English

• 1. Introduction

  Fluorine substitution is a cornerstone of modern drug design because it can dramatically enhance the pharmacological profile of a molecule. Fluorine, with its high electronegativity and small atomic radius, exerts unique electronic and steric effects when introduced into drug candidates. This substitution often improves lipophilicity, metabolic stability, binding affinity, and pK_a, which in turn enhances therapeutic efficacy, bioavailability, and pharmacokinetics. Medicinal chemists frequently refer to fluorine as an "enchanted atom" because even a single fluorine atom can reshape the fate of a drug candidate, reducing failure rates and increasing the likelihood of clinical success. By fine-tuning molecular interactions with biological targets and slowing metabolic degradation, fluorine substitution has become a strategic tool for optimizing lead compounds and ensuring that promising molecules reach the market [1–7]. On the other hand, fluorine plays a unique role in influencing molecular conformation. Its impact extends far beyond simple steric bulk, encompassing a multidimensional influence that integrates spatial, electronic, and conformational dynamics. The van der Waals radius of fluorine (~1.47 Å) is close to that of hydrogen (~1.20 Å), which allows fluorine substitution to often maintain the overall molecular shape. However, as the most electronegative element (3.98, Pauling scale), fluorine strongly polarizes bonds and alters local electron density. These properties make fluorine a key mediator of polar steric effects. In aliphatic scaffolds, fluorine often adopts a stable gauche relationship with adjacent polar bonds, which can preorganize pharmacophores into bioactive orientations. Moreover, when fluorine atom is directly attached to a chiral carbon, its high electronegativity can electronically perturb neighboring groups, creating a unique chiral environment [8].

  One of the central aims of synthetic organic chemistry is the creation of novel biologically active compounds, and researchers therefore monitor advances in approved pharmaceuticals with great attention. In this context, comprehensive review articles are welcomed with particular enthusiasm, as they provide critical insights into emerging trends. Among these, the field of fluorine-containing drugs stands out for its exceptional dynamism. The strategic incorporation of fluorine atoms has repeatedly proven to transform pharmacological properties, influencing potency, selectivity, metabolic stability, and bioavailability. As a result, annual updates in this area are eagerly anticipated, reflecting both the rapid pace of innovation and the profound impact of fluorine substitution on modern drug development [9–15].

  In this review, we highlight fourteen novel fluorine-containing pharmaceuticals that received approval from the U.S. Food and Drug Administration (FDA) for market entry in 2025. These agents include datopotamab deruxtecan (Datroway) (1), suzetrigine (Journavx) (2), mirdametinib (Gomekli) (3), the combination therapy of avutometinib and defactinib (Avmapki) (4), taletrectinib (Ibtrozi) (5), sunvozertinib (Zegfrovy) (6), sebetralstat (Ekterly) (7), rilzabrutinib (Wayrilz) (8), imlunestrant (Inluriyo) (9), paltusotine (Palsonify) (10), remibrutinib (Rhapsido) (11), elinzanetant (Lynkuet) (12), ziftomenib (Komzifti) (13), and zoliflodacin (Nuzolvence) (14). The chemical structures of these newly approved drugs are depicted in Fig. 1, providing a visual overview of their molecular diversity and design.

  Figure 1

  

  Figure 1.  Structures of fourteen novel fluorine-containing pharmaceuticals that received approval from the FDA for market entry in 2025.

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  For each compound, this review examines the path of medicinal chemistry discovery, the therapeutic area addressed, and the timeline leading to FDA approval. Special emphasis is placed on the detailed step-by-step synthetic strategies, with particular focus on the introduction of fluorine and its impact on molecular design. We anticipate that this review will serve as a valuable resource and source of inspiration for practitioners in academia and the pharmaceutical industry, as well as for students engaged in drug design, fluorine chemistry, and medicinal chemistry more broadly.

  2. Datopotamab deruxtecan (Datroway)

  Datopotamab deruxtecan (brand name: Datroway) represents an antibody drug conjugate. The monoclonal antibody targets the trophoblast cell surface antigen 2 (TROP2). The latter is expressed in various tumors, with overexpression occurring particularly in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The FDA approved datopotamab deruxtecan on January 17, 2025, for treating patients who have an unresectable or metastatic form of this type of breast cancer (HR+, HER2-) after getting endocrine-based therapy and chemotherapy for unresectable or metastatic disease before [16].

  The antibody datopotamab is bound to deruxtecan. A thiol group of the antibody is used to form a covalent thioether bond with the maleimide group of deruxtecan in the manner of a Michael addition [17]. Structurally, deruxtecan comprises a maleimidocaproamide spacer, a cleavable tetrapeptide-based linker (G-G-F-G), and the topoisomerase I (TOP1) inhibitor exatecan [18].

  Exatecan (1) is a structural analog of the alkaloid camptothecin, whereby exatecan exhibits a striking fluorination. For camptothecin-derived TOP1 inhibitors, improved metabolic activity was observed as a result of introducing fluorine [19,20]. Fluorination at the A-ring of the pyranoindolizino-quinoline-based core leading to fluorocamptothecins caused, for example, increased cytotoxicity in vitro and in vivo and reduced systemic toxicity in mice compared to camptothecin [21].

  Exatecan (1), the actual fluorine-containing constituent of datopotamab deruxtecan, could be synthesized as follows (Scheme 1). The synthesis started with 2-fluoro-1-methyl-4-nitrobenzene, which was brominated using N-bromosuccinimide (NBS) and sulfuric acid in heptane, followed by platinum-catalyzed hydrogenation reduction of the nitro substituent in ethyl acetate (EtOAc) to give the respective aniline. The latter was then acetylated with acetic anhydride (Ac₂O) in the presence of triethylamine (TEA) in EtOAc to yield the brominated anilide 15. This aryl bromide 15 was subject to a palladium-catalyzed C—C coupling reaction with but-3-enoic acid in the presence of N,N-diisopropylethylamine (DIPEA) to an alkene intermediate, which was then hydrogenated in 2-methyle-tetrahydrofurane (2-MeTHF) to give the acid 16. The carboxylic acid was activated with trifluoroacetic acid (TFA) to react in a kind of intramolecular Friedel-Crafts acylation resulting in the tetrahydronaphthalenone derivative 17. Then, amyl nitrite and potassium tert-butanolate (t-BuOK) in tetrahydrofuran (THF) were used to nitrate in the α-position to the ketone, followed by catalytic hydrogenation of the nitro group to form a primary amine. This was finally converted to compound 18 with Ac₂O in acetic acid (HOAc). Deacetylation of the anilide, selective compared to the carboxylic acid amide of the aliphatic primary amine, was achieved with hot hydrochloric acid in ethanol (EtOH) and yielded the amine 19. This was followed by a reaction with ketone 20, the synthesis of which was also reported in the literature [22]. In 2-hydroxytoluene (o-cresol) and toluene as solvents, the primary aromatic amine 19 reacted with the ketone group of 20 in the presence of pyridinium p-toluenesulfonate (PPTS) to form the enamine 21 in a condensation reaction. This enamine 21 cyclized in a dehydrative manner to the quinoline 22. Since this was obtained as a mixture of diastereomers, it was necessary to perform the most stereoselective possible cleavage of the secondary amide to the primary amine of exatecan (1). This was done, for example, in ethylcyclohexene and 2-methoxyethanol with aqueous methanesulfonic acid (MsOH). This produced the mesylate amine salt dihydrate of exatecan (1) on the one hand and the diastereomer epi-exatecan on the other, which was separated off and underwent an amine reprotection-deprotection-crystallization sequence [23].

