quinolone-resistant strains are susceptible to Delafloxacin. The synthetic process is in line with the classical fluoroquinolone method (Scheme 27) [114]. Trifluorobenzoic acid 198 is initially converted into the corresponding chloride with thionylchloride, and then into β-ketoester 200 via a treatment with potassium monoethylmalonate 199. Compound 200 is then converted into an intermediate vinylether, which is directly transformed into enamine 202 after the reaction with 2,6-diamino-3,5-difluoropyridine 201. The cyclization of compound 202 into the corresponding quinolone by the nucleophilic displacement of ortho fluorine is induced by the addition of DBU. The second aromatic nucleophilic substitution, involving fluorine at position seven, is performed with 3-hydroxyazetidine 203. Compound 204 is then obtained via the protection of an hydroxyl group as an ester to avoid competitive oxidation in the following chlorination step. Chlorination at position eight of the quinolone ring is selectively performed using NCS as a chlorinating agent in an acidic environment. Finally, Delafloxacin is obtained after the deprotection of the hydroxyazetine portion by means of ester hydrolysis with NaOH.

Enasidenib
Enasidenib is sold under the brand name Idhifa and was developed by Celgene. It was approved in August 2017 for the treatment of relapsed or refractory acute myeloid leukemia in patients with specific mutations of the isocitrate dehydrogenase 2 (IDH2) gene [115]. Enasidenib is a first-in-class small-molecule inhibitor of the IDH2-mutant enzyme with oral bioavailability [116]. This drug contains two trifluoromethylpyridine rings, as demonstrated by ab initio calculations with X-ray data; one trifluoromethyl group is important for the CF 3 ···O tetrel bond with Asp312 [117]. The same CF 3 -group is also responsible for C-H···F bonding with Asp312 and N-H···F bonding with Gln316. The synthesis of Enasidenib was patented in 2013 (Scheme 28) [118].

Glecaprevir
Glecaprevir is sold under the brand name Mavyret, as a co-formulation with Pibrentasvir (see Section 7.6), and was developed by AbbVie Inc. It was approved in August 2017 for the treatment of chronic hepatitis C virus (HCV) in adults [119].
In 2019, the FDA expanded the use to children. Glecaprevir is a non-structural (NS) protein 3/4A protease inhibitor, presenting a macrocyclic ring with a difluoromethylene moiety directly linked to a quinoxaline ring [120]. The enabling synthesis of Glecaprevir to produce the quantity needed for Phase I clinical trials is based on ring-closing metathesis (RCM) for the production of the 18-membered macrocycle (Scheme 29) [121].

Glecaprevir
Glecaprevir is sold under the brand name Mavyret, as a co-formulation with Pibrentasvir (see Section 7.6), and was developed by AbbVie Inc. It was approved in August 2017 for the treatment of chronic hepatitis C virus (HCV) in adults [119].
In 2019, the FDA expanded the use to children. Glecaprevir is a non-structural (NS) protein 3/4A protease inhibitor, presenting a macrocyclic ring with a difluoromethylene moiety directly linked to a quinoxaline ring [120]. The enabling synthesis of Glecaprevir to produce the quantity needed for Phase I clinical trials is based on ring-closing metathesis (RCM) for the production of the 18-membered macrocycle (Scheme 29) [121].
for the treatment of chronic hepatitis C virus (HCV) in adults [119].
In 2019, the FDA expanded the use to children. Glecaprevir is a non-structural (NS) protein 3/4A protease inhibitor, presenting a macrocyclic ring with a difluoromethylene moiety directly linked to a quinoxaline ring [120]. The enabling synthesis of Glecaprevir to produce the quantity needed for Phase I clinical trials is based on ring-closing metathesis (RCM) for the production of the 18-membered macrocycle (Scheme 29) [121]. The synthetic route starts with the formation of fluorinated α-hydroxyester 214 via the Indium-mediated allylation of ethyl glyoxylate 213 starting with 3-bromo-3,3-difluoropropene 212. The Swern oxidation of propylphosphonic anhydride (T3P) into intermediate α-ketoester is followed by condensation with ortho-phenylenediamine 215 to produce gem-difluoro quinoxaline 216. Chlorination with thionyl chloride produces derivative 217, possessing a good leaving group for nucleophilic aromatic substitution with Bocprotected hydroxyproline 218. Concurrent methyl ester formation and the removal of Boc protection via treating 219 with HCl in MeOH produces amine 220, which is one of the two main building blocks for macrocycle formation. The second main component, acid 221, is coupled, inducing amide bond formation when employing HATU as an activating agent. Diene 222 is then subjected to RCM using Zhan 1B catalyst after careful screening of the reaction conditions, thereby optimizing the formation of the desired trans macrocycle, 223. Glecaprevir is obtained in two steps via the hydrolysis of 223 into acid 224 and its coupling with the fluorinated aminocyclopropane 225 side-chain, combining EDC and 2-hydroxypyridine-N-oxide (HOPO) as activating agents. Another approach based on ether-bond macrocyclization has also been developed for large-scale synthesis [122].

