The crystal structure of avutometinib has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques.
Keywords: powder diffraction, avutometinib, AVMAKI, Rietveld refinement, density functional theory, crystal structure
Abstract
The crystal structure of avutometinib (systematic name: 3-{[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one), C21H18FN5O5S, has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Avutometinib crystallizes in space group P1 (#2). The crystal structure is composed of layers parallel to the ab plane. N—H⋯O hydrogen bonds link the layers along the a-axis direction. The molecule is Z-shaped.
1. Chemical context
Avutometinib (AVNAPKI) has been approved as a treatment for ovarian cancer. AVNAPKI is administered in capsule form as a co-medication with FAKZYNJA™ (defactinib tablets), for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer for patients that have previously received unsuccessful systemic therapy. The systematic name (CAS Registry Number 946128-88-7) is 3-{[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl}-4-methyl-7-pyrimidin-2-yloxychromen-2-one.
We are unaware of any published powder diffraction data for avutometinib. This work was carried out as part of a project (Kaduk et al., 2014 ▸) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-quality powder diffraction data for them in the Powder Diffraction File (Kabekkodu et al., 2024 ▸).
2. Structural commentary
The root-mean-square difference of the non-H atoms in the Rietveld-refined and VASP-optimized structures of avutometinib, calculated using the Mercury (Macrae et al., 2020 ▸) CSD-Materials/Search/Crystal Packing Similarity tool is 0.059 Å (Fig. 1 ▸); the structures are essentially identical. The root-mean-square Cartesian displacement of the non-H atoms in the refined and optimized structures, calculated using the Mercury Calculate/Molecule Overlay tool, is 0.053 Å (Fig. 2 ▸). The agreements are within the normal range for correct structures (van de Streek & Neumann, 2014 ▸). The asymmetric unit is illustrated in Fig. 3 ▸. The remaining discussion will emphasize the VASP-optimized structure.
Figure 1.
Comparison of the Rietveld-refined (colored by atom type) and VASP-optimized (pale green) structures of avutometinib, calculated using the Mercury CSD-Materials/Search/Crystal Packing Similarity tool. The root-mean-square Cartesian displacement is 0.059 Å. Image generated using Mercury (Macrae et al., 2020 ▸).
Figure 2.
Comparison of the refined structure of avutometinib (red) to the VASP-optimized structure (blue). The comparison was generated using the Mercury Calculate/Molecule Overlay tool; the r.m.s. difference is 0.053 Å. Image generated using Mercury (Macrae et al., 2020 ▸).
Figure 3.
The asymmetric unit of avutometinib, with the atom numbering. The atoms are represented by 50% probability spheroids. Image generated using Mercury (Macrae et al., 2020 ▸).
All of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., 2020 ▸). Only the S1—N8 bond of 1.682 Å [average = 1.628 (17); Z-score = 3.1] is flagged as unusual. The unusual S—N bond distance is an example of a known feature of DFT calculations: too-long S—N bonds in the DFT optimization of sulfonamides have been observed (Kaduk et al., 2025 ▸; Vibha et al., 2023 ▸; Whitfield, 2025 ▸).
Quantum chemical geometry optimization of the isolated avutometinib molecule (DFT/B3LYP/6-31G*/water) using Spartan ’24 (Wavefunction, 2025 ▸) indicated that the observed conformation is 5.7 kcal mol−1 higher in energy than a local minimum, which has a very similar conformation. The global minimum-energy conformation is 79.9 kcal mol−1 lower in energy, but is folded on itself to make intramolecular hydrogen bonds. Intermolecular interactions are thus important in determining the observed solid-state conformation.
3. Supramolecular features
The crystal structure (Fig. 4 ▸) is composed of layers lying parallel to the ab plane. Hydrogen bonds link the layers along the b-axis direction (Table 1 ▸). The molecule is Z-shaped. The mean plane of the pyridine ring near the sulfonamide group is approximately (011), the mean plane of the 2H-chromen-2-one ring system is approximately (01
), and the mean plane of the pyrimidine ring is approximately (123). The Mercury Aromatics Analyser indicates one strong interaction (d = 4.334 Å) between phenyl rings of the 2H-chromen-2-one ring system, and weaker interactions between multiple pairs of rings.
Figure 4.
Crystal structure of avutometinib, viewed down the a-axis. Image generated using DIAMOND (Brandenburg & Putz, 2025 ▸).