  Scheme 1

  

  Scheme 1.  Synthesis of exatecan (1).

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  3. Suzetrigine (Journavx)

  Suzetrigine (2, brand name: Journavx) has been approved by the FDA on January 30, 2025 for the treatment of moderate to severe acute pain. The mode of action is based on the inhibition of the voltage-gated sodium channel Na_V1.8. The inhibition is selective relative to other Na_V channel subtypes [24]. Since suzetrigine (2) is a non-opioid analgesic, the drawbacks of opioids, such as severe side effects, occurrence of tolerance, and dependence, can be better circumvented. Suzetrigine can be considered as an innovation because it is the first approved Na_V inhibitor for pain therapy [25].

  Structurally, suzetrigine (2) is a pyridine derivative that also has an oxolane core (tetrahydrofuran). The latter contains four stereogenic centers of the drug molecule as well as substitution with trifluoromethyl and a 3,4-difluoro-2-methoxyphenyl ring [26]. With regard to the structure-activity relationship (SAR), taking into account other developed Na_V1.8 inhibitors, an aryl-linked amide and fluorination can be identified [27]. Given the hydrophobicity of the fluorine substituents, the binding of the drug to a hydrophobic chasm within the target is supported and metabolic stability is increased [28].

  The synthetic route (Scheme 2) to obtain suzetrigine (2) began with 2-(3,4-difluoro-2-methoxyphenyl)acetic acid. It was activated using 1,1′-carbonyldiimidazole (CDI) in acetonitrile and then treated with (S)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one, subsequently giving the unsaturated γ-lactone 23. The α,β-double bond of the lacton 23 was hydrogenated to the saturated γ-lactone 24 using 5% palladium on carbon in isopropyl alcohol (i-PrOH) as a catalyst. The lactone 24 was further reduced employing diisobutylaluminium hydride (DIBAL-H) in toluene to afford the hemiacetal 25. The latter was acetylated to compound 26 with Ac₂O in toluene using 4-dimethylaminopyridine (DMAP) and TEA. The obtained ester 26 was reacted with trimethylsilyl cyanide in the presence of boron trifluoride etherate to yield the nitrile 27. Hydrolysis with potassium hydroxide in EtOH converted the nitrile 27 into the carboxylic acid 28. With the aid of quinine 29 in i-PrOH, acid 28 formed the salt 30 in order to allow for enantiomeric resolution. To release the free acid, the obtained salt 30 was first treated with aqueous hydrochloric acid in toluene, followed by activation using oxalyl chloride in N,N-dimethylformamide (DMF) to give the acid chloride 31. Formation of the secondary amide 32 was accomplished in the presence of TEA using methyl 4-aminopicolinate. Transformation of the methyl ester to a primary amide by reaction of 32 with ammonia solution in methanol eventually resulted in suzetrigine (2) [29].

  Scheme 2

  

  Scheme 2.  Synthesis of suzetrigine (2).

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  4. Mirdametinib (Gomekli)

  Mirdametinib (3, brand name: Gomekli) acts by inhibiting the mitogen-activated protein kinase kinases 1 and 2 (MEK1/2), thus interfering with the Ras-Raf-MEK1/2-ERK pathway. It was approved by the FDA on February 11, 2025 for the treatment of neurofibromatosis type 1 (NF1) in both adults and children (aged 2 and above) having symptomatic plexiform neurofibromas, i.e., non-cancerous tumors of the peripheral nerve sheath, which are not suitable for complete resection [30].

  The drug represents a derivative of benzohydroxamic acid esterified with glycerol. Its phenyl ring is part of a diphenylamine skeleton, being substituted twice with fluorine, while the other ring bears one fluorine substituent [31]. In the context of fluorine scanning, it was generally found that fluorination can enhance the Raf/MEK inhibition [32]. Reviewing structural features of several MEK inhibitors revealed that fluorinated compounds showed the highest potency against MEK [33,34]. In particular, fluorine substituents of both phenyl rings of the diarylamine core in the structure of mirdametinib contribute to the interaction in the binding pocket of MEK1 via Lys97 and Ser212 [35].

  The preparation of mirdametinib (3) can be performed following a convergent synthesis (Scheme 3). For this approach, the S-configured glycerol acetonide 33 was coupled with N-hydroxyphthalimide (34) in the presence of diethyl azodicarboxylate (DEAD) and PPh₃ to give the isoindole-1,3-dione derivative 35 in 86% yield. The subsequent hydrazinolysis provided the O-substituted hydroxylamine intermediate 36.

  Scheme 3

  

  Scheme 3.  Synthesis of mirdametinib (3).

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  The reaction of 2-fluoro-4-iodoaniline and 2,3,4-trifluorobenzoic acid (37) in the presence of the base lithium amide followed by esterification and hydrolysis led to the diphenylamine 38. Next, the benzoic acid derivative 38 was coupled with the hydroxylamine 36 in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole (EDCI/HOBt) to give the carbamate 39 in 67% yield. The final deprotection of the ketal to give the diol resulted in mirdametinib (3) in 82% yield [36].

  5. Avutometinib and defactinib (Avmapki)

  Avutometinib (4A) and defactinib (4B) are two inhibitors of different kinases, co-packaged (brand name: Avmapki Fakzynja Co-Pack) for the treatment of patients suffering from KRAS-mutated recurrent low-grade serious ovarian cancer (LGSOC) who have already received systemic therapy before. Approval by the FDA was granted in May 2025 [37].

