Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious

Article pubs.acs.org/jmc

Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2‑(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor‑1 Receptor (IGF-1R) Sébastien L. Degorce,*,†,‡ Scott Boyd,† Jon O. Curwen,† Richard Ducray,‡ Christopher T. Halsall,† Clifford D. Jones,†,‡ Franck Lach,‡ Eva M. Lenz,† Martin Pass,† Sarah Pass,† and Catherine Trigwell† †

Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France

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‡

S Supporting Information *

ABSTRACT: Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.

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INTRODUCTION The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that, upon ligand binding, engages with the PI3K-AKT and Ras-Raf-MEK signaling cascades, which are key cellular pathways controlling proliferation and apoptosis. Increasingly, the IGF-1R signaling axis has been linked with resistance to various therapeutic approaches.1 Deregulation of the IGF-1R axis has been implicated in a variety of solid tumor types including lung, breast, colorectal, and prostate. IGF-1R has been considered as a potential therapeutic target for solid cancers for many years, and both monoclonal antibodies and small molecule kinase inhibitors have reached clinical trials with mixed success.2 Among the most studied IGF-1R inhibitors and currently still active in the clinic, linsitinib3 (1, Figure 1) and BMS-7548074 (2) are potent against both IGF-1R and the insulin receptor (IR), highlighting difficulties in obtaining selectivity against this close homologue. Structurally, 1 displays an aminopyrazine hinge binder (HB) motif and 2 an aminopyrazole HB. Our group has previously published the discovery of a series of 2-anilino-4-(imidazo[1,2a]pyridin-3-yl)-pyrimidines5,6 such as compound 3, belonging © 2016 American Chemical Society

to a HB class known internally as mono-anilino-pyrimidines (MAPs). This structural motif is found in a number of clinical candidates such as the CDK inhibitor AZD55977 (4), the macrocyclic CDK2/Flt3/JAK2 inhibitor pacritinib8 (5), and the irreversible covalent EGFRm inhibitor osimertinib9 (6). Our previously reported 2-anilino-4-(imidazo[1,2-a]pyridin3-yl)-pyrimidines showed excellent in vitro kinase inhibitory activity against IGF-1R, along with a good kinase selectivity profile (with the notable exception of the closely related insulin receptor) and adequate DMPK properties for oral dosing. Nevertheless, further optimization was required to improve the overall profile of 3, which has low aqueous solubility, high protein binding, and potent inhibition of CYP3A4 while retaining a suitable level of IGF-1R cellular potency, good pankinase selectivity, and adequate oral exposure for efficacy. Received: February 7, 2016 Published: April 14, 2016 4859

DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866

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anhydride to afford compounds 7−9, 11, 13−16, and 18−21. In the case of 3-methoxy- and 3-ethoxy-4-nitropyrazoles, the alkylation was regioselective. In contrast, 3-methyl and 3-ethyl4-nitropyrazoles afforded a mixture of regioisomers which were separated on silica gel at the nitro stage. Analogues 22−32 were obtained in a similar manner via piperidine intermediate 17 (Scheme 2), which was then alkylated using potassium carbonate in DMF (22−24) or coupled with carboxylic acids under standard HATU conditions (24−32). For examples 29− 32, the appropriate Boc protected amino acid was utilized and the procedure was modified to effect an in situ TFA deprotection following the coupling.