Table 1. Hydrogen-bond geometry (Å, °).
| D—H⋯A | D—H | H⋯A | D⋯A | D—H⋯A | Mulliken overlap | H-bond energy |
|---|---|---|---|---|---|---|
| N8—H44⋯O4i | 1.04 | 1.95 | 2.961 | 165 | 0.054 | 5.4 |
| N10—H45⋯O7ii | 1.03 | 2.22 | 3.223 | 163 | 0.026 | 3.7 |
| N10—H45⋯N9 | 1.03 | 2.49 | 2.977 | 108 | 0.011 | – |
| C24—H41⋯O6iii | 1.09 | 2.42 | 3.183 | 126 | 0.011 | – |
| C33—H51⋯O6iv | 1.09 | 2.35 | 3.170 | 131 | 0.015 | – |
| C21—H39⋯N11i | 1.09 | 2.80 | 3.882 | 170 | 0.012 | – |
| C31—H49⋯N10iv | 1.09 | 2.82 | 3.777 | 145 | 0.011 | – |
Symmetry codes: (i) x − 1, y, z; (ii) −x, −y, 1 − z; (iii) x + 1, y, z; (iv) x + 2, y, z − 1.
Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2024 ▸) indicated that the intramolecular energy is dominated by angle distortion terms, as might be expected for a molecule containing a fused ring system. The intermolecular energy is dominated by van der Waals attractions, which in this force field based analysis include hydrogen bonds. The hydrogen bonds are better discussed using the results of the DFT calculation.
There are two classical N—H⋯O hydrogen bonds in the structure (Table 1 ▸), one intramolecular and one intermolecular. The energies of these hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (2019 ▸). The intermolecular N8—H44⋯O4 hydrogen bonds link the molecules into chains along the a-axis direction, with graph set C11(9) (Etter, 1990 ▸; Bernstein et al., 1995 ▸; Motherwell et al., 2000 ▸). A few C—H⋯O and C—H⋯N hydrogen bonds also contribute to the cohesion of the crystal.
The volume enclosed by the Hirshfeld surface of avutometinib (Fig. 5 ▸, Hirshfeld, 1977 ▸; Spackman et al., 2021 ▸) is 498.97 Å3, 98.27% of half of the unit-cell volume. The packing density is thus typical. The only significant close contacts (red in Fig. 5 ▸) involve the hydrogen bonds. The volume/non-hydrogen atom is smaller than normal, at 15.4 Å3.
Figure 5.
The Hirshfeld surface of avutometinib. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white. Image generated using CrystalExplorer (Spackman et al., 2021 ▸).
The Bravais–Friedel–Donnay–Harker (Bravais, 1866 ▸; Friedel, 1907 ▸; Donnay and Harker, 1937 ▸) algorithm suggests that we might expect lozenge morphology for avutometinib, with {001} as the major faces. A 2nd-order spherical harmonic model for preferred orientation was included. The texture index was 1.002, indicating that the preferred orientation was insignificant in this rotated capillary specimen.
4. Database survey
A reduced cell search of the Cambridge Structural Database (Groom et al., 2016 ▸) yielded no hits.
5. Synthesis and crystallization
Avutometinib was a commercial reagent, purchased from Sigma (Batch #A245684-HA3), and was used as-received.
6. Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the measurement at ∼50 Hz. The powder pattern was measured at 295 K at beam line 11-BM (Lee et al., 2008 ▸; Wang et al., 2008 ▸; Antao et al., 2008 ▸) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.4687342 Å from 0.5–50° 2θ with a step size of 0.001° and a counting time of 0.1 sec/step. The high-resolution powder diffraction data were collected using twelve silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A mixture of silicon (NIST SRM 640c) and alumina (NIST SRM 676a) standards (ratio Al2O3:Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.
Table 2. Experimental details.
| avutometinib | |
|---|---|
| Crystal data | |
| Chemical formula | C21H18FN5O5S |
| M r | 471.46 |
| Crystal system, space group | Triclinic, P
|
| Temperature (K) | 295 |
| a, b, c (Å) | 8.91097 (5), 9.47933 (5), 13.24641 (9) |
| α, β, γ (°) | 83.9821 (4), 81.7759 (3), 66.67667 (9) |
| V (Å3) | 1015.49 (1) |
| Z | 2 |
| Radiation type | Synchrotron, λ = 0.46873 Å |
| μ (mm−1) | 0.02 |
| Specimen shape, size (mm) | Cylinder, 2.0 × 1.5 |
| Data collection | |
| Diffractometer | 11-BM, APS |
| Specimen mounting | Kapton capillary |
| Data collection mode | Transmission |
| Scan method | Step |
| 2θ values (°) | 2θmin = 0.510, 2θmax = 49.995, 2θstep = 0.001 |
| Refinement | |
| R factors and goodness of fit | Rp = 0.058, Rwp = 0.072, Rexp = 0.043, R(F2) = 0.06083, χ2 = 2.941 |
| No. of parameters | 136 |
| No. of restraints | 91 |
| (Δ/σ)max | 1.795 |
Computer programs: GSAS-II (Toby & Von Dreele, 2013 ▸).
