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. 2020 Oct 28;11(12):2519–2525. doi: 10.1021/acsmedchemlett.0c00505

Addition of Fluorine and a Late-Stage Functionalization (LSF) of the Oral SERD AZD9833

James S Scott †,*, Thomas A Moss †,*, Bernard Barlaam †, Paul R J Davey †, Gary Fairley †, Eric T Gangl ‡, Ryan D R Greenwood †, Holia Hatoum-Mokdad ‡, Andrew S Lister †, David Longmire †, Radoslaw Polanski §, Stephen Stokes †, Michael J Tucker †, Jeffrey G Varnes ‡, Bin Yang ‡
PMCID: PMC7734794  PMID: 33335676

Abstract

graphic file with name ml0c00505_0013.jpg

Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, permeability, and metabolism are discussed. Many of these changes were tolerated in terms of pharmacology and resulted in high quality molecules which reached advanced stages of profiling in the testing cascade.

Keywords: Estrogen receptor degrader, fluorine, LSF, medicinal chemistry

Replacement of hydrogen by a fluorine is a commonly employed strategy in medicinal chemistry.1 The high electronegativity of fluorine results in strong, polarized C–F bonds which can be resistant to metabolism, undergo interactions with proteins, and allow modulation of physicochemical properties.2,3 The utility of this atom is reflected in the high proportion of launched drugs4,5 and molecules currently in development6 that contain fluorine within their molecular structures. The increased application of fluorine in drug discovery programs has advanced in tandem with improved synthetic methodologies for C–F bond formation.7−9

Late stage functionalization (LSF) is an emerging paradigm, driven by advances in C–H activation chemistry, for generating close analogues of lead molecules.10 It has the potential to rapidly expand structure activity relationships (SAR) and access substitution patterns that are challenging to achieve using traditional synthetic approaches. Given the importance of fluorine, a number of LSF approaches targeting its introduction have recently been described.11,12

Degradation and antagonism of the estrogen receptor α (ERα) is a clinically validated approach for the treatment of breast cancer.13 Fulvestrant, a selective estrogen receptor degrader (SERD) which has the ability to both completely antagonize ERα signaling and cause degradation of the protein, was approved for second-line treatment of hormone receptor positive metastatic breast cancer nearly two decades ago.14 Fulvestrant is administered clinically via monthly intramuscular injection, with a maximum administrable dose of 500 mg and is currently the only clinically approved SERD.15 Recent efforts have been made to discover orally bioavailable SERDs to further enhance benefit to patients.16,17 We recently disclosed our efforts leading to the discovery of the oral SERD AZD9833 (1) (Figure 1), which is currently being evaluated in phase II clinical trials.18 Notably, both fulvestrant and 1 already contain multiple fluorine atoms (5 and 4, respectively). Herein, we report some of our efforts during the discovery program to generate fluorinated analogues of 1 and showcase some of the synthetic strategies employed to achieve this.

Figure 1.

Figure 1

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Fulvestrant and AZD9833 (1).

Our initial efforts focused on introducing fluorine to the pyridyl D-ring. We anticipated that late-stage electrophilic fluorination of the relatively electron-poor pyridine would be challenging in the presence of the indazole moiety. In addition, oxidative approaches such as Hartwig’s ortho-fluorination of pyridines19 can be sensitive to additional functionality. Drawing on our prior experience from the discovery program that led to 1,18 we expected that the desired tricyclic indazoles should be accessible from a Pictet–Spengler cyclization of a pyridyl aldehyde with the indazole 16 (Scheme 1). Using this approach, the required fluorination pattern could be introduced on a much simpler pyridine substrate. 5-Bromo-3-fluoropicolinaldehyde was readily accessible from commercial suppliers; however, there was very limited availability for the 6-fluoro analogue 15. We accessed this by initial protection of 5-bromopicolinaldehyde as the dimethyl acetal. Hartwig fluorination19 using AgF2 in MeCN smoothly introduced the desired fluorine onto the remaining ortho position of the pyridine, after which acidic hydrolysis of the acetal furnished the desired fluoro-aldehyde in good yield. Pleasingly, both aldehydes readily underwent Pictet–Spengler cyclization to afford the tricyclic indazoles 17 and 18. Finally, Buchwald amination catalyzed by BrettPhos third generation palladium precatalyst20 installed the desired amino-azetidine to afford fluoro-pyridines 2 and 3.

Scheme 1. Synthesis of Pyridyl D-Ring Analogues 2 and 3.