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RESULTS AND DISCUSSION We planned to achieve better physicochemical properties combined with the required cell potency through optimization of ligand lipophilic efficiency11 calculated using cellular potency (thought to be a more relevant end point than enzyme potency as it requires a combination of good cellular penetration and inhibition of the target in a more physiological relevant environment) and experimental log D7.4 (cell LLE = cellular pIC50 − log D7.4). The kinase solvent channel region, which is occupied by the piperazine aniline in 3, is generally most tolerant of hydrophilic substitution. However, previous attempts to improve potency and/or physical properties by aniline substitution was only achieved at the expense of increased inhibition of the hERG ion channel.6 An alternative approach targeted replacements of the aniline based solvent channel groups with suitable heterocyclic replacements occupying a less lipophilic property space. We prepared amino-pyrazole 7 (Table 1), which incorporates a piperidin-4-yl group attached at pyrazole N1. Reasonable IGF-1R activity was maintained relative to 3, with a 5-fold decrease in activity in the biochemical assay and a larger 10-fold decrease in the cellular assay. However, the concurrent decrease in lipophilicity resulted in a more modest decrease in cell LLE (ΔLLE = −0.4). Unfortunately, 7 suffered from a complete lack of selectivity against a number of CDKs as it was found to hit CDK1, -2, -7, -8, and -9 with IC50s of 0.066, 0.025, 0.021, 0.042, and 0.037 μM, respectively. Pan-CDK activity is highly undesirable because it may result in a range of toxicities,12 and we decided to use our internal CDK2 assay as a surrogate for pan-CDK activity. Hitting CDK2 was a drawback that we anticipated based on the fact that similar compounds (e.g., 4) had been developed as CDK2 inhibitors and the known importance of the ortho-methoxy group present in 3 to confer a good selectivity profile in the aniline series.5,6,13 With this knowledge, we prepared various substituted pyrazole derivatives with the aim of restoring an acceptable kinase selectivity profile while retaining or improving cell LLE further. 3-Methoxy-pyrazole 8 was successful in that regard, as it proved almost as potent as, and isolipophilic to, 7, with a 20-fold decrease in CDK2 activity. 3-Methyl analogue 9 showed a >4fold improvement in cell potency for a slightly lower log D, which led to a significant cell LLE improvement over 7 (ΔLLE = +1.0) while maintaining some CDK2 selectivity. Interestingly, the 5-methyl regioisomer 11 had similarly selectivity and potency to 9. Our previous work in the aniline series indicated that the imidazo[1,2-a]pyridine (imidazopyridine) ring can be replaced by the corresponding pyrazolo[1,5-a]pyridine (pyrazolopyridine) heterocycle without loss of IGF-1R activity,6 and thus the matching pyrazolopyridines 14−16 were made and

Figure 1.

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SYNTHESIS Compounds reported herein were synthesized as shown in Schemes 1 and 2. Alkylation of 4-nitro-pyrazoles with N-Boc-4Scheme 1. Synthesis of Substituted Pyrazolesa

a Reagents and conditions: (a) tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate, Cs2CO3, DMF, 120−140 °C, 2−3 h; (b) H2, PtO2, EtOAc/EtOH, 50 PSI (10%−67% over 2 steps); (c) 33 or 34, aminopyrazole, p-TsOH, pentanol, 140 °C; (d) Ac2O (11%−68% over 2 steps).

(methylsulfonyloxy)-piperidine in DMF (Scheme 1), followed by hydrogenation, provided 4-aminopyrazoles which were coupled to either 33 or 34, the syntheses of which were described previously.10 Under the coupling conditions, removal of the Boc protecting group occurred readily to give the free piperidines 10, 12, and 17, which were then acylated with acetic 4860

DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866

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Scheme 2. Synthesis of 3,5-Dimethyl pyrazoles 22−32a

a Reagents and conditions: (a) RCH2X, K2CO3, DMF, 16 h (60%−61%); (b) RCO2H, HATU, DIPEA, DMF, 16 h (25−28, 57%−66%); (c) RCO2H, HATU, DIPEA, DMF, 16 h then TFA, 24 h (29−32, 38%−62%).

