organic compounds
1-{3-[(7-Fluoro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino]piperidin-1-yl}propan-1-one
aInstitute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany, and bDepartment of Organic Chemistry, Johannes Gutenberg Universität Mainz, Duesbergweg 10-14, 55099 Mainz, Germany
*Correspondence e-mail: pierre.koch@uni-tuebingen.de
The title compound, C19H22FN5O, has been synthesized as an inhibitor of glycogen synthase kinase-3β. Two molecules interact via two N—H⋯N hydrogen bonds, forming centrosymmetric dimers.
Keywords: crystal structure; pyrimidoindole; kinase inhibitor.
CCDC reference: 2062292
Structure description
The title compound, Fig. 1, was synthesized by amide coupling of 7-fluoro-N-methyl-N-(piperidin-3-yl)-9H-pyrimido[4,5-b]indol-4-amine and propionic acid and inhibits the glycogen synthase kinase-3β in the low micromolar range (Andreev et al., 2020). The central 13-membered ring is nearly planar with a maximum deviation of 0.137 (2) Å while the piperidine ring has a chair conformation. Two molecules form centrosymmetric dimers connected by two N—H⋯N hydrogen bonds (Table 1) while a three-dimensional network is formed via C—H⋯O and C—H⋯F hydrogen bonds (Table 1, Fig. 2).
Synthesis and crystallization
The title compound was synthesized according to Andreev et al. (2020). Crystals for the X-ray analysis precipitated from a solution of the title compound in DMSO-d6 at 298 K.
Refinement
Crystal data, data collection and structure .
details are summarized in Table 2Structural data
CCDC reference: 2062292
https://doi.org/10.1107/S2414314621001590/bt4108sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314621001590/bt4108Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S2414314621001590/bt4108Isup3.cml
Data collection: X-AREA WinXpose (Stoe & Cie, 2019); cell
X-AREA Recipe (Stoe & Cie, 2019); data reduction: X-AREA Integrate (Stoe & Cie, 2019); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b).C19H22FN5O | Dx = 1.326 Mg m−3 |
Mr = 355.41 | Mo Kα radiation, λ = 0.71073 Å |
Orthorhombic, Pbca | Cell parameters from 7975 reflections |
a = 10.6982 (3) Å | θ = 2.4–28.3° |
b = 19.8473 (8) Å | µ = 0.09 mm−1 |
c = 16.7642 (6) Å | T = 120 K |
V = 3559.5 (2) Å3 | Block, colourless |
Z = 8 | 0.35 × 0.17 × 0.08 mm |
F(000) = 1504 |