Scheme 1

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Reagents and conditions: (a) (MeO)3CH, In(OTf)3, 71%; (b) AgF2, MeCN, 58%; (c) HCl, THF, 96%; (d) 5-bromo-3-fluoropicolinaldehyde or 15, toluene/TFA (9:1), 90 °C, 62–64%; (e) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 50 °C, 71% for 2, 49% for 3.

Both 2-F (2) and 5-F (3) substitutions produced compounds with very similar potencies (Table 1) and only minimal increase in lipophilicity (ΔlogD + 0.1). The degradation was confirmed by Western blot in both MCF-7 and CAMA-1 cell lines and was similar to that observed with 1.21 No significant changes were observed in either free drug levels or rat hepatocyte clearance; however, changes were observed in terms of permeability. Compound 1 showed good permeation (Papp = 13 × 10–6 cm/s) with modest levels of efflux (ER = 4) in a Caco-2 assay.22 F-analogue 2, with the F proximal to the NH, showed an increased permeability (Papp = 24 × 10–6 cm/s) and no efflux (ER = 0.8), potentially due to shielding of the donor by the neighboring fluorine. By contrast, isomeric 3, bearing the F distal to the NH, did not show improvements in either permeability (Papp = 14 × 10–6 cm/s) or efflux (ER = 7).

Table 1. Pyridyl D-Ring Substitution.

graphic file with name ml0c00505_0008.jpg

Cpd ER bind pIC50a ER DR pIC50b LogDc (LLE) Hu % Freed Rat heps Clinte Hu mics Clintf
1 8.6 9.8 (99%) 2.9 (6.9) 23 23 12
2 8.8 9.7 (98%) 3.0 (6.7) 16 36 20
3 8.7 9.6 (98%) 3.0 (6.6) 16 24 19
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a

ER binding based on n ≥ 2 with SEM within 0.3 units.

b

ER degradation based on n ≥ 2 with SEM within 0.3 units.

c

logD7.4 determined by shake flask method with LLE (ER DR pIC50-logD7.4).

d

Plasma protein binding determined from DMSO stock solution by equilibrium dialysis in 10% human plasma supplied by Quintiles.

e

Rate of metabolism (μL/min/106 cells) determined from DMSO stock solution in isolated rat hepatocytes diluted to 1 × 106 cells/mL.

f

Rate of metabolism (μL/min/mg) determined from DMSO stock solution in human microsomes.

We next turned our attention to the B-ring of the tricyclic scaffold (Scheme 2). As a start-point 4-bromo-7-fluoroindazole was available from commercial suppliers. Again drawing on our previous experience, the required alkylated indazole could be accessed by reacting the preformed organolithium species with the cyclic sulfamidate.23 Deprotection of the N-Boc group and alkylation of the amine salt in a 2-step procedure furnished the alkylated indazole 20 in good overall yield. The desired tricyclic indazole 4 was subsequently accessed in the same manner as previous compounds; Pictet–Spengler cyclization with 5-bromopicolinaldehyde was followed by Buchwald amination to install the amino-azetidine group.

Scheme 2. Synthesis of Phenyl B-Ring Analogue 4.

Scheme 2

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Reagents and conditions: (a) n-BuLi, tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide, THF, −78 °C, 64%; (b) HCl, DCM, 99%; (c) ethyl 2,2,2-trifluoroacetate, Et3N, MeOH, 98%; (d) BH3·THF, THF, 71%; (e) 5-bromopicolinaldehyde, toluene/TFA (20:1), 90 °C, 80%; (f) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 50 °C, 54%.

Although 4-bromo-6-fluoroindazole was available from commercial suppliers, we were able to harness a late-stage functionalization approach to access this and other substituents on the 6-position from a common substrate (Scheme 3). Starting from the THP-protected tricyclic indazole 21 (see SI for details), iridium catalyzed borylation24 successfully installed the pinacol boronate as a single regioisomer, which was presumably directed by the neighboring pyridine.25,26 The N2 THP isomer was chosen to avoid a potential competitive directing effect from the oxygen to the 7-position of the indazole that might be anticipated from the alternative N1 protected isomer.27 From this common intermediate, azidation of the boronate28 followed by reduction afforded the aniline 23. The Balz–Schiemann reaction converted this aniline into the fluorine,29 along with concomitant cleavage of the THP protecting group. Finally the azetidine was installed by Buchwald amination to produce the 6-fluorinated indazole 5. The pinacol boronate 22 also allowed access to the methoxy analogue 24, by treatment with Cu(OTf)2 and CsF in MeOH,30 and the phenol 25, by reaction with NaBO3 in THF/H2O.31 In both cases deprotection of the THP group followed by Buchwald amination gave the 6-methoxy and 6-hydroxy substituted indazoles 6 and 7.