The pattern was indexed on a high-quality primitive triclinic unit cell with a = 8.91271, b = 9.47911, c = 13.29736 Å, α = 83.91, β = 81.66, γ = 66.67°, V = 1019.23 Å3, and Z = 2 using JADE Pro (MDI, 2025 ▸). The space group was assumed to be P, which was confirmed by successful solution and refinement of the structure.
The molecular structure of avutometinib was downloaded from PubChem (Kim et al., 2023 ▸) as Conformer3D_COMPOUND_CID_16719221.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020 ▸), and to a Fenske–Hall Z-matrix using OpenBabel (O’Boyle et al., 2011 ▸). The structure was solved using parallel tempering techniques as implemented in FOX (Favre-Nicolin & Černý, 2002 ▸).
Rietveld refinement was carried out using GSAS-II (Toby & Von Dreele, 2013 ▸). Only the 1.9–30.0° portion of the pattern was included in the refinements (dmin = 0.905 Å). The μR value was fixed at 0.02, calculated using the 11-BM web site (https://11bm.xray.aps.anl.gov/absorb/). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Sykes et al., 2011 ▸; Bruno et al., 2004 ▸). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The aromatic rings were restrained to be planar. The restraints contributed 3.7% to the overall χ2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2024 ▸). The Uiso values were grouped by chemical similarity. The peak profiles were described using the generalized microstrain model (Stephens, 1999 ▸). The background was modeled using a six-term shifted Chebyshev polynomial, with a peak at 5.87° 2θ to model the scattering from the Kapton capillary and any amorphous component of the sample.
The final refinement of 136 variables using 28,101 observations and 91 restraints yielded the residuals Rwp = 0.0737 and GOF = 1.72. The largest peak (1.08 Å from C27) and hole (1.82 Å from N8) in the difference-Fourier map are 0.49 (11) and −0.46 (11) eÅ−3, respectively. The final Rietveld plot is shown in Fig. 6 ▸. The largest features in the normalized error plot are in the positions and shapes of some of the strong low-angle peaks, and may indicate a change of the specimen during the measurement.
Figure 6.
The Rietveld plot for avutometinib. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The blue tick marks indicate the peak positions. The vertical scale has been multiplied by a factor of 20× for 2θ > 15.7°.
The crystal structure of avutometinib was optimized (fixed experimental unit cell) with density functional theory techniques using VASP (Kresse & Furthmüller, 1996 ▸) through the MedeA graphical interface (Materials Design, 2024 ▸). The calculation was carried out on 32 cores of a 144-core (768 Gb memory) HPE Superdome Flex 280 Linux server at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å−1 leading to a 2 × 2 × 1 mesh, and took ∼1.1 h. Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., 2023 ▸). (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., 2018 ▸). The basis sets for the H, C, N and O atoms in the calculation were those of Gatti et al. (1994 ▸), and those for F and S were those of Peintinger et al. (2013 ▸). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ∼2.7 h. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File.
Supplementary Material
Crystal structure: contains datablock(s) avutometinib, avutometinib_VASP. DOI: 10.1107/S2056989026004482/ee2030sup1.cif
Supporting information file. DOI: 10.1107/S2056989026004482/ee2030avutometinibsup2.cml
Additional supporting information: crystallographic information; 3D view; checkCIF report
Acknowledgments
Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. We thank Saul Lapidus for his assistance in the data collection. We also thank the ICDD team – Megan Rost, Steve Trimble, and Dave Bohnenberger – for their contribution to research, sample preparation, and in-house XRD data collection and verification.