Stoe IPDS 2T diffractometer | 2840 reflections with I > 2σ(I) |
Radiation source: sealed X-ray tube, 12 x 0.4 mm long-fine focus | Rint = 0.066 |
Detector resolution: 6.67 pixels mm-1 | θmax = 27.9°, θmin = 2.4° |
rotation method, ω scans | h = −14→12 |
9882 measured reflections | k = −22→26 |
4202 independent reflections | l = −19→22 |
Refinement on F2 | Primary atom site location: dual |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.069 | H-atom parameters constrained |
wR(F2) = 0.194 | w = 1/[σ2(Fo2) + (0.0822P)2 + 2.3561P] where P = (Fo2 + 2Fc2)/3 |
S = 1.14 | (Δ/σ)max = 0.001 |
4202 reflections | Δρmax = 0.36 e Å−3 |
237 parameters | Δρmin = −0.41 e Å−3 |
0 restraints |
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. H atoms found in a difference map. Then, they were positioned geometrically and refined using a riding model with C—H = 0.95 Å and Uiso(H) = 1.2Ueq(C) for aromatic CH, C—H = 0.99 Å and Uiso(H) = 1.2Ueq(C) for CH2, C—H = 1.00 Å and Uiso(H) = 1.2Ueq(C) for tertiary H and with C—H = 0.98 Å and Uiso(H) = 1.5Ueq(C) for CH3. The methyl groups were allowed to rotate but not to tip. |
x | y | z | Uiso*/Ueq | ||
F1 | 0.03835 (15) | 0.75389 (8) | 0.26711 (10) | 0.0344 (4) | |
N1 | 0.0797 (2) | 0.56013 (11) | 0.43722 (12) | 0.0247 (5) | |
H1 | 0.011506 | 0.562102 | 0.466503 | 0.030* | |
C2 | 0.1147 (2) | 0.60634 (12) | 0.38014 (14) | 0.0224 (5) | |
C3 | 0.0481 (2) | 0.66282 (13) | 0.35527 (14) | 0.0243 (5) | |
H3 | −0.028161 | 0.676063 | 0.379652 | 0.029* | |
C4 | 0.1002 (2) | 0.69815 (13) | 0.29309 (15) | 0.0260 (5) | |
C5 | 0.2099 (3) | 0.67981 (13) | 0.25432 (16) | 0.0272 (5) | |
H5 | 0.239394 | 0.705203 | 0.210137 | 0.033* | |
C6 | 0.2757 (2) | 0.62393 (13) | 0.28097 (15) | 0.0259 (5) | |
H6 | 0.351084 | 0.610925 | 0.255311 | 0.031* | |
C7 | 0.2302 (2) | 0.58663 (12) | 0.34613 (14) | 0.0221 (5) | |
C8 | 0.2673 (2) | 0.52527 (12) | 0.38809 (14) | 0.0213 (5) | |
C9 | 0.3654 (2) | 0.47773 (12) | 0.38893 (14) | 0.0218 (5) | |
N10 | 0.3530 (2) | 0.42059 (11) | 0.43277 (13) | 0.0255 (5) | |
C11 | 0.2515 (2) | 0.41287 (13) | 0.47767 (15) | 0.0256 (5) | |
H11 | 0.245845 | 0.371894 | 0.506735 | 0.031* | |
N12 | 0.15664 (19) | 0.45588 (11) | 0.48670 (12) | 0.0250 (5) | |
C13 | 0.1679 (2) | 0.51100 (13) | 0.44078 (14) | 0.0230 (5) | |
N14 | 0.47433 (18) | 0.48402 (10) | 0.34654 (12) | 0.0225 (4) | |