Letermovir
Letermovir is sold under the brand name Prevymis and was developed by Merck & Co. It was approved in November 2017 for the treatment of infections caused by cytomegalovirus (CMV) after a bone marrow transplant [123]. Letermovir's mode of action is different from that of other antiviral agents, which act on DNA polymerase; in fact, it interferes with the activity of terminase complex of the virus [124]. The asymmetric synthesis of Letermovir is performed in seven steps with a key part: PTC-mediated aza-Michael cyclization to obtain the chiral fluorinated dihydroquinazoline core (Scheme 30) [125]. The formation of aminocinnamate 228 is based on a Heck reaction between fluoroaniline 226 and methyl acrylate 227. Carbamate 229 is then obtained treating 228 with phenyl chloroformate. Urea 231 is formed via a reaction with anisidine 230. Compound 231 is dehydrated with PCl 5 into carbodiimide 232 and directly converted into guanidine 234 via a treatment with piperazine 233. Compound 234 is the key intermediate used for asymmetric cyclization into compound 236 using fluorinated cinchona-based derivative 235 as a PTC catalyst. Precursor 236 is converted into Letermovir via the hydrolysis of the methyl ester moiety. Other asymmetric approaches to Letermovir synthesis were developed later [126,127].

Pibrentasvir
Pibrentasvir is sold under the brand name Mavyret, as a co-formulation with Glecaprevir (see Scheme 29), and was developed by AbbVie Inc. It was approved in August 2017 for the treatment of chronic hepatitis C virus (HCV) in adults [119]. Pibrentasvir is an NS5A inhibitor antiviral agent with two symmetric fluorobenzimidazole rings linked to a central trans pyrrolidine core [128]. The method for the patented synthesis of Pibrentasvir is shown in Scheme 31 [129].

Pibrentasvir
Pibrentasvir is sold under the brand name Mavyret, as a co-formulation with Glecaprevir (see Scheme 29), and was developed by AbbVie Inc. It was approved in August 2017 for the treatment of chronic hepatitis C virus (HCV) in adults [119]. Pibrentasvir is an NS5A inhibitor antiviral agent with two symmetric fluorobenzimidazole rings linked to a central trans pyrrolidine core [128]. The method for the patented synthesis of Pibrentasvir is shown in Scheme 31 [129].
Fluoro-acetophenone 237 was brominated using the methyl group, producing αbromoketone 238. The ZnCl 2 -mediated C-C coupling of 237 with 238 produces diketone 239. Stereoselective reduction in the presence of prolinol-derived catalyst 240 yields an intermediate diol, which is directly converted into dimesylate 241. Double nucleophilic displacement with aniline 242 produces trans pyrrolidine 243, which is then treated with N-Boc prolinamide under Buchwald conditions to yield N-arylation at both rings in compound 244. The latter substance is converted into bis-benzimidazole 245 via the hydrogenation of nitro groups, AcOH-mediated cyclization and TFA-induced deprotection. Diamine 245 is finally converted into Pibrentasvir via coupling with protected O-methyl-threonine 246 with EDC and HOBt as an activating agent.