supplementary crystallographic information
3-{[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one (avutometinib). Crystal data
| C21H18FN5O5S | γ = 66.67667 (9)° |
| Mr = 471.46 | V = 1015.49 (1) Å3 |
| Triclinic, P1 | Z = 2 |
| a = 8.91097 (5) Å | Dx = 1.542 Mg m−3 |
| b = 9.47933 (5) Å | Synchrotron radiation, λ = 0.46873 Å |
| c = 13.24641 (9) Å | µ = 0.02 mm−1 |
| α = 83.9821 (4)° | T = 295 K |
| β = 81.7759 (3)° | cylinder, 2.0 × 1.5 mm |
3-{[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one (avutometinib). Data collection
| 11-BM, APS diffractometer | Scan method: step |
| Specimen mounting: Kapton capillary | 2θmin = 0.510°, 2θmax = 49.995°, 2θstep = 0.001° |
| Data collection mode: transmission |
3-{[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one (avutometinib). Refinement
| Least-squares matrix: full | 136 parameters |
| Rp = 0.058 | 91 restraints |
| Rwp = 0.072 | 27 constraints |
| Rexp = 0.043 | Weighting scheme based on measured s.u.'s |
| R(F2) = 0.06083 | (Δ/σ)max = 1.795 |
| 49486 data points | Background function: Background function: "chebyschev-1" function with 6 terms: 39.70(6), -8.12(8), -5.86(7), 0.45(8), -3.44(7), -0.18(6), Background peak parameters: pos, int, sig, gam: 5.871(8), 5.48(8)e3, 4.80(12)e3, 0.100, |
| Profile function: Finger-Cox-Jephcoat function parameters U, V, W, X, Y, SH/L: peak variance(Gauss) = Utan(Th)2+Vtan(Th)+W: peak HW(Lorentz) = X/cos(Th)+Ytan(Th); SH/L = S/L+H/L U, V, W in (centideg)2, X & Y in centideg 1.163, -0.126, 0.063, 0.000, 0.000, 0.002, | Preferred orientation correction: Simple spherical harmonic correction Order = 2 Coefficients: 0:0:C(2,-2) = 0.0570; 0:0:C(2,-1) = -0.0160; 0:0:C(2,0) = -0.0620; 0:0:C(2,1) = -0.0340; 0:0:C(2,2) = 0.0470 |
3-{[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one (avutometinib). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
| x | y | z | Uiso*/Ueq | ||
| S1 | −0.24645 (18) | 0.18626 (18) | 0.42794 (12) | 0.0421 (6)* | |
| F2 | −0.0709 (3) | 0.4497 (3) | 0.18047 (17) | 0.0346 (5)* | |
| O3 | 0.7085 (3) | 0.3231 (4) | 0.0934 (2) | 0.0365 (4)* | |
| O4 | 0.5286 (3) | 0.4613 (4) | 0.2123 (2) | 0.0365 (4)* | |
| O5 | 1.1225 (4) | 0.0538 (4) | −0.1592 (2) | 0.0466 (7)* | |
| O6 | −0.4215 (3) | 0.2499 (3) | 0.4256 (2) | 0.0429 (9)* | |
| O7 | −0.1487 (3) | 0.0326 (3) | 0.4038 (2) | 0.0429 (9)* | |
| N8 | −0.1842 (3) | 0.2993 (4) | 0.3460 (2) | 0.0346 (5)* | |
| N9 | 0.0824 (4) | 0.1928 (4) | 0.3953 (2) | 0.0346 (5)* | |
| N10 | −0.2097 (4) | 0.2032 (3) | 0.5409 (2) | 0.0407 (13)* | |
| N11 | 1.3412 (4) | 0.0840 (4) | −0.2574 (3) | 0.0466 (7)* | |
| N12 | 1.0651 (3) | 0.2462 (5) | −0.2842 (3) | 0.0466 (7)* | |