C15 | 0.5310 (2) | 0.54981 (13) | 0.33467 (16) | 0.0283 (6) | |
H15A | 0.612776 | 0.551050 | 0.360984 | 0.042* | |
H15B | 0.476882 | 0.584631 | 0.357578 | 0.042* | |
H15C | 0.541595 | 0.558115 | 0.277441 | 0.042* | |
C16 | 0.5572 (2) | 0.42482 (13) | 0.34154 (15) | 0.0252 (5) | |
H16 | 0.503095 | 0.383843 | 0.338129 | 0.030* | |
C17 | 0.6387 (3) | 0.42663 (14) | 0.26687 (16) | 0.0289 (6) | |
H17A | 0.691916 | 0.467432 | 0.267526 | 0.035* | |
H17B | 0.585136 | 0.428388 | 0.218752 | 0.035* | |
C18 | 0.7214 (3) | 0.36317 (14) | 0.26433 (16) | 0.0308 (6) | |
H18A | 0.668171 | 0.322908 | 0.256490 | 0.037* | |
H18B | 0.779753 | 0.366247 | 0.218634 | 0.037* | |
C19 | 0.7956 (2) | 0.35565 (14) | 0.34126 (15) | 0.0291 (6) | |
H19A | 0.842958 | 0.312818 | 0.340020 | 0.035* | |
H19B | 0.856282 | 0.393090 | 0.345791 | 0.035* | |
N20 | 0.7121 (2) | 0.35610 (11) | 0.41082 (13) | 0.0275 (5) | |
C21 | 0.6384 (2) | 0.41798 (13) | 0.41636 (15) | 0.0272 (6) | |
H21A | 0.694825 | 0.457341 | 0.420976 | 0.033* | |
H21B | 0.584720 | 0.416496 | 0.464414 | 0.033* | |
C22 | 0.6811 (2) | 0.29723 (13) | 0.44725 (15) | 0.0261 (5) | |
O23 | 0.72866 (19) | 0.24321 (10) | 0.42863 (11) | 0.0328 (5) | |
C24 | 0.5879 (3) | 0.30135 (14) | 0.51579 (16) | 0.0317 (6) | |
H24A | 0.610597 | 0.339869 | 0.550410 | 0.038* | |
H24B | 0.503685 | 0.310256 | 0.493727 | 0.038* | |
C25 | 0.5829 (3) | 0.23828 (16) | 0.56585 (18) | 0.0421 (8) | |
H25A | 0.554350 | 0.200474 | 0.532942 | 0.063* | |
H25B | 0.524624 | 0.244955 | 0.610271 | 0.063* | |
H25C | 0.666367 | 0.228412 | 0.586876 | 0.063* |
U11 | U22 | U33 | U12 | U13 | U23 | |
F1 | 0.0314 (8) | 0.0340 (9) | 0.0379 (9) | 0.0069 (7) | 0.0044 (7) | 0.0117 (7) |
N1 | 0.0215 (10) | 0.0274 (11) | 0.0252 (10) | 0.0027 (9) | 0.0058 (8) | 0.0051 (8) |
C2 | 0.0205 (11) | 0.0266 (13) | 0.0202 (11) | 0.0000 (10) | 0.0010 (9) | 0.0013 (9) |
C3 | 0.0201 (11) | 0.0290 (13) | 0.0238 (12) | −0.0001 (10) | 0.0015 (10) | −0.0001 (10) |
C4 | 0.0242 (12) | 0.0254 (13) | 0.0285 (12) | 0.0026 (10) | −0.0004 (10) | 0.0052 (10) |
C5 | 0.0257 (13) | 0.0279 (13) | 0.0279 (13) | −0.0023 (11) | 0.0026 (10) | 0.0062 (10) |
C6 | 0.0198 (12) | 0.0311 (14) | 0.0267 (12) | −0.0010 (10) | 0.0048 (10) | 0.0042 (10) |
C7 | 0.0200 (11) | 0.0243 (12) | 0.0220 (11) | −0.0020 (9) | 0.0009 (9) | −0.0014 (9) |