Table 1a

All IC50 data are expressed in micromolar (μM) and are means of at least n = 2 independent measurements. Each has a SEM ± 0.3 log units. Enzymatic IGF-1R assay.5,6 cEnzymatic CDK2 assay.7 dInhibition of the autophosphorylation of IGF-1R after IGF1 stimulation using fibroblasts from muIGF-1R knockout mice stably transfected with human IGF-1R. eInhibition of hERG channel in a electrophysiology (IonWorks) assay.16 f Measured using shake-flask methodology with a buffer/octanol volume ratio of 100:1. gLLE = IGF-1R cell pIC50 − log D7.4. a b

relative to methoxy analogue 14) but was accompanied by slightly increased hERG potency (IC50 = 6.4 μM). The increased lipophilicity of the 3- and 5-ethylpyrazole isomers 20 and 21 was not balanced by an increase in cellular potency, and so these were less attractive than their methyl counterparts 15 and 16. To confirm the origin of the observed selectivity improvements with substituted pyrazoles, we obtained crystal structures of the 3-methyl and 5-methyl des-acetyl analogues 10 and 12 (showing similar potency to their N−Ac counterparts, and selected for their improved solubility due to their basicity, but were otherwise flawed with strong CYP inhibition) bound to an unphosphorylated construct of the kinase domain of IGF-1R. The overlay of these structures (Figure 3a) shows an excellent alignment of the ligands where the 2-aminopyrimidine interact with the hinge in a classical manner and where protein can accommodate a methyl group on either side of the pyrazole ring. Both methyl groups induced a similar 32° twist of the

evaluated. These compounds were representative of a trend which is shown in Figure 2a: pyrazolopyridines were typically slightly more potent against IGF-1R in our enzyme assay (ΔpIC50 = +0.32 ± 0.27, N = 39) while increasing CDK2 activity by a similar factor (ΔpIC50 = +0.24 ± 0.18, N = 40), resulting in retention of selectivity versus CDK2 (ΔΔpIC50 = +0.08 ± 0.32, N = 39). The similar cellular LLEs of 8/11 versus 14/16 suggested that the improved potency is due to the increased lipophilicity of pyrazolopyridines compared to imidazopyridines. This was again confirmed across a number of matched pairs (Figure 2b), which showed similar increases in lipophilicity (Δ log D7.4 = +0.28 ± 0.19, N = 30) and cell potency (ΔpIC50 = +0.32 ± 0.34, N = 36), resulting in a near neutral effect on cell LLE (ΔLLE = +0.07 ± 0.40, N = 30). Fortunately, in this case, exchanging increased lipophilicity for cellular potency had no detrimental effect on other lipophilicity driven parameters such as hERG activity. In contrast, the bulkier ethoxypyrazole 19 improved cell LLE (ΔLLE = +0.6 4861

DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866

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Figure 3. X-ray crystal structures of 10 (cyan, PDB code 5FXR), 12 (purple, PDB code 5FXQ), and 24 (green, PDB code 5FXS) bound to IGF-1R. (a) Overlay of 10 and 12. (b) Overlay of 10 and 24.

Figure 2. Imidazopyridine vs pyrazolopyridine matched pairs. (a) IGF1R and CDK2 enzyme potencies (ΔpIC50) and CDK2 selectivity expressed as ΔΔpIC50(IGF-1R−CDK2). (b) IGF-1R cell potency (ΔpIC50), Δ log D7.4, and ΔLLE. The number of matched pairs (Count), median change (Median), mean change (Avg), and standard deviation (StdDev) are indicated in the tables.

Figure 4. Kinase selectivity profiles for compounds 16, 18, and 28 in an external panel of 60 kinases: single shot %inhibition @ 1 μM. Every marker represents the mean inhibition (n = 2) against a kinase of the panel. Markers are colored by %inhibition and shaped by kinase.

pyrazole and that close to the hinge region (and present in 10) was assumed to play a similar role as the o-methoxy group mentioned earlier. These results suggested that 3,5-disubstituted pyrazoles in the solvent channel could potentially improve both potency and selectivity. This was observed with both dimethyl pyrazoles 13 and 18, where the selectivity ratio against CDK2 was improved further to 34- and 48-fold, respectively, which was a significant improvement over the single methyl isomers. The changes in selectivity profiles observed versus CDK2 were mirrored in broader kinase selectivity panels: monomethyl pyrazole 16 had a suboptimal profile with 7 (excluding IGF-1R and IR) of the 60 kinases tested, showing an inhibition greater than 75% at 1 μM in external enzyme assays (Figure 4). However, dimethyl pyrazole 18 gave a much improved kinase inhibition profile compared to both 16 and 3, with only three kinase hits above 75% inhibition