Voxilaprevir
Voxilaprevir is sold under the brand name Vosevi, as a co-formulation with sofosbuvir (see Section 8.2) and velpatasvir and was developed by Gilead. It was approved in July 2017 for the treatment of chronic hepatitis C virus (HCV) in adults [130]. Voxilaprevir is an NS protein 3/4A protease inhibitor, possessing an 18-membered gem-difluoro methylene quinoxaline portion similar to that of Glecaprevir (Scheme 29). Additionally, the synthetic pathways are quite similar (Scheme 32) [131]. Scheme 32. Synthesis of Voxilaprevir.
The synthetic method starts with the formation of fluorinated α-ketoester 247 via the lithium exchange and allylation of diethyl oxalate, starting with 3-bromo-3,3-difluoro-propene 212. Condensation with methoxy ortho-phenylenediamine 248 produces gemdifluoro quinoxaline 249, which is chlorinated with POCl3 to produce derivative 250, which possesses a good leaving group for nucleophilic aromatic substitution with Bocprotected ethyl hydroxyproline 251. The Boc removal of 252 with HCl furnishes amine 253, which is one of the two main building blocks for macrocycle formation. The second main component, acid 254, is coupled to it by inducing amide bond formation and Scheme 32. Synthesis of Voxilaprevir.
The synthetic method starts with the formation of fluorinated α-ketoester 247 via the lithium exchange and allylation of diethyl oxalate, starting with 3-bromo-3,3-difluoropropene 212. Condensation with methoxy ortho-phenylenediamine 248 produces gemdifluoro quinoxaline 249, which is chlorinated with POCl 3 to produce derivative 250, which possesses a good leaving group for nucleophilic aromatic substitution with Boc-protected ethyl hydroxyproline 251. The Boc removal of 252 with HCl furnishes amine 253, which is one of the two main building blocks for macrocycle formation. The second main component, acid 254, is coupled to it by inducing amide bond formation and employing HATU as an activating agent. Diene 255 is then subjected to RCM using Zhan 1B catalyst, causing the formation of the desired trans macrocycle, 256. Glecaprevir is obtained in two steps by means of the hydrogenation of the double bond of 256 and t-Bu ester removal to produce acid 257 and its coupling with fluorinated aminocyclopropane 225 side-chain using HATU as an activating agent.

FDA-Approved Drugs in 2016
In 2016, the FDA approved 22 new drugs, including 13 small molecules [132]. Eleven out of thirteen molecules contain at least one heterocyclic ring, and four out of thirteen molecules have at least one fluorine atom. In the following paragraphs, two heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 33 and 34).

Rucaparib
Rucaparib is sold under the brand name Rubraca and was developed by Clovis Oncology. It was approved in December 2016 for the treatment of ovarian cancer [133]. Rucaparib is the first-in-class inhibitor of DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1); notably, the presence of fluorine at the indole ring enhances the in vitro potency tenfold in comparison to that of the unfluorinated analogue [134]. Rucaparib synthesis is completed in five steps, starting with fluoroindole 258 (Scheme 33) [135]. The alkylation of 258 with nitroacetate 259 yields compound 260, which is reduced using Zinc in an acid medium and directly cyclized under basic conditions into azepino-indole 261. The bromuration of indole C-2 produces 262, which undergoes to a Suzuki reaction with formyl boronic acid 263. The obtained aldehyde 264 is converted into Rucaparib by means of reductive amination with NaBH 3 CN.

FDA-Approved Drugs in 2016
In 2016, the FDA approved 22 new drugs, including 13 small molecules [132]. Eleven out of thirteen molecules contain at least one heterocyclic ring, and four out of thirteen molecules have at least one fluorine atom. In the following paragraphs, two heterocyclic compounds bearing a fluorinated moiety directly linked to the ring are reported (Schemes 33 and 34).

Rucaparib
Rucaparib is sold under the brand name Rubraca and was developed by Clovis Oncology. It was approved in December 2016 for the treatment of ovarian cancer [133]. Rucaparib is the first-in-class inhibitor of DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1); notably, the presence of fluorine at the indole ring enhances the in vitro potency tenfold in comparison to that of the unfluorinated analogue [134]. Rucaparib synthesis is completed in five steps, starting with fluoroindole 258 (Scheme 33) [135]. The alkylation of 258 with nitroacetate 259 yields compound 260, which is reduced using Zinc in an acid medium and directly cyclized under basic conditions into azepino-indole 261. The bromuration of indole C-2 produces 262, which undergoes to a Suzuki reaction with formyl boronic acid 263. The obtained aldehyde 264 is converted into Rucaparib by means of reductive amination with NaBH3CN. Scheme 33. Synthesis of Rucaparib.

Sofosbuvir
Sofosbuvir is sold under the brand name Epclusa, as a co-formulation with velpatavsir, and was developed by Gilead Science. It was approved in June 2016 for the treatment of six major forms of HCV [136]. Sofsbuvir has also been FDA-approved since 2014 for the treatment of HCV, alone or co-administered with other drugs [137]. Sofosbuvir acts as an HCV NS5B polymerase inhibitor and is administered as a prodrug [138]. The synthesis of Sofosbuvir was described by Bao et al. in 2010 (Scheme 34). Sofosbuvir was originally obtained from cytidine derivative 270 via the hydrolysis of the amino group and Bz removal, followed by the installation of a phosphoramidate side-chain on 272 in the Scheme 33. Synthesis of Rucaparib.