C8 | 0.0177 (11) | 0.0255 (12) | 0.0207 (11) | 0.0003 (9) | 0.0004 (9) | 0.0011 (9) |
C9 | 0.0181 (11) | 0.0262 (12) | 0.0210 (11) | −0.0019 (10) | 0.0000 (9) | −0.0005 (9) |
N10 | 0.0202 (10) | 0.0286 (11) | 0.0276 (11) | 0.0000 (9) | 0.0027 (8) | 0.0040 (8) |
C11 | 0.0209 (11) | 0.0300 (14) | 0.0260 (12) | −0.0015 (10) | 0.0013 (10) | 0.0048 (10) |
N12 | 0.0215 (10) | 0.0268 (11) | 0.0268 (11) | −0.0005 (9) | 0.0029 (8) | 0.0049 (8) |
C13 | 0.0176 (11) | 0.0293 (14) | 0.0220 (12) | −0.0016 (10) | −0.0005 (9) | 0.0004 (9) |
N14 | 0.0174 (10) | 0.0234 (11) | 0.0266 (10) | −0.0002 (8) | 0.0038 (8) | 0.0002 (8) |
C15 | 0.0212 (12) | 0.0285 (14) | 0.0352 (14) | −0.0009 (10) | 0.0026 (11) | 0.0026 (11) |
C16 | 0.0204 (12) | 0.0285 (13) | 0.0266 (12) | 0.0023 (10) | 0.0032 (10) | 0.0004 (10) |
C17 | 0.0276 (13) | 0.0321 (14) | 0.0269 (13) | 0.0036 (11) | 0.0057 (11) | 0.0041 (10) |
C18 | 0.0299 (14) | 0.0337 (15) | 0.0288 (13) | 0.0047 (12) | 0.0072 (11) | −0.0003 (11) |
C19 | 0.0244 (12) | 0.0332 (14) | 0.0299 (13) | 0.0020 (11) | 0.0075 (10) | 0.0008 (11) |
N20 | 0.0242 (11) | 0.0306 (12) | 0.0277 (11) | 0.0049 (9) | 0.0029 (9) | −0.0007 (9) |
C21 | 0.0241 (12) | 0.0295 (14) | 0.0279 (13) | 0.0018 (10) | −0.0003 (10) | −0.0004 (10) |
C22 | 0.0239 (12) | 0.0298 (14) | 0.0246 (12) | 0.0007 (10) | −0.0011 (10) | −0.0006 (10) |
O23 | 0.0362 (11) | 0.0302 (10) | 0.0320 (10) | 0.0063 (9) | 0.0065 (8) | 0.0003 (8) |
C24 | 0.0318 (14) | 0.0364 (15) | 0.0270 (13) | 0.0003 (12) | 0.0057 (11) | −0.0014 (11) |
C25 | 0.0496 (19) | 0.0461 (19) | 0.0305 (15) | 0.0016 (15) | 0.0114 (13) | 0.0051 (13) |
F1—C4 | 1.361 (3) | C15—H15C | 0.9800 |
N1—C13 | 1.359 (3) | C16—C17 | 1.526 (3) |
N1—C2 | 1.377 (3) | C16—C21 | 1.532 (4) |
N1—H1 | 0.8800 | C16—H16 | 1.0000 |
C2—C3 | 1.392 (3) | C17—C18 | 1.540 (4) |
C2—C7 | 1.417 (3) | C17—H17A | 0.9900 |
C3—C4 | 1.375 (3) | C17—H17B | 0.9900 |
C3—H3 | 0.9500 | C18—C19 | 1.522 (4) |
C4—C5 | 1.389 (4) | C18—H18A | 0.9900 |
C5—C6 | 1.388 (4) | C18—H18B | 0.9900 |
C5—H5 | 0.9500 | C19—N20 | 1.469 (3) |
C6—C7 | 1.406 (3) | C19—H19A | 0.9900 |
C6—H6 | 0.9500 | C19—H19B | 0.9900 |
C7—C8 | 1.461 (3) | N20—C22 | 1.360 (3) |
C8—C13 | 1.411 (3) | N20—C21 | 1.462 (3) |
C8—C9 | 1.411 (3) | C21—H21A | 0.9900 |
C9—N10 | 1.358 (3) | C21—H21B | 0.9900 |