| C13 | 0.4224 (3) | 0.3609 (5) | 0.0948 (3) | 0.0365 (4)* | |
| C14 | 0.4605 (3) | 0.2760 (5) | 0.0115 (3) | 0.0365 (4)* | |
| C15 | 0.2494 (3) | 0.4418 (3) | 0.1438 (3) | 0.0346 (5)* | |
| C16 | 0.6307 (3) | 0.2123 (5) | −0.0350 (3) | 0.0365 (4)* | |
| C17 | 0.1945 (3) | 0.3467 (5) | 0.2286 (3) | 0.0346 (5)* | |
| C18 | 0.7480 (3) | 0.2434 (6) | 0.0065 (3) | 0.0365 (4)* | |
| C19 | 0.5500 (3) | 0.3855 (5) | 0.1392 (3) | 0.0365 (4)* | |
| C20 | 0.3333 (4) | 0.2424 (5) | −0.0335 (3) | 0.0365 (4)* | |
| C21 | 0.6807 (4) | 0.1290 (6) | −0.1232 (3) | 0.0365 (4)* | |
| C22 | 0.9097 (4) | 0.1913 (5) | −0.0337 (3) | 0.0365 (4)* | |
| C23 | 0.0353 (3) | 0.3584 (5) | 0.2461 (3) | 0.0346 (5)* | |
| C24 | 0.3001 (3) | 0.2514 (5) | 0.2970 (3) | 0.0346 (5)* | |
| C25 | 0.9547 (4) | 0.1156 (5) | −0.1231 (3) | 0.0365 (4)* | |
| C26 | 0.8430 (4) | 0.0789 (6) | −0.1659 (3) | 0.0365 (4)* | |
| C27 | −0.0221 (3) | 0.2850 (5) | 0.3307 (3) | 0.0346 (5)* | |
| C28 | 0.2402 (4) | 0.1795 (5) | 0.3777 (3) | 0.0346 (5)* | |
| C29 | 1.1788 (4) | 0.1324 (5) | −0.2371 (3) | 0.0466 (7)* | |
| C30 | −0.2810 (6) | 0.3515 (4) | 0.5876 (3) | 0.0407 (13)* | |
| C31 | 1.3927 (3) | 0.1638 (6) | −0.3335 (4) | 0.0466 (7)* | |
| C32 | 1.1255 (5) | 0.3191 (5) | −0.3622 (3) | 0.0466 (7)* | |
| C33 | 1.2907 (6) | 0.2808 (6) | −0.3893 (3) | 0.0466 (7)* | |
| H34 | 0.23891 | 0.55099 | 0.17829 | 0.0415* | |
| H35 | 0.16192 | 0.47507 | 0.08245 | 0.0415* | |
| H36 | 0.20524 | 0.32410 | −0.00294 | 0.0438* | |
| H37 | 0.34758 | 0.11858 | −0.01145 | 0.0438* | |
| H38 | 0.35062 | 0.25904 | −0.12025 | 0.0438* | |
| H39 | 0.58774 | 0.10215 | −0.16017 | 0.0438* | |
| H40 | 1.00374 | 0.21103 | 0.00682 | 0.0438* | |
| H41 | 0.43511 | 0.23367 | 0.28555 | 0.0437* | |
| H42 | 0.88436 | 0.00750 | −0.23630 | 0.0438* | |
| H43 | 0.33257 | 0.10460 | 0.43208 | 0.0437* | |
| H44 | −0.26680 | 0.38460 | 0.30380 | 0.0437* | |
| H45 | −0.24990 | 0.13320 | 0.59250 | 0.0489* | |
| H46 | −0.17896 | 0.37943 | 0.61243 | 0.0489* | |
| H47 | −0.37075 | 0.34632 | 0.65705 | 0.0489* | |
| H48 | −0.34902 | 0.44468 | 0.52986 | 0.0489* | |
| H49 | 1.52990 | 0.13446 | −0.35462 | 0.0559* | |
| H50 | 1.03796 | 0.41730 | −0.40887 | 0.0559* | |
| H51 | 1.34347 | 0.34168 | −0.45476 | 0.0559* |
3-{[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl}-4-methyl-7-(pyrimidin-2-yloxy)chromen-2-one (avutometinib). Geometric parameters (Å, º)
| S1—O6 | 1.4366 (19) | C22—C25 | 1.376 (2) |
| S1—O7 | 1.413 (2) | C22—H40 | 1.140 (3) |
| S1—N8 | 1.640 (2) | C23—F2 | 1.353 (2) |
| S1—N10 | 1.6130 (18) | C23—C17 | 1.365 (2) |
| F2—C23 | 1.353 (2) | C23—C27 | 1.3987 (18) |
| O3—C18 | 1.369 (2) | C24—C17 | 1.386 (2) |
| O3—C19 | 1.3724 (18) | C24—C28 | 1.365 (3) |