Scheme 3. Synthesis of Phenyl B-Ring Analogues 5–7.

Scheme 3

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Reagents and conditions: (a) [Bpin]2, [Ir(OMe)(cod)]2, THF, 66 °C, 64%; (b) NaN3, CuSO4, MeOH, RT, then NaBH4, 66%; (c) NaNO2, HBF4, THF/H2O, 150 °C, 8%; (d) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 70 °C, 25%; (e) Cu(OTf)2, CsF, MeOH, RT, 56%; (f) NaBO3, THF/H2O; (g) 4 N HCl in dioxane, MeOH, RT, 82% from 24, 49% over 2 steps from 25 including step f; (h) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 65–70 °C, 29% for 6, 4% for 7.

The 7-F (4) substitution was tolerated with similar potency but a gain in lipophilicity relative to 1, leading to an erosion of LLE (Table 2). This showed good degradation of ERα in both MCF-7 (98%) and CAMA-1 (97%) cell lines, comparable with 1. The 6-F (5) was weaker in terms of binding and degradation potency. Notably this substitution reduced lipophilicity resulting in a significant difference in lipophilicity (ΔlogD −0.5) between the isomers 4 and 5. Methoxy (6) substitution led to a further drop in binding and potency as well as a reduction in the observed Dmax, resulting in a partial degrader phenotype. The corresponding phenol (7) was weaker still in terms of degradation but did show a more complete Dmax. While none of these compounds offered improvements over the unsubstituted core, LSF allowed rapid exploration of SAR at the 6-position and convinced us not to invest further chemistry exploring this region.

Table 2. Phenyl B-Ring Substitutiona.

graphic file with name ml0c00505_0009.jpg

Cpd ER bind pIC50 ER DR pIC50 LogD (LLE) Hu % Free Rat heps Clint Hu mics Clint
4 9.3 9.7 (98%) 3.2 (6.5) 14 20 19
5 7.8 8.3 (95%) 2.7 (5.6) 19 11 8
6 6.3b 8.6 (40%) 2.4 (6.2) 32 6 26
7 7.4 6.9 (>80%) 2.3 (4.6)   11 5
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a

Legend as Table 1.

b

SEM 0.79.

Fluorination of the A-ring of the indazole was explored in conjunction with fluorination of the pyridyl ring explored in Table 1 (Scheme 4). Electrophilic fluorination of the tricyclic indazole proved to be unsuccessful due to unwanted oxidation of the relatively labile C–H bond in the piperidine ring, leading to formation of an iminium ion. To mitigate against this inherent reactivity toward oxidants, we decided to install the 3-fluoro at an earlier stage. Treatment of 4-bromoindazole with Selectfluor in DMA afforded 4-bromo-3-fluoroindazole 26 in modest yield.32 From here, a similar procedure to Scheme 2 was employed; formation of the organolithium and reaction with the cyclic sulfamidate gave the free amine after removal of the N-Boc group. Subsequent alkylation produced 27 which underwent Pictet–Spengler cyclization smoothly with both fluorinated aldehydes. Finally, Buchwald amination installed the amino-azetidine to afford 8 and 9.

Scheme 4. Synthesis of Indazole A-Ring Analogues 8 and 9.

Scheme 4

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Reagents and conditions: (a) Selectfluor, DMA, 26%; (b) n-BuLi, tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide, THF, −78 °C, 90%; (c) 4 N HCl in dioxane, RT, 94%; (d) 2,2,2-trifluoroethyl trifluoromethanesulfonate, DIPEA, 1,4-dioxane, 94%; (e) 5-bromo-6-fluoropicolinaldehyde or 5-bromo-3-fluoropicolinaldehyde, toluene/TFA (9:1), 90 °C, 69–82%; (f) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 90 °C, 58% for 8, 64% for 9.

As shown in Table 3, both compounds 8 and 9 were exquisitely potent degraders of ERα (pIC50 > 10). This was confirmed by Western blot for 9 which showed high levels of degradation in both MCF-7 (96%) and CAMA-1 (100%) cell lines. Lipophilicity was significantly increased in both cases, but the LLE remained high (cf. 8 with 2 and 9 with 3). Additionally, the effect of fluorination maintained the permeability of 9 (Papp = 12 × 10–6 cm/s) but reduced efflux (ER = 1.4) relative to its matched pair 3. One notable difference was that the rat hepatocyte clearance was lowered in both cases compared with their matched pairs in Table 1. Unfortunately, despite the improvement in rat hepatocyte clearance, the turnover in human microsomes was increased for both matched pairs.

Table 3. Indazole A-Ring Substitutiona.