C9—N14 | 1.370 (3) | C22—O23 | 1.227 (3) |
N10—C11 | 1.330 (3) | C22—C24 | 1.523 (4) |
C11—N12 | 1.335 (3) | C24—C25 | 1.508 (4) |
C11—H11 | 0.9500 | C24—H24A | 0.9900 |
N12—C13 | 1.343 (3) | C24—H24B | 0.9900 |
N14—C15 | 1.453 (3) | C25—H25A | 0.9800 |
N14—C16 | 1.474 (3) | C25—H25B | 0.9800 |
C15—H15A | 0.9800 | C25—H25C | 0.9800 |
C15—H15B | 0.9800 | ||
C13—N1—C2 | 108.6 (2) | C17—C16—C21 | 110.5 (2) |
C13—N1—H1 | 125.7 | N14—C16—H16 | 107.6 |
C2—N1—H1 | 125.7 | C17—C16—H16 | 107.6 |
N1—C2—C3 | 127.3 (2) | C21—C16—H16 | 107.6 |
N1—C2—C7 | 109.4 (2) | C16—C17—C18 | 109.4 (2) |
C3—C2—C7 | 123.2 (2) | C16—C17—H17A | 109.8 |
C4—C3—C2 | 115.5 (2) | C18—C17—H17A | 109.8 |
C4—C3—H3 | 122.2 | C16—C17—H17B | 109.8 |
C2—C3—H3 | 122.2 | C18—C17—H17B | 109.8 |
F1—C4—C3 | 117.4 (2) | H17A—C17—H17B | 108.2 |
F1—C4—C5 | 118.3 (2) | C19—C18—C17 | 110.9 (2) |
C3—C4—C5 | 124.3 (2) | C19—C18—H18A | 109.5 |
C6—C5—C4 | 119.2 (2) | C17—C18—H18A | 109.5 |
C6—C5—H5 | 120.4 | C19—C18—H18B | 109.5 |
C4—C5—H5 | 120.4 | C17—C18—H18B | 109.5 |
C5—C6—C7 | 119.7 (2) | H18A—C18—H18B | 108.1 |
C5—C6—H6 | 120.1 | N20—C19—C18 | 110.8 (2) |
C7—C6—H6 | 120.1 | N20—C19—H19A | 109.5 |
C6—C7—C2 | 118.0 (2) | C18—C19—H19A | 109.5 |
C6—C7—C8 | 136.0 (2) | N20—C19—H19B | 109.5 |
C2—C7—C8 | 105.9 (2) | C18—C19—H19B | 109.5 |
C13—C8—C9 | 114.8 (2) | H19A—C19—H19B | 108.1 |
C13—C8—C7 | 105.3 (2) | C22—N20—C21 | 124.2 (2) |
C9—C8—C7 | 139.8 (2) | C22—N20—C19 | 120.0 (2) |
N10—C9—N14 | 116.1 (2) | C21—N20—C19 | 112.5 (2) |
N10—C9—C8 | 119.4 (2) | N20—C21—C16 | 109.1 (2) |
N14—C9—C8 | 124.5 (2) | N20—C21—H21A | 109.9 |
C11—N10—C9 | 118.8 (2) | C16—C21—H21A | 109.9 |
N10—C11—N12 | 127.7 (2) | N20—C21—H21B | 109.9 |
N10—C11—H11 | 116.2 | C16—C21—H21B | 109.9 |
N12—C11—H11 | 116.2 | H21A—C21—H21B | 108.3 |
C11—N12—C13 | 112.8 (2) | O23—C22—N20 | 122.4 (2) |
N12—C13—N1 | 123.2 (2) | O23—C22—C24 | 120.7 (2) |
N12—C13—C8 | 126.2 (2) | N20—C22—C24 | 116.9 (2) |
N1—C13—C8 | 110.6 (2) | C25—C24—C22 | 113.5 (2) |
C9—N14—C15 | 120.5 (2) | C25—C24—H24A | 108.9 |
C9—N14—C16 | 117.9 (2) | C22—C24—H24A | 108.9 |
C15—N14—C16 | 117.21 (19) | C25—C24—H24B | 108.9 |
N14—C15—H15A | 109.5 | C22—C24—H24B | 108.9 |
N14—C15—H15B | 109.5 | H24A—C24—H24B | 107.7 |
H15A—C15—H15B | 109.5 | C24—C25—H25A | 109.5 |
N14—C15—H15C | 109.5 | C24—C25—H25B | 109.5 |