  In particular, avutometinib (4A) also interferes with the Ras-Raf-MEK-ERK signaling pathway, but in a distinct manner by inhibiting both Raf and MEK kinases. Based on this dual acting, avutometinib inhibits the MAPK pathway more efficiently than a conventional MEK inhibitor [38]. Structurally, avutometinib (4A) has a 4-methylchromen-2-one scaffold, which is pyrimidine-2-yloxy-substituted and also carries a pyridin-4-ylmethyl substituent. The latter is methylsulfamoylamino-substituted in position 2 and fluorinated in position 3. The fluorine substituent at the pyridine increases the metabolic stability and contributes to the lipophilicity of the drug [39].

  The synthesis of avutometinib (4A) (Scheme 4) started from nucleophilic substitution of 5-chloro-2,3-difluoropyridine by acetamide in the presence of sodium hexamethyldisilazide (NaHMDS) leading to the intermediate 40 in 72% yield. Then, formylation of the intermediate 40 using morpholine-4-carbaldehyde in the presence of lithium hexamethyldisilazide (LiHMDS) generated aldehyde 41, which underwent condensation reaction with ethyl 3-oxobutanoate followed by reduction yielding the intermediate 42. Further reaction with resorcinol under acidic conditions yielded the 7-hydroxylated coumarin derivative 43 in a Pechmann condensation. The phenol 43 was deprotonated using potassium carbonate, followed by a reaction with 2-bromopyrimidine in THF to give the phenolic ether 44 in 76% yield. Finally, reaction with methylsulfamoyl chloride in MeCN and coexistence of a base such as pyridine afforded avutometinib (4A) [40].

  Scheme 4

  

  Scheme 4.  Synthesis of avutometinib (4A).

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  Defactinib (4B) is an inhibitor of the non-receptor tyrosine kinase, focal adhesion kinase (FAK) [41]. In addition, the proline-rich tyrosine kinase-2 (Pyk2) is inhibited by defactinib (4B), too. Chemically, defactinib (4B) consists of a 2,4-diaminopyrimidine core, which is widely discussed as a structural feature of FAK inhibitors [42–44]. However, the pyrimidine ring also carries a trifluoromethyl substituent in position 5 in the structure of defactinib. This fluorine-containing substituent forms a halogen bond with Asp564 in a hydrophobic site of FAK, thus contributing to the binding [45]. The fluorination improves affinity and metabolic stability [39].

  To prepare defactinib (4B) in a convergent synthetic strategy (Scheme 5), 2-chloropyrazine (45) was reacted in MeCN with N-methylmethanesulfonamide, which was deprotonated using cesium carbonate, to obtain the aromatic sulfonamide 46 in 73% yield. Next, reduction of the nitrile to the (aminomethyl)pyrazine 47 was achieved with catalytic hydrogenation in methanolic ammonia, followed by treatment with HOAc in EtOAc.

  Scheme 5

  

  Scheme 5.  Synthesis of defactinib (4B).

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  The 5-trifluoromethyl-substituted pyrimidine derivative 48 was converted to the diarylamine intermediate 49 with 4-amino-N-methylbenzamide using zinc(Ⅱ) bromide and TEA in dichloroethane (DCE) and tert-butanol (t-BuOH). Finally, (aminomethyl)pyrazine 47 and diarylamine 49 were coupled within a nucleophilic substitution again in DCE and t-BuOH with DIPEA serving as a non-nucleophilic base to result in defactinib (4B) in 78% yield [46].

  6. Taletrectinib (Ibtrozi)

  Taletrectinib (5, brand name: Ibtrozi) is an oral medication originally discovered by Daiichi Sankyo and developed by Nuvation Bio Inc. for treating adults with locally advanced or metastatic, ROS1-positive NSCLC [47–49]. It is a potent and selective inhibitor that primarily targets the ROS1 tyrosine kinase. The drug is specifically designed to treat tumors driven by ROS1 gene fusions. Its mechanism of action involves selectively blocking the ROS1 receptor tyrosine kinase. This blockade effectively disrupts the downstream signaling cascades that cancer cells depend on for their growth and survival. By inhibiting these pathways, taletrectinib (5) reduces the proliferation of ROS1-positive tumor cells. The drug also exhibits activity against the related neurotrophic tyrosine receptor kinase (NTRK) family of kinases (TRKA/B/C) and it has shown effectiveness against certain ROS1 resistance mutations that can emerge after earlier lines of therapy [50–52]. SAR studies revealed that the fluorine substituent on the phenyl ring shows an important role in the ROS1 kinase inhibitory activity (Fig. 2). For example, compound 51 with a fluorine atom showed a high inhibitory activity with < 20 nmol/L ROS1 IC₅₀ value. A decreased inhibitory activity was observed for the compound 50 without fluorine substituent [53]. On June 11, 2025, taletrectinib (5) received FDA approval for treating adult patients with locally advanced or metastatic, ROS1-positive NSCLC [54].

  Figure 2

  

  Figure 2.  SAR optimization for taletrectinib (5).

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  The synthesis of taletrectinib (5) was illustrated in Scheme 6. It commenced with the reaction of (R)-1-(3-fluorophenyl)ethan-1-amine with 3-bromo-6-chloroimidazo[1,2-b]pyridazine in dimethyl sulfoxide (DMSO) to afford (R)-3-bromo-N-(1-(3-fluorophenyl)ethyl)imidazo[1,2-b]pyridazin-6-amine. Then, this aryl bromide underwent a Suzuki coupling reaction with boronic acid 52, affording Boc-protected amine 53 in 66% yield. Sequential acidolysis/deprotection of Boc-protected amine 53 led to the formation of taletrectinib (5) in 91% yield [55,56].

  Scheme 6

  

  Scheme 6.  Synthesis of taletrectinib (5).