Cpd ER bind pIC50 ER DR pIC50 LogD (LLE) Hu % Free Rat heps Clint Hu mics Clint
8 9.0b 10.3 (99%) 3.7 (6.6) 6.8 10 44
9 8.9 10.0 (99%) 3.6 (6.4) 5.4 10 34
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a

Legend as Table 1.

b

SEM 0.34.

Exemplars of a fluorinated A-ring (9) and nonfluorinated A-ring (2) were evaluated in terms of their rat pharmacokinetic profile (Table 4). In line with the in vitro data, the clearance of 9 was significantly lower than 2 leading to an increase in both half-life and oral bioavailability.

Table 4. Rat Pharmacokinetic Parameters for 2 and 9a.

Cpd Clpa (mL/min/kg) Vdss (L/kg) IV half-life (h) PO AUC (μM.h) Bioavailability F (%)
2 65 7.7 1.9 0.22 34
9 24 17 9.6 0.76 60
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a

Compound was dosed intravenously at 0.5 mg/kg in 5% DMSO:95% hydroxylpropyl β-cyclodextrin or 10% DMA:90% Captisol and orally as 1 mg/kg using a 0.1% HMPC/tween suspension or 10% DMSO:90% cyclodextrin solution. The data shown is the mean of the data generated in two male rats.

Turning our attention to ring C, fluorination of the methyl substituent was examined as a way to modulate the pKa of the piperidine ring nitrogen (Scheme 5). Previously the chiral methyl group had been incorporated by ring-opening of the enantiopure cyclic sulfamidate. We initially attempted to transfer this methodology; however, we were unable to successfully access the required difluoromethylated cyclic sulfamidate. Instead, an asymmetric alkylation methodology was investigated. 1,3-Dibromotoluene was treated with n-BuLi and quenched with DMF to install the aldehyde, which was directly reduced to the benzyl alcohol by treatment with NaBH4. An Appel reaction then produced the required benzyl bromide 28. Asymmetric phase-transfer catalyzed alkylation of the glycine imine Schiff base33 with the Corey-Lygo type cinchona alkaloid derived phase transfer catalytst34 afforded 29 in good yield and as a 98:2 ratio of enantiomers (see SI for details). Hydrolysis of the imine and reduction of the ester then gave the chiral amino-alcohol 30. Following our previously established methodology,35 alkylation of the amine was followed by Buchwald amination with benzophenone imine, which gave the required diamine 31 after acidic hydrolysis. Cyclization occurred through a Pictet–Spengler reaction with 5-bromopicolinaldehyde under slightly modified conditions. In order to achieve reaction turnover the reaction was performed in AcOH with H2O present as an additive. Without the addition of H2O the initial product arose from condensation of the free aniline onto the aldehyde. This intermediate appeared to undergo subsequent Pictet–Spengler cyclization very slowly; it was thus hypothesized that the presence of a small amount of H2O would keep enough free aniline in equilibrium to allow cyclization to occur more readily. Pleasingly this was observed to be the case, and diamine 31 formed the desired cyclization product after heating with excess aldehyde. A major byproduct observed was the desired cyclization product where the free aniline had recondensed onto the excess aldehyde; thus, the product was treated with NH2OH·HCl and KOAc to hydrolyze the imine back to the free aniline. With the cyclization product in hand the tricyclic indazole 32 was formed by treatment of the aniline with NaNO2 in propionic acid. After the free alcohol was oxidized to the aldehyde, the indazole was protected with a THP group and the aldehyde was converted to difluoromethyl by treatment with DAST. Finally, the amino-azetidine was installed in the usual manner through Buchwald amination to afford 11 after cleavage of the THP group.

Scheme 5. Synthesis of C-Ring Difluoromethyl Analogue 11.

Scheme 5

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Reagents and conditions: (a) n-BuLi, THF, DMF, then NaBH4, MeOH, RT, 100%; (b) CBr4, PPh3, DCM, RT, 90%; (c) tert-butyl 2-((diphenylmethylene)amino)acetate, [PTC]* (see SI for details), aq KOH, toluene, 0 °C, 80%, 98:2 ratio of enantiomers as determined by chiral HPLC; (d) aq HCl, EtOAc, RT, 84%; (e) LiBH4, THF, 40 °C, 100%; (f) 2,2-difluoroethyl trifluoromethanesulfonate, DIPEA, 1,4-dioxane, RT, 91%; (g) benzophenone imine, NaOtBu, Pd2(dba)3, rac-BINAP, toluene, 90 °C, then aq HCl, 78%; (h) 5-bromopicolinaldehyde, AcOH, H2O, then NH2OH·HCl, KOAc, 63%; (i) NaNO2, propionic acid, H2O, −15 °C, 34%; (j) SO3·Py, Et3N, DCM, DMSO, 5 °C, 64%; (k) 3,4-dihydro-2H-pyran, PTSA, DCM, then DAST, 40%; (l) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 70 °C, then TFA, DCM, RT, 53%.