Sofosbuvir
Sofosbuvir is sold under the brand name Epclusa, as a co-formulation with velpatavsir, and was developed by Gilead Science. It was approved in June 2016 for the treatment of six major forms of HCV [136]. Sofsbuvir has also been FDA-approved since 2014 for the treatment of HCV, alone or co-administered with other drugs [137]. Sofosbuvir acts as an HCV NS5B polymerase inhibitor and is administered as a prodrug [138]. The synthesis of Sofosbuvir was described by Bao et al. in 2010 (Scheme 34). Sofosbuvir was originally obtained from cytidine derivative 270 via the hydrolysis of the amino group and Bz removal, followed by the installation of a phosphoramidate side-chain on 272 in the presence of N-methylimidazole (NMI) [139]. Compound 270 has been previously synthesized, starting with chiral cyclic sulfate 265 [140]. Sulfate opening using fluoride is followed by a hydrolytic step, allowing the obtainment of fluorinated chiral compound 266. Acetonide hydrolysis, performed with HCl in EtOH, straightforwardly produces lactone 267, which is protected as it is Bz ester 268, and then reduced and coupled with pyrimidine derivative 269 to produce compound 270.
presence of N-methylimidazole (NMI) [139]. Compound 270 has been previously synthesized, starting with chiral cyclic sulfate 265 [140]. Sulfate opening using fluoride is followed by a hydrolytic step, allowing the obtainment of fluorinated chiral compound 266. Acetonide hydrolysis, performed with HCl in EtOH, straightforwardly produces lactone 267, which is protected as it is Bz ester 268, and then reduced and coupled with pyrimidine derivative 269 to produce compound 270. Scheme 34. Synthesis of Sofosbuvir.

Conclusions
The use and the importance of fluorinated heterocyclic compounds is continuously increasing in the field of medicinal chemistry. Drug discovery is often linked to the presence of a fluorinated moiety that is able to improve the drug's potency or the metabolic stability of different heterocycles. These features allow the constant increase in these molecular entities, among other new drugs and among blockbuster and best-selling compounds. The only restriction, up to now, could be due to the limitation of fluorinated building blocks for synthetic purposes. In fact, all the reported synthetic schemes are based on available fluorinated heterocyclic compounds or their precursors, while late fluorination strategies are limited to 18 F probes due to the short half-life of this isotope. The installation of fluorinated moieties at the end of the synthesis could be a different approach that could characterize future research in this field.
Author Contributions: C.R., S.A., I.P., A.P., S.B. and A.P.P. equally contributed to writing this review. All authors have read and agreed to the published version of the manuscript.
Funding: C.R. thanks PNR: Next-Generation EU, DM737/2021, CUP B79J21038330001, for funding. This work was supported by PNRR-PE0000019-"HEAL ITALIA-Health Extended Alliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine".

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.
Acknowledgments: The University of Palermo is gratefully acknowledged.

Conflicts of Interest:
There are no conflict to declare.

Conclusions
The use and the importance of fluorinated heterocyclic compounds is continuously increasing in the field of medicinal chemistry. Drug discovery is often linked to the presence of a fluorinated moiety that is able to improve the drug's potency or the metabolic stability of different heterocycles. These features allow the constant increase in these molecular entities, among other new drugs and among blockbuster and best-selling compounds. The only restriction, up to now, could be due to the limitation of fluorinated building blocks for synthetic purposes. In fact, all the reported synthetic schemes are based on available fluorinated heterocyclic compounds or their precursors, while late fluorination strategies are limited to 18 F probes due to the short half-life of this isotope. The installation of fluorinated moieties at the end of the synthesis could be a different approach that could characterize future research in this field.
Author Contributions: C.R., S.A., I.P., A.P., S.B. and A.P.P. equally contributed to writing this review. All authors have read and agreed to the published version of the manuscript.
Funding: C.R. thanks PNR: Next-Generation EU, DM737/2021, CUP B79J21038330001, for funding. This work was supported by PNRR-PE0000019-"HEAL ITALIA-Health Extended Alliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine".
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.