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  7. Sunvozertinib (Zegfrovy)

  Sunvozertinib (6, brand name: Zegfrovy) is an oral, covalent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Dizal (Jiangsu) Pharmaceuticals for the treatment of NSCLC. In July 2025, the FDA granted accelerated approval to sunvozertinib (6) for adults with locally advanced or metastatic NSCLC carrying EGFR exon 20 insertion mutations whose disease has progressed following platinum-based chemotherapy. Preclinical studies, including work in cell lines and xenograft models, have shown that sunvozertinib (6) has strong antitumor activity. Sunvozertinib (6) displays strong inhibitory activity against a broad range of EGFR exon20ins variants while exerting comparatively limited effects on wild-type EGFR, an attribute intended to reduce dose-limiting toxicity. Mechanistically, the drug forms an irreversible covalent bond within the ATP-binding pocket of the EGFR kinase domain, thereby blocking downstream signaling pathways that drive tumor cell proliferation and survival [57–72]. Fluorine contributes a surface that is largely hydrophobic in shape yet still carries distinct electronic features, allowing the molecule to fit more effectively into hydrophobic pockets within EGFR. The SAR studies showed high inhibitory activity with IC₅₀ values against pEGFR T790M of 0.32, 0.3, and 1.1 nmol/L for compounds 54, 55, and sunvozertinib (6), respectively. Notably, introducing both 4-fluoro and 5-chloro substitutions into compound 54 successfully reduced human hepatocyte clearance from 34 (μL/min)/(10⁶ cells) to 7.1 (μL/min)/(10⁶ cells) (Fig. 3) [73].

  Figure 3

  

  Figure 3.  SAR optimization for sunvozertinib (6).

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  The synthesis of sunvozertinib (6) was shown in Scheme 7 [73–75]. Substitution reaction between 2-(2-amino-4-chloro-5-fluorophenyl)propan-2-ol and 2,4-dichloropyrimidine with DIPEA as a base generated the intermediate in 50% yield, which underwent another substitution reaction by 4-fluoro-2-methoxy-5-nitroaniline affording the intermediate 56 in 86% yield. Subsequently, treatment of intermediate 56 with (R)-N,Ndimethylpyrrolidin-3-amine in the presence of K₂CO₃ yielded the nitro compound 57 in 87% yield. A reductive transformation of nitro compound 57 using zinc and NH₄Cl proceeded cleanly under heating to give the amine intermediate 58 in 63% yield. In the final synthetic step, reaction of amine 58 with acryloyl chloride in the presence of DIPEA afforded the desired sunvozertinib (6) in 10.5% yield.

  Scheme 7

  

  Scheme 7.  Synthesis of sunvozertinib (6).

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  8. Sebetralstat (Ekterly)

  There are several orally available small-molecule protein kinase A (PKa) inhibitors that have entered clinical trials [76–82], such as avoralstat [83], berotralstat [84], ATN-249 [85,86], and sebetralstat (7). Among them, sebetralstat (7, brand name: Ekterly) developed by Kalvista Pharmaceuticals was approved by the FDA in July 2025 for the treatment of hereditary angioedema (HAE). By inhibiting plasma kallikrein, it prevents the excessive generation of bradykinin and thereby helps to stop or diminish the development of a swelling episode. HAE attacks stem from the overactivation of the kallikrein–kinin system, which increases vascular permeability and leads to fluid leakage into tissues [87].

  The SAR insights gained from the early plasma-kallikrein inhibitor series guided the development of the more potent scaffolds represented by compounds 59 and 60, both featuring a benzylpyridone P4 moiety and a pyrazole amide core (Fig. 4). These findings prompted a re-examination of how ligands engage the P1 region, exploring binding modes that do not depend on the classical ionic interaction with Asp189. Compound 60 emerged as a suitable template for designing a series of phenyl-based P1 substituents. Subsequent lead-optimization steps produced compound 61, which incorporated two key improvements: (ⅰ) Including modification of the pyrazole core to enhance membrane permeability, and (ⅱ) introduction of a pyridine P1 group to reduce lipophilicity and increase aqueous solubility to form the structure of sebetralstat (7) [88]. Sebetralstat (7) contains a strategically positioned fluoro substituent. Fluorine can also contribute to productive hydrophobic interactions within the kallikrein binding pocket and can influence the preferred molecular geometry through stereoelectronic effects such as the gauche effect. Together, these features help balance lipophilicity, permeability, and clearance, contributing to the favorable pharmacokinetic profile of sebetralstat (7).

  Figure 4

  

  Figure 4.  SAR optimization for sebetralstat (7).

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  The synthesis of sebetralstat (7) was shown in Scheme 8. The N-benzylpyridone alcohol intermediate 62 was prepared through a regioselective alkylation of 2-hydroxypyridine with a 4-(chloromethyl)benzyl alcohol. Functional group interconversion of alcohol 62 to 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one 63 in 93% yield was achieved via the formation of methanesulfonate to afford a suitably activated electrophile for subsequent coupling steps. Intermediate 63 was reacted with a methoxymethyl-substituted pyrazole ester 64 under basic conditions affording intermediate 65 in 47% yield. Hydrolysis of the ester 65 yielded the corresponding carboxylic acid 66 in 34% yield, which was subsequently coupled with (3-fluoro-4-methoxypyridin-2-yl)methanamine (67) under general amination conditions to give the target sebetralstat (7) in 64% yield [88].

  Scheme 8

  

  Scheme 8.  Synthesis of sebetralstat (7).

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  9. Rilzabrutinib (Wayrilz)

  Rilzabrutinib (8, brand name: Wayrilz) is a product of the clear evolution from irreversible, cancer-focused Bruton's tyrosine kinase (BTK) inhibitors to reversible, more selective inhibitors for autoimmune diseases. Its "lead molecules" are both the pioneering ibrutinib [89–95] and the reversible predecessors like fenebrutinib [96] that validated the approach of targeting BTK without a covalent bond. The FDA approved drug developed by Sanofi, rilzabrutinib (8), on August 29, 2025, for adults with persistent or chronic immune thrombocytopenia (ITP). This treatment is specifically for patients who have already tried other therapies, such as immunoglobulins, anti-D therapy, and corticosteroids, without sufficient success. It is not intended as a first-line treatment. Rilzabrutinib (8) works by reversibly inhibiting a protein called BTK. This action helps regulate the faulty attack on platelets by the immune system. For patients, this can lead to a relatively quick and lasting increase in platelet counts, as well as an improvement in other symptoms related to ITP.

  Rilzabrutinib (8) tackles ITP in two keyways. First, it calms down the overactive B-cells of the immune system by blocking a key signal (BTK-mediated B-cell receptor signaling). This reduces the production of harmful "autoantibodies" that mistakenly tag the own platelets of the body for destruction. Second, it helps protect the platelets that are already in circulation. It does this by interfering with messages that tell immune cells called macrophages to "eat" the antibody-coated platelets, a process that primarily happens in the spleen and liver. Because it addresses this underlying immune misfiring, rilzabrutinib (8) is often described as an orphan drug that targets a root cause of ITP, rather than just boosting platelet production like other treatments (thrombopoietin receptor agonists) do [97,98].