| O4—C19 | 1.213 (3) | C24—H41 | 1.136 (2) |
| O5—C25 | 1.403 (3) | C25—O5 | 1.403 (3) |
| O5—C29 | 1.363 (3) | C25—C22 | 1.376 (2) |
| O6—S1 | 1.4366 (19) | C25—C26 | 1.383 (3) |
| O7—S1 | 1.413 (2) | C26—C21 | 1.384 (3) |
| N8—S1 | 1.640 (2) | C26—C25 | 1.383 (3) |
| N8—C27 | 1.383 (2) | C26—H42 | 1.140 (3) |
| N8—H44 | 1.030 (3) | C27—N8 | 1.383 (2) |
| N9—C27 | 1.338 (2) | C27—N9 | 1.338 (2) |
| N9—C28 | 1.349 (3) | C27—C23 | 1.3987 (18) |
| N10—S1 | 1.6130 (18) | C28—N9 | 1.349 (3) |
| N10—C30 | 1.459 (2) | C28—C24 | 1.365 (3) |
| N10—H45 | 1.029 (3) | C28—H43 | 1.140 (3) |
| N11—C29 | 1.3283 (17) | C29—O5 | 1.363 (3) |
| N11—C31 | 1.335 (3) | C29—N11 | 1.3283 (17) |
| N12—C29 | 1.3248 (17) | C29—N12 | 1.3248 (17) |
| N12—C32 | 1.349 (3) | C30—N10 | 1.459 (2) |
| C13—C14 | 1.357 (2) | C30—H46 | 1.140 (4) |
| C13—C15 | 1.506 (2) | C30—H47 | 1.140 (4) |
| C13—C19 | 1.457 (3) | C30—H48 | 1.140 (5) |
| C14—C13 | 1.357 (2) | C31—N11 | 1.335 (3) |
| C14—C16 | 1.459 (2) | C31—C33 | 1.351 (3) |
| C14—C20 | 1.504 (2) | C31—H49 | 1.140 (3) |
| C15—C13 | 1.506 (2) | C32—N12 | 1.349 (3) |
| C15—C17 | 1.515 (2) | C32—C33 | 1.371 (3) |
| C15—H34 | 1.140 (3) | C32—H50 | 1.140 (3) |
| C15—H35 | 1.140 (3) | C33—C31 | 1.351 (3) |
| C16—C14 | 1.459 (2) | C33—C32 | 1.371 (3) |
| C16—C18 | 1.388 (2) | C33—H51 | 1.140 (3) |
| C16—C21 | 1.397 (2) | H34—C15 | 1.140 (3) |
| C17—C15 | 1.515 (2) | H35—C15 | 1.140 (3) |
| C17—C23 | 1.365 (2) | H36—C20 | 1.140 (4) |
| C17—C24 | 1.386 (2) | H37—C20 | 1.140 (5) |
| C18—O3 | 1.369 (2) | H38—C20 | 1.140 (4) |
| C18—C16 | 1.388 (2) | H39—C21 | 1.140 (3) |
| C18—C22 | 1.369 (3) | H40—C22 | 1.140 (3) |
| C19—O3 | 1.3724 (18) | H41—C24 | 1.136 (2) |
| C19—O4 | 1.213 (3) | H42—C26 | 1.140 (3) |
| C19—C13 | 1.457 (3) | H43—C28 | 1.140 (3) |
| C20—C14 | 1.504 (2) | H44—N8 | 1.030 (3) |
| C20—H36 | 1.140 (4) | H45—N10 | 1.029 (3) |
| C20—H37 | 1.140 (5) | H46—C30 | 1.140 (4) |
| C20—H38 | 1.140 (4) | H47—C30 | 1.140 (4) |
| C21—C16 | 1.397 (2) | H48—C30 | 1.140 (5) |
| C21—C26 | 1.384 (3) | H49—C31 | 1.140 (3) |
| C21—H39 | 1.140 (3) | H50—C32 | 1.140 (3) |
| C22—C18 | 1.369 (3) | H51—C33 | 1.140 (3) |
| O6—S1—O7 | 121.73 (17) | H36—C20—H38 | 109.5 (4) |
| O6—S1—N8 | 103.46 (18) | H37—C20—H38 | 109.5 (3) |
| O7—S1—N8 | 107.88 (19) | C16—C21—C26 | 120.21 (16) |
| O6—S1—N10 | 108.15 (18) | C16—C21—H39 | 120.0 (2) |
| O7—S1—N10 | 105.89 (17) | C26—C21—H39 | 119.8 (3) |
| N8—S1—N10 | 109.38 (17) | C18—C22—C25 | 118.60 (17) |
| C18—O3—C19 | 122.01 (12) | C18—C22—H40 | 120.0 (2) |
| C25—O5—C29 | 118.2 (3) | C25—C22—H40 | 121.4 (2) |
| S1—N8—C27 | 122.28 (18) | F2—C23—C17 | 117.97 (14) |
| S1—N8—H44 | 120.1 (2) | F2—C23—C27 | 119.41 (14) |