(excluding IGF-1R and IR): CDK2 (82%, which translated into a modest IC50 = 1.38 μM in our internal enzyme assay), Flt1 (80%), and JNK1 (76%). The lack of selectivity with the monomethyl pyrazole was hypothesized to be related to the accessibility of an alternative binding mode where the methyl group is oriented away from the kinase hinge region. This would place the substituted piperidine into a different orientation, which is presumably less favorable for IGF-1R but is accommodated in a range of other kinases. With the more selective dimethyl pyrazole, one methyl group is necessarily directed toward the hinge in either orientation, which is acceptable in IGF-1R but presumably not the majority of other kinases. 4862

DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866

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Table 2. PK Parameters of Selected Compounds in Rata and Dogb entry 15 16 18 25 28

rat/dog %freec 7.2/− 5.7/8.1 8.6/12 9.1/12 18/12

rat/dog/human CLintd

rat/dog CLe

rat/dog Vdssf

48/−/− 77/4.8/98% ee. Efficacy. In the in vivo studies using the P12 allograft described herein, 5 × 106 cells were inoculated subcutaneously into female nude (nu/nu) mice and allowed to grow for 7 days before animals were randomized into groups. One group was dosed orally once daily with vehicle (1% ploysorbate 80), while three other groups were dosed with compound 28 at 25, 12.5, or 6.25 mg/kg. In the experiment using the Colo205 human line, 3 × 106 cells were inoculated subcutaneously into female nude mice in 50% Matrigel and allowed to grow for 8 days before animals were randomized into five groups. Three of these groups were dosed with vehicle, compound 28 orally at 50 mg/kg for 2 days per week, or gemcitabine alone twice weekly via the intraperitoneal route at 100 mg/kg. Two more groups were dosed with the agents in combination using 50 or 25 mg/kg compound 28. The group receiving 50 mg/kg compound 28 as part of the combination were dosed for 1 week only, while animals dosed with 25 mg/kg compound 28 were dosed for two weekly cycles.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00203. 4865

DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866

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Complete experimental details for the syntheses of intermediates and all final compounds are described together with assay statistical analyses (PDF) Molecular formula strings (CSV) Accession Codes

Crystallographic data. Authors will release the atomic coordinates and experimental data upon article publication under the following PDB accession codes: 5FXR (10), 5FXQ (12), 5FXS (24).

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AUTHOR INFORMATION

Corresponding Author

*Phone: +44 (0)1625 514382. Fax: +44 (0)1625 514382. Email: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge Calum Cook, Steven Glossop, Maryannick Lamorlette, Antoine Le Griffon, Arshed Mahmood, Mickael Maudet, and Fabrice Renaud for the synthesis of some of the compounds described herein. We also thank Paul R. Davey, Marta Wylot, and Steven Glossop for assistance with accurate mass and NMR spectral data, Patrice Koza for purification of some final compounds, and Dawn Brison for technical input to the mouse allograft studies. Christopher Phillips is thanked for assistance with the deposition of crystal structures and Caroline Truman for the generation of enzyme data. Finally, we thank Jamie Scott for his valuable suggestions to the manuscript.

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ABBREVIATIONS USED ADME, absorption, distribution, metabolism and excretion; CYP, cytochrome P450; DIPEA, N,N-diisopropylethylamine; DMF, N,N-dimethylformamide; HATU, O-(7-azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; hERG, human ether-à-go-go related gene; LLE, ligand lipophilic efficiency; PPB, plasma protein binding; RT, room temperature

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REFERENCES

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DOI: 10.1021/acs.jmedchem.6b00203 J. Med. Chem. 2016, 59, 4859−4866