  The single fluorine atom in the chemical structure of rilzabrutinib is a key design feature that significantly enhances the efficacy of the drug. Rilzabrutinib (8) exhibited a high inhibitory activity against BTK with an IC₅₀ value of 1.3 nmol/L. In the human whole blood (HWB) CD69 B-cell activation assay, it also demonstrated a trend toward high potency (IC₅₀ = 123 ± 38 nmol/L; n = 8). The early SAR studies disclosed that fluorine atom was a preferred substituent for the diaryl ether linkage, affording improved inhibition of CD69 expression on anti-IgM-stimulated B cells in HWB [99].

  The synthesis of rilzabrutinib (8) was outlined in Scheme 9 [99,100]. The aldehyde 69 and nitrile 75 are the key intermediates which were made in a convergent synthesis. The aldehyde 69 was synthesized from isobutyraldehyde. Isobutyraldehyde was brominated to form 2-bromo-isobutyraldehyde 67, which directly reacted with the 1-(oxetan-3-yl)piperazine (68) in the presence of DIPEA to provide aldehyde 69. Another key cyanoamide intermediate 75 was obtained through a five-step linear sequence starting from iodination of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (70) by using N-iodosuccinimide (NIS). Then, Mitsunobu reaction of the intermediate 71 with tert-butyl (S)-3-hydroxypiperidine-1-carboxylate in the presence of diisopropyl azodicarboxylate (DIAD) and PPh₃ afforded the intermediate 72, which underwent Suzuki–Miyaura coupling with (2-fluoro-4-phenoxyphenyl)boronic acid yielding the intermediate 73 in 76% yield. Boc-deprotection followed by an amidation reaction with cyanoacetic acid using ethyldimethylaminopropyl carbodiimide (EDC)/HOBt as coupling agents gave the cyanoamide intermediate 75. Final step for the construction of the targeted rilzabrutinib (8) was achieved through the Knoevenagel condensation between cyanoamide 75 and aldehyde 69 in 69% yield as a 9:1 E/Z mixture. The unwanted Z isomer was removed by purification via flash column chromatography to afford rilzabrutinib (8) in 29% yield.

  Scheme 9

  

  Scheme 9.  Synthesis of rilzabrutinib (8).

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  10. Imlunestrant (Inluriyo)

  Imlunestrant (9, brand name: Inluriyo) is a brain-penetrant selective estrogen receptor degrader (SERD) developed by Eli Lilly and Company (Indianapolis, IN, USA) to provide continuous inhibition of estrogen receptor (ER) α, including ESR1-mutant variants that increase endocrine resistance in ER-positive, HER2-negative advanced breast cancer [101,102]. On September 25, 2025, it received its first approval from the FDA for the treatment of ER+, HER2- estrogen receptor 1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy [101–103]. Imlunestrant (9) binds to and degrades ERα with high potency (K_i = 0.64 nmol/L; DC₅₀ < 1 nmol/L) and maintains strong affinity for the Y537S mutant (K_i = 2.8 nmol/L), outperforming non-trifluoromethylated analogs 76 (K_i = 8.11–27.23 nmol/L) as illustrated in Fig. 5, emphasizing the effect of strategic fluorine substitution on receptor engagement and metabolic stability [104]. Clinically, Imlunestrant (9) monotherapy achieves mPFS values of 5.5–7.2 months and shows superior efficacy in ESR1-mutated tumors, with a favorable safety profile dominated by low-grade gastrointestinal symptoms and fatigue [105]. With potent ER degradation, mutation-agnostic activity, and brain penetration, imlunestrant (9) represents a significant advancement in endocrine therapy and a strong backbone for future combination strategies [101–105].

  Figure 5

  

  Figure 5.  Structure of imlunestrant (9) and its non-trifluoromethylated analog (76).

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  The synthesis of imlunestrant (9) as outlined in Scheme 10 started with aldehyde 77, which was treated with 4-fluorophenylmagnesium bromide in THF at –78 ℃, followed by MnO₂-mediated oxidation under reflux in dichloromethane (DCM) to afford the ketone intermediate 78. Subsequent demethylation with boron tribromide yielded the corresponding phenolic derivative 79. This intermediate 79 then underwent a Mitsunobu reaction with 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (80) to provide ether-linked product 81 in 61% yield. A palladium-catalyzed Suzuki–Miyaura coupling with (4-(trifluoromethyl)phenyl)boronic acid furnished the biaryl quinoline ketone 82. Reduction of this ketone 82 with lithium triethylborohydride in 1,4-dioxane, followed by cyclization using NaH under reflux conditions, afforded racemic imlunestrant ((±)-9). Finally, chiral supercritical fluid chromatography (SFC) resolution afforded the enantiopure product imlunestrant (9) [106].

  Scheme 10

  

  Scheme 10.  Synthesis of imlunestrant (9).

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  11. Paltusotine (Palsonify)

  Paltusotine (10, brand name: Palsonify) is a 4-(4-aminopiperidinyl)-3,6-diarylquinoline derivative manufactured by Crinetics Pharmaceuticals Inc. (San Diego, USA) as a selective orally non-peptide somatostatin receptor subtype 2 (SST₂) agonist for the treatment of acromegaly and neuroendocrine tumors (NETs) [107–109]. Paltusotine (10) demonstrated exceptional potency (hSST₂ EC₅₀ = 0.25 nmol/L, pEC₅₀ = 9.6 ± 0.2) and > 1000-fold selectivity over other somatostatin receptor subtypes (SST₁, SST₃, SST₄, and SST₅), showing significantly greater activity compared to other analogs bearing fluoro and cyano substituents (compound 84, EC₅₀ = 10 nmol/L) and to compound 85, which contains two hydrogens instead of fluorine atoms (EC₅₀ = 1.9 ± 0.1 nmol/L) as illustrated in Fig. 6 [107]. Palsonify provides a once-daily oral therapy that effectively suppresses growth hormone (GH) secretion and reduces insulin-like growth factor-1 (IGF-1) levels, thereby maintaining biochemical control in acromegaly patients [108,109]. Following promising clinical results in Phase Ⅱ studies demonstrating durable GH and IGF-1 suppression in patients switched from injectable somatostatin analogs, the FDA approved Palsonify on September 25, 2025, for the treatment of acromegaly in adults who had an inadequate response to surgery and/or for whom surgery is not an option [110]. This approval marks Palsonify as the first non-peptide SST₂ agonist to reach the market, representing a major advancement in the management of acromegaly through convenient effective oral therapy [107–110].