H15A—C15—H15C | 109.5 | H25A—C25—H25B | 109.5 |
H15B—C15—H15C | 109.5 | C24—C25—H25C | 109.5 |
N14—C16—C17 | 111.8 (2) | H25A—C25—H25C | 109.5 |
N14—C16—C21 | 111.4 (2) | H25B—C25—H25C | 109.5 |
C13—N1—C2—C3 | 177.1 (2) | C2—N1—C13—C8 | 2.7 (3) |
C13—N1—C2—C7 | −0.5 (3) | C9—C8—C13—N12 | −3.8 (4) |
N1—C2—C3—C4 | −175.6 (2) | C7—C8—C13—N12 | 174.0 (2) |
C7—C2—C3—C4 | 1.7 (4) | C9—C8—C13—N1 | 178.6 (2) |
C2—C3—C4—F1 | −179.8 (2) | C7—C8—C13—N1 | −3.6 (3) |
C2—C3—C4—C5 | 1.7 (4) | N10—C9—N14—C15 | −146.1 (2) |
F1—C4—C5—C6 | 178.7 (2) | C8—C9—N14—C15 | 35.4 (3) |
C3—C4—C5—C6 | −2.7 (4) | N10—C9—N14—C16 | 9.8 (3) |
C4—C5—C6—C7 | 0.4 (4) | C8—C9—N14—C16 | −168.7 (2) |
C5—C6—C7—C2 | 2.7 (4) | C9—N14—C16—C17 | 154.3 (2) |
C5—C6—C7—C8 | 176.5 (3) | C15—N14—C16—C17 | −49.0 (3) |
N1—C2—C7—C6 | 173.9 (2) | C9—N14—C16—C21 | −81.5 (3) |
C3—C2—C7—C6 | −3.9 (4) | C15—N14—C16—C21 | 75.2 (3) |
N1—C2—C7—C8 | −1.7 (3) | N14—C16—C17—C18 | −179.1 (2) |
C3—C2—C7—C8 | −179.4 (2) | C21—C16—C17—C18 | 56.2 (3) |
C6—C7—C8—C13 | −171.2 (3) | C16—C17—C18—C19 | −54.0 (3) |
C2—C7—C8—C13 | 3.1 (3) | C17—C18—C19—N20 | 54.8 (3) |
C6—C7—C8—C9 | 5.8 (5) | C18—C19—N20—C22 | 101.4 (3) |
C2—C7—C8—C9 | −179.9 (3) | C18—C19—N20—C21 | −58.9 (3) |
C13—C8—C9—N10 | 6.0 (3) | C22—N20—C21—C16 | −98.9 (3) |
C7—C8—C9—N10 | −170.8 (3) | C19—N20—C21—C16 | 60.4 (3) |
C13—C8—C9—N14 | −175.5 (2) | N14—C16—C21—N20 | 176.0 (2) |
C7—C8—C9—N14 | 7.7 (5) | C17—C16—C21—N20 | −59.1 (3) |
N14—C9—N10—C11 | 177.4 (2) | C21—N20—C22—O23 | 164.3 (2) |
C8—C9—N10—C11 | −4.0 (4) | C19—N20—C22—O23 | 6.4 (4) |
C9—N10—C11—N12 | −1.0 (4) | C21—N20—C22—C24 | −18.4 (4) |
N10—C11—N12—C13 | 3.2 (4) | C19—N20—C22—C24 | −176.4 (2) |
C11—N12—C13—N1 | 176.8 (2) | O23—C22—C24—C25 | 11.8 (4) |
C11—N12—C13—C8 | −0.6 (4) | N20—C22—C24—C25 | −165.5 (3) |
C2—N1—C13—N12 | −175.1 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···N12i | 0.88 | 1.99 | 2.849 (3) | 164 |
C5—H5···O23ii | 0.95 | 2.47 | 3.380 (3) | 161 |
C11—H11···O23iii | 0.95 | 2.54 | 3.482 (3) | 174 |
C19—H19A···O23 | 0.99 | 2.37 | 2.764 (3) | 103 |
C19—H19A···F1iv | 0.99 | 2.49 | 3.246 (3) | 133 |
Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x+1, y+1/2, −z+1/2; (iii) x−1/2, −y+1/2, −z+1; (iv) −x+1, y−1/2, −z+1/2. |
References
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