| C27—N8—H44 | 117.7 (2) | C17—C23—C27 | 122.57 (11) |
| C27—N9—C28 | 117.74 (16) | C17—C24—C28 | 119.33 (12) |
| S1—N10—C30 | 121.0 (2) | C17—C24—H41 | 120.0 (2) |
| S1—N10—H45 | 109.5 (2) | C28—C24—H41 | 120.7 (3) |
| C30—N10—H45 | 103.5 (3) | O5—C25—C22 | 117.7 (3) |
| C29—N11—C31 | 114.62 (10) | O5—C25—C26 | 120.7 (3) |
| C29—N12—C32 | 114.34 (10) | C22—C25—C26 | 120.73 (16) |
| C14—C13—C15 | 123.60 (17) | C21—C26—C25 | 119.86 (16) |
| C14—C13—C19 | 120.69 (10) | C21—C26—H42 | 120.1 (3) |
| C15—C13—C19 | 115.64 (17) | C25—C26—H42 | 120.1 (3) |
| C13—C14—C16 | 119.32 (10) | N8—C27—N9 | 119.01 (15) |
| C13—C14—C20 | 122.09 (13) | N8—C27—C23 | 121.04 (14) |
| C16—C14—C20 | 118.57 (13) | N9—C27—C23 | 119.86 (10) |
| C13—C15—C17 | 114.1 (2) | N9—C28—C24 | 124.01 (15) |
| C13—C15—H34 | 109.5 (2) | N9—C28—H43 | 120.0 (3) |
| C17—C15—H34 | 107.1 (3) | C24—C28—H43 | 116.0 (3) |
| C13—C15—H35 | 108.7 (3) | O5—C29—N11 | 116.0 (3) |
| C17—C15—H35 | 108.7 (2) | O5—C29—N12 | 116.1 (3) |
| H34—C15—H35 | 108.7 (2) | N11—C29—N12 | 127.94 (13) |
| C14—C16—C18 | 118.57 (10) | N10—C30—H46 | 109.4 (4) |
| C14—C16—C21 | 123.50 (15) | N10—C30—H47 | 109.5 (4) |
| C18—C16—C21 | 117.81 (14) | H46—C30—H47 | 109.5 (3) |
| C15—C17—C23 | 121.66 (17) | N10—C30—H48 | 109.4 (3) |
| C15—C17—C24 | 121.79 (17) | H46—C30—H48 | 109.5 (4) |
| C23—C17—C24 | 116.40 (10) | H47—C30—H48 | 109.5 (4) |
| O3—C18—C16 | 121.12 (11) | N11—C31—C33 | 123.81 (16) |
| O3—C18—C22 | 116.32 (15) | N11—C31—H49 | 120.0 (4) |
| C16—C18—C22 | 122.50 (15) | C33—C31—H49 | 116.2 (4) |
| O3—C19—O4 | 115.99 (17) | N12—C32—C33 | 122.95 (16) |
| O3—C19—C13 | 118.12 (12) | N12—C32—H50 | 120.0 (4) |
| O4—C19—C13 | 125.85 (17) | C33—C32—H50 | 117.1 (4) |
| C14—C20—H36 | 109.5 (2) | C31—C33—C32 | 116.29 (17) |
| C14—C20—H37 | 109.5 (4) | C31—C33—H51 | 120.0 (4) |
| H36—C20—H37 | 109.5 (3) | C32—C33—H51 | 123.7 (4) |
| C14—C20—H38 | 109.5 (3) |
(avutometinib_VASP). Crystal data
| C21H18FN5O5S | α = 83.98° |
| Mr = 471.46 | β = 81.78° |
| Triclinic, P1 | γ = 66.68° |
| a = 8.91097 Å | V = 1015.53 Å3 |
| b = 9.47933 Å | Z = 2 |
| c = 13.24641 Å |
(avutometinib_VASP). Data collection
| h = → | l = → |
| k = → |
(avutometinib_VASP). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
| x | y | z | Biso*/Beq | ||
| S1 | −0.24757 | 0.18753 | 0.42895 | ||
| F2 | −0.07477 | 0.45568 | 0.17671 | ||
| O3 | 0.71646 | 0.31732 | 0.09192 | ||
| O4 | 0.53929 | 0.45121 | 0.21599 | ||
| O5 | 1.12701 | 0.05321 | −0.16336 | ||
| O6 | −0.42292 | 0.24813 | 0.42629 | ||
| O7 | −0.14823 | 0.03113 | 0.40340 | ||
| N8 | −0.19006 | 0.30945 | 0.34680 | ||
| N9 | 0.07524 | 0.19945 | 0.39447 | ||
| N10 | −0.21091 | 0.20419 | 0.54292 | ||