  Figure 6

  

  Figure 6.  Structure of paltusotine (10) and its monofluorinated and non-fluorinated analogs.

  DownLoad: Full-Size Img PowerPoint

  The synthesis of paltusotine (10), as depicted in Scheme 11, commenced with 6-bromo-3,4-dichloroquinoline (86), which was treated with tert-butyl piperidin-4-ylcarbamate (87) and DIPEA in DMSO, affording the intermediate 88 in 63% yield. This intermediate was then subjected to a Suzuki coupling with boronate 89 in the presence of PdCl₂(dppf) and KOAc in THF/H₂O at 80 ℃ to produce the intermediate 90. This intermediate 90 underwent a second Suzuki coupling with (3,5-difluorophenyl)boronic acid, catalyzed by Pd(AmPhos)Cl₂ and K₂CO₃ in 1,4-dioxane/H₂O to afford the intermediate 91. Finally, removal of the protecting group under acidic conditions furnished paltusotine (10) in 52% yield [107].

  Scheme 11

  

  Scheme 11.  Synthesis of paltusotine (10).

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  12. Remibrutinib (Rhapsido)

  Remibrutinib (11, brand name Rhapsido) is a highly selective covalent Bruton's tyrosine kinase (BTK) inhibitor developed by Novartis Pharmaceuticals (Basel, Switzerland) [111]. On September 30, 2025, Rhapsido received its first approval from the FDA for oral use in adult patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite second-generation H1-antihistamine therapy [112]. The incorporation of fluorine into the chemical structure of Remibrutinib (11) significantly enhances its pharmacological potency compared to that of the analog 92 (Fig. 7). This modification exhibits superior BTK inhibition (IC₅₀ = 1.3 ± 0.9 nmol/L vs. 3.8 ± 0.32 nmol/L). Similar trends are observed across additional pharmacological assays, including FcγR/IL-8 inhibition in THP-1 cells (2.5 ± 0.7 nmol/L vs. 11 ± 6 nmol/L) and BCR/CD69 activation in B cells (18 ± 5 nmol/L vs. 106 ± 51 nmol/L). Furthermore, fluorination improves membrane permeability (logP_e−4.3 vs. −5.0), thereby increasing cellular absorption [111,113]. In clinical trials, including Phase Ⅱ and Ⅲ studies, Remibrutinib showed early and sustained efficacy in CSU patients, with significant reductions in urticaria activity scores (UAS7 = 0 or ≤6) as early as week 1, particularly at the 25 mg twice-daily dose [112,114]. Additionally, remibrutinib (11) demonstrated therapeutic potential in other BTK-mediated diseases such as multiple sclerosis, chronic lymphocytic leukemia (CLL), and B-cell malignancies [115]. Thanks to all above information as well as its oral administration and a favorable safety profile, remibrutinib (11) represents a promising targeted therapy for patients with moderate to severe CSU and other mast cell-, basophil-, and B-cell-driven disorders [112–114].

  Figure 7

  

  Figure 7.  Structure of remibrutinib (11) and its analog 92.

  DownLoad: Full-Size Img PowerPoint

  The synthetic preparation of remibrutinib (11) was shown in Scheme 12. First, borylation of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene using bis(pinacolato)diboron (BISPIN), Pd(dppf)Cl₂, and potassium acetate afforded boronic ester 94, which was subsequently reduced by catalytic hydrogenation to give aniline 95. In parallel, Suzuki coupling of methyl 4-bromo-2-fluorobenzoate with cyclopropylboronic acid produced ester 96, which underwent NaHMDS-mediated amide formation with aniline 95 to give the boronic ester intermediate 97. The second fragment of the molecule was assembled starting from 2,4-dichloro-3-methoxypyrimidine 98, which was converted to aminopyrimidine 99 via amination, followed by demethylation with boron tribromide to give aminopyrimidinol 100. Introduction of the linker was achieved through a Mitsunobu reaction with N-Boc-N-methyl-2-hydroxyethylamine in the presence of DIAD and polymer-supported triphenylphosphine (Smopex-301), forming the intermediate 101. Next, the Suzuki coupling of intermediates 97 and 101 afforded the Boc-protected intermediate 102. Finally, Boc deprotection and amide coupling with acrylic acid using propylphosphonic anhydride (T3P) provided the final product remibrutinib (11) [111,116].

  Scheme 12

  

  Scheme 12.  Synthesis of remibrutinib (11).

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  13. Elinzanetant (Lynkuet)

  Elinzanetant (12, brand name Lynkuet) is a potent and selective dual neurokinin-1 and neurokinin-3 (NK1/NK3) receptor antagonist developed by Bayer AG (Leverkusen, Germany). On October 24, 2025, it received its first approval from the FDA for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause [117]. Elinzanetant (12) exerts its therapeutic effect through simultaneous antagonism of NK1 and NK3 receptors (pK_i = 8.7–10.2 and 8.0–8.8, respectively; K_i ≈ 0.2–2 nmol/L), thereby modulating the neurokinin kisspeptin system that regulates thermoregulatory and reproductive hormone signaling [118,119]. Fluorine incorporation into the molecular scaffold enhances receptor binding affinity and stability compared to its analog 104 (K_i ≈ 1–10 nmol/L) as illustrated in Fig. 8 [119,120]. In Phase Ⅱ and Ⅲ trials, Elinzanetant significantly reduced the mean daily frequency of moderate to severe vasomotor episodes by 6.5 episodes at week 4 and 7.8 episodes at week 12 [117,121]. Treatment also improved sleep quality and mood, while serious adverse events were rare (≤2.5%) [117,120]. Additionally, elinzanetant (12) has shown promise in suppressing reproductive hormone levels, including estradiol and luteal-phase progesterone, without inducing vasomotor side effects, suggesting potential utility in hormone-driven conditions such as uterine fibroids and endometriosis [121]. With its non-hormonal mechanism, robust efficacy, and favorable safety profile, Lynkuet represents a novel targeted therapy addressing the unmet need for effective management of menopausal vasomotor symptoms and related endocrine conditions [117–122].

  Figure 8

  

  Figure 8.  Structure of elinzanetant (12) and its analog 104.