Once again, fluorination was tolerated resulting in 11 being a subnanomolar degrader of ERα (Table 5). However, the associated rise in lipophilicity resulted in a drop in LLE relative to 10(18) and there were no beneficial effects in terms of physicochemical parameters to justify the additional synthetic complexity.

Table 5. C-Ring Substitutiona.

graphic file with name ml0c00505_0011.jpg

Cpd ER bind pIC50 ER DR pIC50 LogD (LLE) Hu % Free Rat heps Clint Hu mics Clint
10 8.4 9.5 (99%) 2.4 (7.1) 40 22 28
11 8.6 9.3 (97%) 2.7 (6.6) 28 32 34
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a

Legend as Table 1.

As a final area of exploration, we turned our attention to the alkyl chain. The concept of “motif reorganization” has been proposed as a way to smuggle carbon atoms into fluoroalkyl chains without adding to the lipophilic burden.36 In order to access this substitution pattern we envisaged that a late-stage fluorine replacement of a terminal hydroxy moiety on the alkyl chain might be possible (Scheme 6). N-Alkylated indazole 33 was synthesized according to previously established procedures (see SI for details). From here, Pictet–Spengler cyclization and subsequent protection of the indazole with a THP afforded 34. Next, the silyl protecting group was selectively cleaved and the alcohol 35 was activated as the triflate. Treatment of the alkyl triflate with TBAF smoothly formed the terminal fluoro compound 36,37 which following deprotection of the THP underwent Buchwald amination to afford 12.

Scheme 6. Synthesis of Trifluoro Side Chain Analogue 12.

Scheme 6

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Reagents and conditions: (a) 5-bromopicolinaldehyde, toluene/TFA (20:1), 110 °C, 82%; (b) 3,4-dihydro-2H-pyran, PTSA, DCM, 40 °C, 68%; (c) 1 N TBAF in THF, THF, RT, 77%; (d) Tf2O, 2,6-lutidine, DCM; (e) 1 N TBAF in THF, THF, RT, 69% over 2 steps; (f) TFA, DCM, RT, 82%; (g) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane, 60 °C, 37%.

In this case, compound 12 showed a small increase in both potency (+0.3) and lipophilicity (+0.2) resulting in similar LLE (6.7) relative to its trifluoromethyl matched pair 3 (Table 6). Other physicochemical properties were similar, offering no specific advantage other than a chemical diversification option.

Table 6. CH2-Extension to Alkyl Chaina.

graphic file with name ml0c00505_0012.jpg

Cpd ER bind pIC50 ER DR pIC50 LogD (LLE) Hu % Free Rat heps Clint Hu mics Clint
12 8.7b 9.9 (98%) 3.2 (6.7)   55 26
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a

Legend as Table 1.

b

SEM 0.32.

In conclusion, we have described the incorporation of fluorine into a drug candidate using a range of synthetic and LSF approaches. Notably, the inclusion of fluorine was tolerated in five of the six positions investigated, with effects on pIC5o ranging from −0.3 to +0.6. Only one position on the B-ring showed a large drop off in potency (ΔpIC5o −1.5). In terms of lipophilicity, the effects on logD ranged from −0.2 to +0.5 with most compounds retaining a high LLE. Benefits were seen in terms of increased permeability and reduced efflux for one example (2) and lower rat clearance and higher bioavailability for another (9).

Acknowledgments

The Analytical and Purification teams at AstraZeneca are thanked for their contributions. Matt Leese, Tom Heightman, Nicky Whalley, and Ray Finlay are thanked for their valuable contributions regarding the manuscript.

Glossary

Abbreviations

BINAP

(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene

Bpin

pinacolatoboron

Brettphos

2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl

Clp

plasma clearance

DAST

(diethylamino)sulfur trifluoride

dba

dibenzylideneacetone

ER

efflux ratio

ERα

estrogen receptor α

LLE

ligand lipophilic efficiency

LSF

late stage functionalization

Papp

apparent permeability

PTSA

para-toluene sulfonic acid

r.t.

room temperature

SAR

structure–activity relationship

Selectfluor

1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

SERD

selective estrogen receptor degrader

Vdss

steady-state volume of distribution

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00505.

  • Data tables, experimental procedures, and characterization data (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml0c00505_si_001.pdf (350.9KB, pdf)

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