| N11 | 1.34192 | 0.08760 | −0.25877 | ||
| N12 | 1.06472 | 0.25390 | −0.28664 | ||
| C13 | 0.42895 | 0.35914 | 0.09446 | ||
| C14 | 0.46617 | 0.27131 | 0.01093 | ||
| C15 | 0.25568 | 0.44005 | 0.14351 | ||
| C16 | 0.63371 | 0.20853 | −0.03693 | ||
| C17 | 0.19668 | 0.34780 | 0.22776 | ||
| C18 | 0.75384 | 0.23729 | 0.00578 | ||
| C19 | 0.55739 | 0.38083 | 0.13895 | ||
| C20 | 0.33632 | 0.24377 | −0.03426 | ||
| C21 | 0.68522 | 0.12449 | −0.12629 | ||
| C22 | 0.91658 | 0.18843 | −0.03742 | ||
| C23 | 0.03348 | 0.36349 | 0.24311 | ||
| C24 | 0.30019 | 0.24992 | 0.29808 | ||
| C25 | 0.96096 | 0.10896 | −0.12596 | ||
| C26 | 0.84706 | 0.07495 | −0.17096 | ||
| C27 | −0.02552 | 0.28926 | 0.32727 | ||
| C28 | 0.23404 | 0.17983 | 0.37918 | ||
| C29 | 1.17844 | 0.13683 | −0.24060 | ||
| C30 | −0.28532 | 0.35499 | 0.58704 | ||
| C31 | 1.39657 | 0.16416 | −0.33617 | ||
| C32 | 1.12400 | 0.32658 | −0.36442 | ||
| C33 | 1.29130 | 0.28551 | −0.39322 | ||
| H34 | 0.24832 | 0.54394 | 0.17773 | ||
| H35 | 0.16996 | 0.48068 | 0.08520 | ||
| H36 | 0.22340 | 0.27002 | 0.01837 | ||
| H37 | 0.37818 | 0.12413 | −0.05544 | ||
| H38 | 0.30606 | 0.31650 | −0.10496 | ||
| H39 | 0.59597 | 0.09911 | −0.16153 | ||
| H40 | 1.00632 | 0.21209 | −0.00181 | ||
| H41 | 0.42946 | 0.23167 | 0.29139 | ||
| H42 | 0.88621 | 0.01237 | −0.24077 | ||
| H43 | 0.31035 | 0.10618 | 0.43672 | ||
| H44 | −0.27345 | 0.36968 | 0.29517 | ||
| H45 | −0.08805 | 0.14370 | 0.55085 | ||
| H46 | −0.22639 | 0.43396 | 0.55260 | ||
| H47 | −0.27350 | 0.33849 | 0.66903 | ||
| H48 | −0.41643 | 0.40770 | 0.57712 | ||
| H49 | 1.52997 | 0.12683 | −0.35303 | ||
| H50 | 1.03244 | 0.42144 | −0.40429 | ||
| H51 | 1.33943 | 0.34281 | −0.45717 |
(avutometinib_VASP). Hydrogen-bond geometry (Å, º)
| D—H···A | D—H | H···A | D···A | D—H···A |
| N8—H44···O4i | 1.036 | 1.947 | 2.961 | 165.2 |
| N10—H45···O7ii | 1.030 | 2.222 | 3.223 | 163.4 |
| N10—H45···N9 | 1.030 | 2.491 | 2.977 | 108.1 |
| C24—H41···O6iii | 1.087 | 2.417 | 3.183 | 126.3 |
| C33—H51···O6iv | 1.087 | 2.350 | 3.170 | 130.9 |
| C21—H39···N11i | 1.091 | 2.803 | 3.882 | 170.3 |
| C31—H49···N10iv | 1.094 | 2.826 | 3.777 | 145.3 |
Symmetry codes: (i) x−1, y, z; (ii) −x, −y, −z+1; (iii) x+1, y, z; (iv) x+2, y, z−1.
Funding Statement
Funding for this research was provided by: International Centre for Diffraction Data (grant No. 09-03).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Crystal structure: contains datablock(s) avutometinib, avutometinib_VASP. DOI: 10.1107/S2056989026004482/ee2030sup1.cif
Supporting information file. DOI: 10.1107/S2056989026004482/ee2030avutometinibsup2.cml
Additional supporting information: crystallographic information; 3D view; checkCIF report