  DownLoad: Full-Size Img PowerPoint

  The synthesis of elinzanetant (12) was depicted in Scheme 13. It was started with 4-chloro-5-nitropyridin-2(1H)-one (105), which was subjected to Suzuki coupling with 4-fluoro-2-methylphenylboronic acid in the presence of Pd(dppf)Cl₂ and K₂CO₃ in 1,4-dioxane/H₂O, affording the intermediate 106. This intermediate was then reacted with POCl₃ to produce chlorinated compound 107. The resulting nitro derivative underwent catalytic hydrogenation using 10% Pd/C in EtOH under 50 psi H₂ to afford amine 108. Subsequent amide coupling of amine 108 with acyl chloride 109 afforded the intermediate 110. N-Methylation of resulting 110 with MeI and Cs₂CO₃ in DMF furnished the key intermediate 111, which was then coupled via nucleophilic aromatic substitution (S_NAr) with the upper fragment 112 using DIPEA and KI in N-methylpyrrolidone (NMP) to form the intermediate 113. Salt formation with 4 mol/L HCl in dioxane/isopropanol delivered compound 114·hydrochloride. Finally, treatment with NaOH followed by crystallization from isopropanol/acetone yielded elinzanetant (12) as anhydrous crystalline compound [123].

  Scheme 13

  

  Scheme 13.  Synthesis of elinzanetant (12).

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  14. Ziftomenib (Komzifti)

  Ziftomenib (13, brand name Komzifti) is a potent selective menin inhibitor developed by Kura Oncology (San Diego, California, USA) for the treatment of relapsed or refractory acute myeloid leukemia (AML) driven by nucleophosmin 1 (NPM1) mutations or lysine methyltransferase 2A/mixed lineage leukemia 1 (KMT2A/MLL1) rearrangements. On November 13, 2025, it received its first approval from the FDA for adult patients with relapsed or refractory AML harboring a susceptible NPM1 mutation lacking satisfactory alternative treatment options [124,125]. Ziftomenib showed high biochemical and cellular potency, with an IC₅₀ < 50 nmol/L with menin and a peptide containing the high affinity menin binding motif found (in MLL in a fluorescence polarization assay) and GI₅₀ < 10 nmol/L (in MLLAF9 bone marrow cells) [126]. Ziftomenib effectively disrupts the menin–MLL1 protein–protein interaction, a central epigenetic driver sustaining leukemogenic transcriptional programs involving HOX, MEIS1, PBX3, FLT3, and BCL2 [126,127]. In clinical studies, Ziftomenib demonstrated a manageable safety profile with expected hematologic toxicities and differentiation syndrome (15%). The recommended 600-mg dose achieves complete remission (CR) with partial hematologic recovery (CRh) in 25% of patients with KMT2A rearrangements or NPM1 mutations, including 35% CR in the NPM1mut subgroup [127]. Based on promising preclinical data and clinical complete responses, Komzifti represents a major advance in precision epigenetic therapy and has the potential to become the next novel class of targeted therapy in leukemias [124–127].

  The synthetic preparation of ziftomenib (13), as outlined in Scheme 14, began with the construction of the thienopyrimidine core. Treatment of 2-amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide (115) with bis(trichloromethyl) carbonate (BTC) furnished the key bicyclic intermediate 116. Subsequent chlorination using a combination of PCl₅ and POCl₃ produced compound 117, which then underwent nucleophilic substitution with tert-butyl 4-aminopiperidine-1-carboxylate 118 in the presence of DIPEA to afford the mono-substituted chloride intermediate 119. A second substitution with methylamine in heated EtOH provided compound 120, followed by Boc deprotection with trifluoroacetic acid to form the corresponding diamine fragment 121. Next, the resulting fragment underwent reductive amination with (S)-indole derivative 122 in the presence of TEA and NaBH(OAc)₃ to afford protected the indole–piperazine conjugate 123, which was subsequently subjected to Boc-removal using excess of TFA to furnish free indole–piperazine amine 124. Finally, mesylation with mesyl chloride (MsCl) and TEA provided ziftomenib (13) [128,129].

  Scheme 14

  

  Scheme 14.  Synthesis of ziftomenib (13).

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  15. Zoliflodacin (Nuzolvence)

  Zoliflodacin (14, brand name Nuzolvence) is a novel oral antibiotic that was approved by the FDA in December 2025 for the treatment of uncomplicated genitourinary gonorrhea infections in adults and adolescents aged 12 years or older (weighing ≥35 kg) [130,131]. It has a unique mechanism of action and is effective against multidrug-resistant strains. Zoliflodacin (14) is a first-in-class oral antibiotic belonging to the spiropyrimidinetrione class [132]. It exerted bactericidal effects by inhibiting the DNA replication of Neisseria gonorrhoeae, specifically through targeting a particular subunit of bacterial topoisomerase Ⅳ [133,134]. Its unique mechanism of action ensured no cross-resistance with existing antibiotics such as fluoroquinolones, and it remained active against multidrug-resistant strains, including those resistant to ceftriaxone and azithromycin.

  The SAR studies showed that the analog of zoliflodacin (14) with chloro on the benzo[d]isoxazole unit featured a decreased human plasma protein binding (PPB) f_u value and a lower solubility (510 μmol/L). Although a similar Escherichia coli FP-based DNA gyrase inhibitory activity was obtained, distilling f_u, antibacterial activity, and rat clearance (Cl) disclosed that zoliflodacin (14) was a more favorable compound (Fig. 9). Compared with its analogs, zoliflodacin (14) showed virtually no evidence of genotoxicity at the highest concentrations tested in both mouse micronucleus chromosome aberration assay (MMA) and mouse lymphoma assay (MLA). Also, the mammalian cellular toxicity studies disclosed that zoliflodacin (14) showed no activity against myeloid and erythroid cell lines at the highest concentration tested of 100 μmol/L. Moreover, zoliflodacin (14) demonstrated efficacy in a S. aureus neutropenic thigh infection model in mice. It showed a static response at about 10 mg kg^-1 d^-1. Maximal responses of nearly a 2-log reduction in CFU were seen at 25 and 50 mg kg^-1 d^-1. Based on these results, zoliflodacin (14) was selected for preclinical development [132].

  Figure 9

  

  Figure 9.  Structure of zoliflodacin (14) and its analog 125.

  DownLoad: Full-Size Img PowerPoint

  The synthesis of zoliflodacin (14) was shown in Scheme 15 [132], which involved the key steps of constructing benzisoxazole, oxazolidinone, and chiral fused morpholine cyclic unit. First, the protection of 2,3,4-trifluorobenzaldehyde by glycol resulted in the corresponding acetal in 78% yield, which underwent a fluorine-directed ortho-lithiation followed by treatment with DMF to form the aldehyde intermediate 126. Subsequently, aldehyde 126 was converted into oxime 127, which was further treated with N-chlorosuccinimide (NCS), yielding oximoyl chloride 128. Then, chloride displacement of oximoyl chloride 128 by (S)-2-aminopropan-1-ol to give the intermediate 129. Cyclization of the intermediate 129 in the presence of an inorganic base afforded the benzisoxazole intermediate 130 in 80% yield. The second cyclization reaction of aminoalcohol 130 with CDI furnished the oxazolidinone 131, which underwent the hydrolysis of the acetal group affording aldehyde intermediate 132. The fluoride adjacent to the aldehyde group in compound 132 was displaced by chiral dimethylmorpholine via a S_NAr reaction furnishing the intermediate 133, which underwent a Knövenagel condensation with pyrimidine-2,4,6(1H, 3H, 5H)-trione in the presence of acetic acid followed by a tertiary amino effect reaction affording the desired zoliflodacin (14) with 9:1 distereoselectivity. The major isomer zoliflodacin (14) could be separated from the minor diastereomers.

  Scheme 15

  

  Scheme 15.  Synthesis of zoliflodacin (14).

  DownLoad: Full-Size Img PowerPoint

  16. Conclusions and outlook

  The fourteen newly approved fluorine-containing drugs discussed in this article display wide-ranging structural diversity, chemical functionality, and therapeutic applications. Yet they share notable common features: All but three contain heterocyclic moieties, and most are chiral compounds, reflecting the dominance of heterocycles in drug scaffolds and the growing emphasis on enantiopure development. Fluorination patterns also follow established medicinal chemistry strategies. Aromatic mono-fluorination is observed in compounds 1, 3, 4A, 5, 6, 7, 8, 11, 12, and 14; difluorination in 2, 3, and 10; aromatic trifluoromethyl (CF₃) substitution in 4B, 9, and 12; and aliphatic fluorination in 2, 9, and 13. This distribution mirrors trends seen in previous years, underscoring the enduring role of fluorine in fine-tuning drug properties. Aromatic fluorination remains the most common approach, as it subtly modulates electron density and metabolic stability without adding steric bulk, while CF₃ groups and difluorination enhance lipophilicity and block metabolic "hot spots". Aliphatic fluorination, though less frequent, stabilizes C–H bonds and influences conformational preferences. Together, these recurring motifs highlight how heterocycles, chirality, and fluorine substitution continue to serve as reliable design principles for optimizing potency, selectivity, and pharmacokinetics in modern drug development.

  Fluorine scanning and structural editing have become indispensable strategies in contemporary medicinal chemistry, exerting a profound influence on the broader field of organic synthesis. By systematically exploring fluorine substitution, researchers can fine-tune molecular properties such as potency, selectivity, metabolic stability, and pharmacokinetics. This methodological integration has transformed drug discovery pipelines, making fluorination not merely a tactical modification but a central design principle.

  It should be noted that the introduction of fluorine atoms may also lead to increased potential toxicity due to enhanced metabolic stability. Moreover, enzymatic metabolism of the active agent may lead to a loss of fluorination and the formation of metabolites that could probably affect the safety of therapy. Consequently, the prevalence of fluorinated pharmaceuticals on the global market is projected to continue its steady expansion in the coming years, reflecting both the proven success of fluorine chemistry and its enduring role in shaping next-generation therapeutics.

  There are still great challenges and good opportunities in the design and development of fluorine-containing drugs in the future. These include developing greener and more efficient fluorination synthetic methods, exploring new fluorination patterns, utilizing artificial intelligence to assist in predicting the fluorine atom sites in the optimization of lead compounds, and assessing the persistence and degradation of fluorine-containing drugs in the environment.

  CRediT authorship contribution statement

  Qian Wang: Writing – original draft, Software, Methodology. Yeping Bian: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Conceptualization. Elias Abouchabaka: Writing – original draft, Software, Methodology, Data curation. Daniel Baecker: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Gagan Dhawan: Writing – original draft, Validation, Methodology, Formal analysis. Anas Semghouli: Writing – original draft, Software, Methodology, Formal analysis. Loránd Kiss: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Wei Zhang: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Formal analysis, Conceptualization. Vadim A. Soloshonok: Writing – review & editing, Writing – original draft, Supervision, Project administration, Investigation, Formal analysis, Data curation, Conceptualization. Jianlin Han: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21761132021), the Qing-Lan Project of Jiangsu Province (for Han), the National Research, Development and Innovation Office of Hungary (No. NKFIH/OTKA K 142266), and IKERBASQUE, Basque Foundation for Science (for Soloshonok). The publication of this article was funded by Freie Universität Berlin.

  
  
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• 

  Figure 1  Structures of fourteen novel fluorine-containing pharmaceuticals that received approval from the FDA for market entry in 2025.

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  Scheme 1  Synthesis of exatecan (1).

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  Scheme 2  Synthesis of suzetrigine (2).

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  Scheme 3  Synthesis of mirdametinib (3).

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  Scheme 4  Synthesis of avutometinib (4A).

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  Scheme 5  Synthesis of defactinib (4B).

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  Figure 2  SAR optimization for taletrectinib (5).

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  Scheme 6  Synthesis of taletrectinib (5).

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  Figure 3  SAR optimization for sunvozertinib (6).

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  Scheme 7  Synthesis of sunvozertinib (6).

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  Figure 4  SAR optimization for sebetralstat (7).

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  Scheme 8  Synthesis of sebetralstat (7).

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  Scheme 9  Synthesis of rilzabrutinib (8).

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  Figure 5  Structure of imlunestrant (9) and its non-trifluoromethylated analog (76).

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  Scheme 10  Synthesis of imlunestrant (9).

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  Figure 6  Structure of paltusotine (10) and its monofluorinated and non-fluorinated analogs.

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  Scheme 11  Synthesis of paltusotine (10).

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  Figure 7  Structure of remibrutinib (11) and its analog 92.

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  Scheme 12  Synthesis of remibrutinib (11).

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  Figure 8  Structure of elinzanetant (12) and its analog 104.

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  Scheme 13  Synthesis of elinzanetant (12).

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  Scheme 14  Synthesis of ziftomenib (13).

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  Figure 9  Structure of zoliflodacin (14) and its analog 125.

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  Scheme 15  Synthesis of zoliflodacin (14).

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•